- Email: [email protected]
Diagnosis and prophylaxis for high-altitude acclimatization: Adherence to molecular rationale to evade high-altitude illnesses
Life Sciences 203 (2018) 171–176
Contents lists available at ScienceDirect
Life Sciences journal homepage: www.elsevier.com/locate/lifescie
Review article
Diagnosis and prophylaxis for high-altitude acclimatization: Adherence to molecular rationale to evade high-altitude illnesses
T
⁎
Subhojit Paul, Anamika Gangwar, Kalpana Bhargava, Pankaj Khurana, Yasmin Ahmad
Peptide & Proteomics Division, Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India
A R T I C LE I N FO
A B S T R A C T
Keywords: High-altitude acclimatization Prophylactics Proteomics Biomarkers Proteins Redox homeostasis Energy homeostasis HAPE HACE AMS
Lack of zero side-effect, prescription-less prophylactics and diagnostic markers of acclimatization status lead to many suffering from high altitude illnesses. Although not fully translated to the clinical setting, many strategies and interventions are being developed that are aimed at providing an objective and tangible answer regarding the acclimatization status of an individual as well as zero side-effect prophylaxis that is cost-effective and does not require medical supervision. This short review brings together the twin problems associated with highaltitude acclimatization, i.e. acclimatization status and zero side-effect, easy-to-use prophylaxis, for the reader to comprehend as cogs of the same phenomenon. We describe current research aimed at preventing all the highaltitude illnesses by considering them an assault on redox and energy homeostasis at the molecular level. This review also entails some proteins capable of diagnosing either acclimatization or high-altitude illnesses. The future strategies based on bioinformatics and systems biology is also discussed.
1. Introduction High altitude areas have become focal for both leisure and adventure travel, attracting millions of visitors each year. Both the leisure and adventure travelers, as well as the deployed security forces in these areas, seek out uncharted pristine territory which requires high levels of cognitive and physical function. High-altitude areas are inversely related to high-level cognitive and physical performance [1,2]. High altitude areas, apart from the difficult terrain and uncomfortable weather conditions, also expose one to hypobaric hypoxia (HH). HH, on its own, can cause notable decreases in cognitive and physical functions. If unattended, these decreases become severe enough to cause maladies like Acute mountain sickness (AMS) and High altitude pulmonary/cerebral edema (HACE/HAPE), collectively referred to as High altitude illnesses (HAI). The preferred treatment for HAI is either immediate descent, supplemental oxygen or both [3,4]. But in practical life and death situations, both can be difficult to administer. Thus, to prevent such a situation from occurring many pharmacological interventions like nifedipine, dexamethasone and tadalafil have been advocated and marketed. Such interventions, although useful for most of the high-altitude visitors, are contra-indicated for individuals suffering from cardiac, renal and hepatic issues. Also, all such interventions require proper medical supervision for prescription and dosing with both over and under dosing causing harm [5]. Over the years, many solutions
⁎
Corresponding author. E-mail address: [email protected] (Y. Ahmad).
https://doi.org/10.1016/j.lfs.2018.04.040 Received 11 January 2018; Received in revised form 13 April 2018; Accepted 21 April 2018 Available online 23 April 2018 0024-3205/ © 2018 Elsevier Inc. All rights reserved.
have been proposed which circumvent the issues related to both faster acclimatization and better side-effect free prophylaxis. The treatment options mentioned above are useful only when there is quick and accurate detection of HAI, preferably before descent and oxygen are essential. As an aside, the incidence rates for AMS are reported to be 75% (Finnish Kilimanjaro trekkers, altitude attained 4730 m)-10% (Nepali Himalayas, 3000–4000 m group); with most studies showing AMS incidence increases with both high rate of ascent and the altitude obtained [6–12]. Mt. Kilimanjaro trekkers are reported to have a high incidence of AMS, with most researchers concurring that rapid ascent in this region due to socio-economic reasons is the culprit [6,9]. Basnyat has compiled various studies to give the range of HAPE/ HACE incidence as between 2% to 31% [13]. Currently, diagnosis is based generally on consensus clinical parameters, which maybe subjective to some extent, e.g. Lake Louise self-scoring criteria for AMS. The current impetus, thus, is also towards ensuring a more objective assessment of HAI and acclimatization, before clinical symptoms like pulmonary and cerebral edema manifest themselves. In this regard also, the authors' lab has made considerable progress towards blood plasma based diagnosis of acclimatization/HAI as well as providing a novel method for faster acclimatization [14]. This short review aims to present the notable advances made in the twin areas of biomarker discovery and prophylaxis/therapy for high-altitude. We first introduce the various HAI concisely, discussing their current diagnosis and treatment options. To conclude, we present the newer advances
Life Sciences 203 (2018) 171–176
S. Paul et al.
combined with labored breathing are the hallmarks of HAPE accompanied by cough, dyspnea at rest, tachycardia and tachypnea. It usually occurs above 2500 m upon 1–3 days of arrival. Cold ambient temperatures, rapid ascent rate (> 500 m/day), vigorous physical exertion, hampered pulmonary system (due to pulmonary infection and hypertension) and being male with previous history of high altitude illness are considered pre-disposing factors for HAPE incidence [23]. HAPE incidence is reported to be between 6.4%–0.4% (based on individual's age being over or below 20 years) by none other than Hultgren himself [24]. Other authors have stated the same to be 5% [10]–1.9% [12]. Although descent, supplemental oxygen and rest thereafter are critical for resolving HAPE, the adjunctive interventions cannot be left out.
towards faster diagnosis based on molecular perturbations and sideeffect free methods of prophylaxis with smaller doses and shorter dosing regimens. An overriding insight across the various aspects of HAI and acclimatization is that managing redox and energy homeostasis is sufficient to prevent HAI and assure acclimatization. 2. Acute mountain sickness Acute mountain sickness (AMS) affects individuals above 2500 m elevation. Its symptoms include general fatigue, headache, nausea, vomiting, palpitations, persistent rapid pulse, loss of appetite, excessive flatulating, insomnia, dizziness, peripheral edema, pins and needles, nose bleeds and shortness of breath [15]. The pathophysiology of AMS remains unclear [16] and according to a popular theory of tight-fit hypothesis which suggests that increased brain volume with hypobaric hypoxia elevates intracranial pressure and, when accompanied by impaired or diminished intracranial buffering capacity, contributes to the development of the symptoms that define AMS [17]. The incidence and severity of AMS can be measured by Environmental Symptoms Questionnaire and the Lake Louise AMS symptom score [18]. Different individuals have different susceptibility to AMS. Some may not be highly affected by the primary symptoms while others may develop HAPE and HACE if left untreated.
4.1. Current prescribed treatment Nifedipine (30 mg PO every 12 h during ascent) is the most widely used intervention for preventing HAPE. Phosphodiesterase inhibitors like sildenafil and tadalafil are also used extensively and they are quite recent additions. Tadalafil with a longer half-life is more commonly used. Salmeterol, a new inhalable drug, is also being prescribed nowadays [25]. 5. From physiological to molecular: changing perspectives Physiologists approached high altitude illnesses via categorizing them between lung or brain. When viewed from the prism of molecular events, it is obvious that all these diseases may be linked to each other more than expected previously. All acute high-altitude illnesses show extravasation of fluids into the extracellular spaces, whether in brain or lung. Bao et al. reported that some Chronic Mountain Sickness (CMS) patients have deranged cerebral hemodynamics and cerebral edema linking CMS and HACE [26]. Bailey et al. report that AMS and HACE are better explained by the interactions between free radicals and the trigeminal system rather than classical edema of the brain [27]. Also, there is offset redox balance in above mentioned tissues evident from the increased levels of oxidative damage products (TBARS, 8-OHdG) and free radicals (ROS) upon exposure to hypobaric hypoxia [28–30]. Hultgren et al. reviewed the medical records of 150 HAPE patients in Colorado Rocky Mountain ski area and found that 14% had symptoms of cerebral edema [31]. Lt. Col. A. Chawla reported that 41% of HAPE patients in Western Himalayas had mild to severe AMS symptoms and though the two don't share a common pathophysiology, Lake Louise scores showed AMS co-existed with HAPE in these patients [32]. Further, oblique evidence can be derived from the efficacy of a common drug (e.g. dexamethasone) for all high-altitude illnesses [33]. Thus, future interventions will be targeted at overcoming the systemic molecular events that result in such pathophysiologies summarily rather than categorizing medicines to be effective against a single illness. The future may view AMS, HACE and HAPE through the lens of molecular/ omics data as branches of the same tree, i.e. systemic redox imbalance due to hypobaric hypoxia exposure. Notable advances have been made in providing proof-of-concept regarding agents and modalities for treating the redox imbalance caused due to hypobaric hypoxia. These may become future prescriptions for faster, safer acclimatization to high altitude. The next two sections will focus on: a) the probable biomarkers for hypobaric hypoxia and b) the prophylactics and therapeutics with potential to prevent HAI.
2.1. Current prescribed treatment Although immediate descent, supplemental oxygen and rest are still considered the best treatment, acetazolamide at 125 mg–250 mg twice daily starting from 24 h before ascent till few hours after descent to either prevent AMS is the most recommended [19]. Acetazolamide 750 mg has been proven effective for treating AMS. Also, 500 mg acetazolamide was categorically rejected as ineffective for treating AMS. Some reports suggest dexamethasone to be better at treating AMS. In the same study, dexamethasone 8–16 mg was found to be equally effective as 750 mg acetazolamide in treating AMS above 4000 m [20]. 3. High altitude cerebral edema High altitude cerebral edema (HACE) is considered the extreme escalation of pathological events that began during AMS. Extravascular fluid accumulation in the brain begins during AMS. Further ascent causes greater fluid accumulation leading to coma, ataxia, convulsions and death. Thus, apart from pharmacological interventions, the primary focus for anyone diagnosed with AMS should be either rest at that altitude or descent of at least 1000 m. Once HACE occurs, the only true treatment is rapid descent [21]. Maximal HACE incidence is reported to be 31%(Gosainkund, Nepal, 4300 m) by Basnyat et al. [10]. The pharmacological alternatives are just to help the person survive. Nonetheless, pharmacological alternatives should be provided immediately to either prevent or delay HACE symptoms, with focus being on prevention. 3.1. Current prescribed treatment The primary rescue medicine for HACE beyond 3000–4000 m is dexamethasone [22], when rapid descent is a difficulty due to weather and terrain during long excursions. Acetazolamide and nifedipine both are useful in preventing HACE, at concentrations similar to those taken for preventing AMS. Hyperbaric therapy, immediate descent and supplemental oxygen remain the mainstay in treating and resolving HACE cases.
6. Biomarkers reflecting high-altitude maladies and acclimatization status for high-altitude hypoxia The term biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” (NIH Biomarkers Definitions Working Group, 1998) [34].
4. High altitude pulmonary edema High altitude pulmonary edema (HAPE) is the extravascular fluid accumulation in alveolar airspaces of lung. Pink frothy sputum 172
Life Sciences 203 (2018) 171–176
S. Paul et al.
1Receptor Agonist (IL-1RA), Heat Shock Protein-70 (HSP-70), and adrenomedullin were lower in AMS-susceptible subjects as compared to control subjects throughout 10 h of hypobaric hypoxia [49]. The authors recently reported that glutathione peroxidase 3, SOD1, hemopexin, catalase, malate dehydrogenase 1, STAT-3, thioredoxin reductase 2, RXR, tubulin, phenol sulfotransferase and MCP-1 can provide a credible status of acclimatization when following a particular acclimatization strategy [14]. Julian et al. also suggest that although a major anti-inflammatory/anti-permeability response accompanies AMS-susceptibility, the converse isn't true [50]. Further, some authors have questioned cerebral edema being held as the cause of AMS and HACE, suggesting free radicals and their interaction with trigeminal nerve to be the cause [27]. An important mystery thus far, remains as to why the high-altitude natives (HAN) are not susceptible to the radicals and the subsequent inflammation caused by their excess generation. Among the plasma proteins of high altitude natives compared against normal control group, vitamin D-binding protein, hemopexin, alpha-1–antitrypsin, haptoglobin b-chain, apolipoprotein A1, transthyretin and hemoglobin beta chain were up-regulated. The down-regulated proteins were transferrin, complement C3, serum amyloid, complement C4A and plasma retinol binding protein. Ahmad et al. suggested a fine balance of inflammatory processes with anti-inflammatory proteins dominant in natives that prevented any altitude related patho-physiologies developing in HAN [51]. Other works elucidating adaptive mechanisms in HAN detail genetic polymorphisms related to erythropoiesis and hemostasis [52–55]. All such probable biomarkers will in the near future make the assessment of acclimatization status during ascent to high altitude much more objective and immediate, thus nullifying life and death situations to a great extent.
In case of high altitude associated hypobaric hypoxia, a biomarker thus should be any molecule derived from easily accessible tissue (blood) that can be measured and evaluated (plasma proteins) to indicate a patho-physiological response (systemic redox imbalance). Hence, this short review is focused on blood plasma derived proteins that have been shown to be putative biomarkers due to their significant differential expression levels either during hypobaric hypoxia exposure or in patients of HAI as compared to control groups. HAPE is known to be a life-threatening HAI. Its current diagnosis is completely dependent on chest X-rays showing edema in lungs [35]. But, Ahmad et al. showed distinct protein signatures in HAPE patients and healthy controls' plasma. 14 proteins were found to be differentially expressed in HAPE patients. Of these, haptoglobin and Apo A1 were observed to have the most significant (p < 0.05) differential expression between HAPE patients and controls after validation using immunoblots [36]. Related to edema are the aspects of thrombosis and inflammation. Tyagi et al. showed that platelet proteins and calpain activity can be a predictor of thrombosis, a major health risk in hypoxic environments [37]. Further, molecules like asymmetric dimethylarginine (ADMA), serotonin (5-HT), 8-isoprostaglandin F2α (8-isoPGF2α), endothelin-1 (ET-1), plasma renin activity (PRA), plasma aldosterone concentration (PAC), superoxide dismutase (SOD) and nitric oxide (NO) levels were estimated in HAPE patients, high altitude travelers and high-altitude natives. It was observed that ADMA, 5-HT, 8-isoPGF2α, ET-1 levels, and PAC were significantly higher (p < 0.0001, each), whereas SOD activity and NO level were significantly lower in HAPE patients than high altitude travelers(p ≤ 0.001) [38]. Metabolite signatures for HAPE (C8-ceramide, sphingosine and glutamine) have also been determined [39] but these are still at a very nascent stage to be used definitively among clinicians. This is due to the fact that the large datasets obtained are entangled in myriad pathways, which currently can't be quantified as either a susceptibility indicator or a consequence of HAPE. Among all these leads, a headline protein for diagnosing HAPE in plasma samples is sulfotransferase 1A1 (Sult 1A1). Sult 1A1, with no other known implications in cardiorespiratory insufficiencies, shows highly significant differential expression in HAPE patients as compared to control groups [41]. NT-proBNP, supposed to be a cardiac biomarker, has also gained a lot of attention and evidence recently to be counted as a probable biomarker for diagnosis of severe AMS and susceptible marker of HAPE [42–44]. But other studies have highlighted many contradictions and drawbacks also. As per the study of Toshner et al., there is no increase in NT-proBNP in healthy resting subjects after ascending to 5200 m despite a significant rise in pulmonary artery systolic pressure (PASP) [43]. Gao et al. have given rather confusing results and views regarding BNP and HAPE. They stated clearly that in high-altitude travelers, whether afflicted by HAPE or not, NT-proBNP levels are higher as compared to sea-level controls. HAPE treatment lowered the levels of NT-proBNP in patients. But then they contradict their own findings and state that BNP can be a marker for HAPE [45]. Woods et al. have reported that severe AMS has better correlation with both BNP and NT-proBNP [42]. Mellor et al. have reported that hs-cTnT and natriuretic peptides are associated with high PASP and AMS [46]. Thus, in view of the tangential findings, one can conclude two things. First, BNP/NT-proBNP are associated with high PASP (which may or may not develop into HAI/HAPE as other related mechanisms are involved [47,48]) and secondly, one molecule alone is not a good way to demarcate HAI from normal stress responses at high altitude. AMS and HACE, observed to be related to increasing degrees of blood-brain-barrier (BBB) disruption, are currently dependent on a scoring system scored by the patient and MRI scans of brain to ascertain fluid accumulation, respectively. Lake Louise is completely subjective while MRI scans (MRI equipment mostly not available in remote highaltitude areas) show the end-stage of disease making immediate descent and oxygen inevitable. Although not as many molecules have been identified decisively as in HAPE, important molecules like Interleukin-
7. Prophylactics and therapeutics: without side-effects and contra-indications Coming back to ascent and acclimatization to high-altitude, its crystal clear that better prophylactics and therapeutics are still required to treat those who can't acclimatize or need to ascend rapidly. The current pharmaceuticals available for this purpose require extensive medical supervision, monitoring the side-effects of doses as well as the periodicity and quantity of these doses and are contra-indicated in people with cardiac, renal and hepatic ailments. Thus, this aspect is being looked at thoroughly to find such prophylactics/therapeutics that have least or no side-effects and are not contra-indicated in people suffering from any other ailments. Also, these newer alternatives should require minimal repeated dosing and prescription may not be essential. These are discussed below. 8. Nano-cerium particles (CNPs) In case of molecular advances in life sciences too, nano-materials have opened up new domains whether it be cancer or wound healing. To prevent or nullify the negative effects of hypobaric hypoxia, cerium nanoparticles (CNPs) have been employed. CNPs do not require mammoth quantities in terms of dosing. They are till now considered sideeffect free at the prescribed doses. The only two drawbacks are they require specific modes and strategies of dosing with the dose being a very minute quantity. The authors' lab has been a major proponent of CNPs and their efficacy in combating hypobaric hypoxia associated maladies. Arya et al. have shown the efficacy of CNPs against hypobaric hypoxia. They have shown that CNPs protects the lungs and brain against hypobaric hypoxia induced oxidative stress, inflammation, loss of mitochondrial membrane potential and memory impairment, respectively [56,57]. An important feature was the ability of CNPs to promote neurogenesis. Arya et al. elucidated the neuro-protective mechanism of CNPs in brain as being through the 5′-adenine 173
Life Sciences 203 (2018) 171–176
S. Paul et al.
for renal or cardiac insufficiencies [80]. The stable aqueous solution tides over the cost hurdle and increases bio-availability making the requirement of multiple daily doses (common with complex formulations available) redundant. SMN was observed to protect the rodent lung from HH-induced oxidative stress and inflammation at 50 mg/kg/ day single oral doses repeated over 5 days [81]. With all the known benefits and proven efficacy against HH-induced oxidative stress and inflammation, the authors are of the view that SMN is a ready to market alternative to current pharmacological interventions particularly in individuals suffering from renal and hepatic ailments.
monophosphate-activated protein kinase–protein kinase C–cyclic adenosine monophosphate response element-binding protein binding (AMPK-PKC-CBP). They also used PEG(polyethylene glycol)-ylation to localize the CNPs in rodent brain tissue in vivo [58]. 9. Peptides/peptide mimetics of biological proteins and antioxidant substances as interventions against hypobaric hypoxia Since the proteome shows significant perturbations upon exposure to hypobaric hypoxia, it makes sense to designate the affected proteins and sort them based on functions. The proteins with proven beneficial effects against hypobaric hypoxia can be further checked for functional domains. Such functional domain-specific peptides can then be synthesized as therapeutic peptides to be used as therapies/prophylactics. The positive aspect of such a strategy is the high efficacy, minimal chances of side-effects, requirement of minute doses and specific profile of effects. However, the high cost of production both economically and technically remains a hurdle to mass-production. Nonetheless, two proteins have shown significant efficacy against hypobaric hypoxia. Vasonatrin peptide (VNP) treatment for a week at 50 μg/kg/day i.p. was shown to have significantly reduced mean pulmonary arterial pressure, pulmonary vascular resistance, right ventricular hypertrophy and muscularization of the pulmonary arteries. Blood flow was also increased in this group. In addition, significantly lower levels of plasma Endothelin-1 and Angiotensin II and cardiac natriuretic peptide receptor-C mRNA expression were observed in VNP-treated as compared with saline-treated HH-induced pulmonary hypertension rats. Yu et al. summarized that VNP has therapeutic effects against pulmonary hypertension caused by hypobaric hypoxia exposure [59]. The authors lab has put in considerable effort in this domain with NAP. NAP peptide at 2 μg/kg/day (intranasal) was shown to protect the rodent brain against chronic and acute HH lasting to a maximum of 28 days (simulated altitude of 25,000 ft.) [60]. In primary culture of hippocampal region cells, only 15fM of NAP provided sufficient protection against severe hypoxia for 72 h [61]. In all the above articles, NAP was elucidated to have mechanistic effects on antioxidant proteins (Nrf2 mediated oxidative stress response, HO-1, SOD), energy production pathways (AMPK signaling) and Rho family GTPases pathway. NAP, thus has significant effects on antioxidant and signaling proteins in the rodent brain causing a prophylactic response against hypobaric hypoxia. In terms of antioxidants used against hypobaric hypoxia to attenuate oxidative stress caused by it, phyto-extracts have been in the limelight for long. Natural origins reducing the need for synthesis, biocompatibility without requirement of much safety testing at fairly high doses, non-requirement of medical supervision in most cases and easy availability make them a favorite of the research community. Notable phyto-extracts with considerable effects on redox stress during hypobaric hypoxia exposure include, but are not limited to, Withania somnifera extracts [62,63], quercetin [64], Ginkgo biloba extracts [65–69] and Bacopa monniera extracts [70]. Other substances of natural/synthetic origin found to be effective against hypobaric hypoxia induced oxidative stress are ascorbic acid [71], acetyl-L-carnitine [72,73], alphalipoic acid, alpha-ketoglutaric acid [74], 5-hydroxymethylfurfural [75,76], Ceftriaxone [77] and Gabapentin [78,79]. The authors have also dabbled with phyto-extracts to overcome the problems with current pharmacological interventions like cost, sideeffects, contra-indications in individuals with existing renal, cardiac and hepatic conditions, risks of over-dosing and medical supervision for use. The efforts have culminated with the development of a novel stable aqueous suspension of micronized silymarin (SMN). SMN has no known severe side-effects, has tolerance values approaching or even higher than 10 g/kg (oral; dogs) and 300 mg/kg (single IV bolus; dogs) [61], is already proven safe for humans with over 35 formulations already marketed (formulations are complex thereby increasing cost) as a hepatoprotective oral supplement with no known complications observed
10. Conclusion When looked through the prism of physiology, high altitude and the resulting hypobaric hypoxia assumes multiple forms as various HAI. Each HAI has its own set of symptoms, affecting a different organ. Also, by the time indisputable symptoms of any HAI whether AMS, HACE, HAPE or CMS emerge, the situation is already out of hand causing emergency descent and oxygen supplementation. In context of security forces and their style of functioning, it means that a single troop afflicted by HAI will require between two to six other fit troops to descent and survive depending on the prevailing situation. This can be catastrophic during their large-scale mobilization. Also, as is obvious, it becomes a logistical and medical burden to help such a troop recover knowing that he may not be able to re-ascend immediately and be deployed. In case of the numerous leisure/adventure travelers, they may not be capable of performing rescue descents in all terrain, thus either perishing or calling in emergency services wherever possible. This will also hamper the eco-tourism vistas as they place a socioeconomic burden on the native populace during such incidents. Thus, the requirement of finding statistically significant biomarkers in plasma which can be used to quickly and objectively monitor the acclimatization status of individuals before any severe symptoms of HAI develop is paramount. In the same vein, we must acknowledge that with or without biomarkers, HAI are a clear and present danger to all sojourners stationed at high-altitude. The current crop of interventions, although effective, remains ridden with contra-indications and sideeffects. Thus, a new set of prophylactics, based more on natural sources (our own physiology and plant extracts) is required which can show greater efficacy at lower doses and need not be prescription medicines. Also, all these measures need to be cost-effective enough to be employed at a huge scale. The authors, based on published data, have firm belief that the biomarkers as well as the prophylactic/therapeutics listed here (Table 1) will be able to solve the majority of current issues related to prognosis and prophylaxis at high altitude thereby reducing the occurrence of sudden emergency descent. It goes without saying that such an improvement will not only improve the quality of life and travel at high altitude but also provide a safer experience to all at high altitude. In the near future, authors speculate that systems biology and bioinformatics as well as patient repositories with genetic details, lifestyle choices, hereditary factors and other medical history will play decisive roles in high altitude environment.
Author contribution SP and AG wrote the review. YA developed the whole conception of the review. KB and PK substantially contributed to the editing of the final version. Acknowledgement The authors acknowledge Aditya Arya for valuable inputs in designing artwork. Subhojit Paul is recipient of CSIR fellowship. Anamika Gangwar is a recipient of DST-INSPIRE fellowship. 174
Life Sciences 203 (2018) 171–176
S. Paul et al.
Table 1 List of future prophylactic interventions (Table1.a) and putative protein biomarkers (Table1.b) for facilitating and monitoring high-altitude acclimatization.
[3] P. Bärtsch, High altitude pulmonary edema, Respiration 64 (6) (1997) 435–443. [4] G.W. Rodway, L.A. Hoffman, M.H. Sanders, High-altitude-related disorders—part I: pathophysiology, differential diagnosis, and treatment, Heart Lung 32 (6) (2003) 353–359. [5] A.M. Luks, E.R. Swenson, Medication and dosage considerations in the prophylaxis and treatment of high-altitude illness, Chest 133 (3) (March 2008) 744–755. [6] H. Karinen, J. Peltonen, H. Tikkanen, Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania: an observational study, High Alt. Med. Biol. 9 (4) (2008) 301–306. [7] S.A. Gallagher, P.H. Hackett, High-altitude illness, Emerg. Med. Clin. 22 (2) (2004) 329–355. [8] J. Vardy, J. Vardy, K. Judge, Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya, Aviat. Space Environ. Med. 77 (7) (2006) 742–744. [9] S.J. Jackson, et al., Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro, High Alt. Med. Biol. 11 (3) (2010) 217–222. [10] B. Basnyat, et al., Disoriented and ataxic pilgrims: an epidemiological study of acute mountain sickness and high-altitude cerebral edema at a sacred lake at 4300 m in the Nepal Himalayas, Wilderness Environ. Med. 11 (2) (2000) 89–93. [11] C.S. Houston, Incidence of acute mountain sickness: a study of winter visitors to six Colorado resorts, Am. Alpine J. 27 (1985) 162–165. [12] Y. Ren, et al., Incidence of high altitude illnesses among unacclimatized persons who acutely ascended to Tibet, High Alt. Med. Biol. 11 (1) (2010) 39–42. [13] B. Basnyat, High altitude cerebral and pulmonary edema, Travel Med. Infect. Dis. 3 (4) (2005) 199–211. [14] S. Paul, et al., STAT3-RXR-Nrf2 activates systemic redox and energy homeostasis upon steep decline in pO2 gradient, Redox Biol. 14 (2018) 423–438. [15] R.C. Roach, J.A. Loeppky, M.V. Icenogle, Acute mountain sickness: increased severity during simulated altitude compared with normobaric hypoxia, J. Appl. Physiol. 81 (5) (1996) 1908–1910. [16] K. Kallenberg, et al., Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness, J. Cereb. Blood Flow Metab. 27 (5) (2007) 1064–1071. [17] M.H. Wilson, J. Milledge, Direct measurement of intracranial pressure at high altitude and correlation of ventricular size with acute mountain sickness: Brian Cummins' results from the 1985 Kishtwar expedition, Neurosurgery 63 (5) (2008) 970–975. [18] R. Roach, et al., The Lake Louise acute mountain sickness scoring system, Hypoxia Mol. Med. 272 (1993) 4. [19] L.P. Queiroz, A.M. Rapoport, High-altitude headache, Curr. Pain Headache Rep. 11 (4) (2007) 293–296. [20] L. Dumont, C. Mardirosoff, M.R. Tramèr, Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review, BMJ 321 (7256) (2000) 267. [21] P.H. Hackett, High altitude cerebral edema and acute mountain sickness, Hypoxia, Springer, 1999, pp. 23–45. [22] M.B. Rabold, Dexamethasone for prophylaxis and treatment of acute mountain sickness, J. Wilderness Med. 3 (1) (1992) 54–60. [23] H. Lobenhoffer, R. Zink, W. Brendel, High altitude pulmonary edema: analysis of 166 cases, High Alt. Physiol. Med. (1982) 219–231. [24] H. Hultgren, High altitude pulmonary edema, Hypoxia, High Altitude and the Heart, Karger Publishers, 1970, pp. 24–31. [25] A. Pennardt, High-altitude pulmonary edema: diagnosis, prevention, and treatment, Curr. Sports Med. Rep. 12 (2) (2013) 115–119. [26] H. Bao, et al., Cerebral edema in chronic mountain sickness: a new finding, Sci. Rep. 7 (2017) 43224. [27] D.M. Bailey, et al., Emerging concepts in acute mountain sickness and high-altitude cerebral edema: from the molecular to the morphological, Cell. Mol. Life Sci. 66 (22) (2009) 3583–3594. [28] P. Maiti, et al., Hypobaric hypoxia induces oxidative stress in rat brain, Neurochem. Int. 49 (8) (2006) 709–716. [29] J. Magalhães, et al., Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle, J. Appl. Physiol. 99 (4) (2005) 1247–1253. [30] J. Magalhaes, et al., Acute and severe hypobaric hypoxia-induced muscle oxidative stress in mice: the role of glutathione against oxidative damage, Eur. J. Appl. Physiol. 91 (2–3) (2004) 185–191. [31] H.N. Hultgren, et al., High-altitude pulmonary edema at a ski resort, West. J. Med. 164 (3) (1996) 222–227. [32] A. Chawla, Incidence of acute mountain sickness in patients of high altitude pulmonary edema: is the Lake Louise scoring accurate, Ind. J. Aerospace Med. 53 (1) (2009) 1–5. [33] A.M. Luks, et al., Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness, Wilderness Environ. Med. 21 (2) (2010) 146–155. [34] Biomedical, F., NIH definition of biomarker, Clin. Pharmacol. Ther. 69 (2001) 89–95. [35] A.M. Sophocles, High-altitude pulmonary edema in Vail, Colorado, 1975–1982, West. J. Med. 144 (5) (1986) 569–573. [36] Y. Ahmad, et al., Identification of haptoglobin and apolipoprotein AI as biomarkers for high altitude pulmonary edema, Funct. Integr. Genomics 11 (3) (2011) 407. [37] T. Tyagi, et al., Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype, Blood 123 (8) (2014) 1250–1260. [38] Z. Ali, et al., Interactions among vascular-tone modulators contribute to high altitude pulmonary edema and augmented vasoreactivity in highlanders, PLoS One 7 (9) (2012) e44049.
Table 1.a S.NO.
Prophylactic
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
NAP peptide Vasonatrin peptide Gabapentin Silymarin Ceftriaxone 5-Hydroxymethylfurfural Alpha-ketoglutaric acid Alpha-lipoic acid Acetyl-L-carnitine Ascorbic acid Bacopa monnieri extracts Ginkgo biloba extracts Quercetin Withania somnifera extracts Cerium nanoparticles
Table 1.b S.No.
Putative biomarkers
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.
Haptoglobin Apolipoprotein A1 Calpain Asymmetric dimethylarginine (ADMA) Serotonin (5-HT) 8-Iso-prostaglandin F2α (8-isoPGF2α) Endothelin-1 (ET-1) Plasma renin activity (PRA) Plasma aldosterone Nitric oxide C8-ceramide Sphingosine Glutamine Sult 1A1 (PST) hs-cTnT BNP/NT-proBNP Interleukin-1Receptor Agonist (IL-1RA) Heat Shock Protein-70 (HSP-70) Glutathione peroxidase 3 (GPx3) Superoxide dismutase 1 (SOD1) Hemopexin Catalase Malate dehydrogenase 1 (MDH-1) Signal transducer and activator of Transcription 3 (STAT-3) Thioredoxin reductase 2 (TR2) Retinoid X receptor (RXR) Tubulin Monocyte chemo-attractant protein-1(MCP-1) Vitamin D-binding protein (VDBP) Alpha-1–antitrypsin Transthyretin Hemoglobin beta chain Transferrin Complement C3, C4A Serum amyloid protein Plasma retinol binding protein (RBP)
Competing interests The authors have no conflicts of interest or financial ties to disclose. References [1] B. Shukitt-Hale, L.E. Banderet, H.R. Lieberman, Elevation-dependent symptom, mood, and performance changes produced by exposure to hypobaric hypoxia, Int. J. Aviat. Psychol. 8 (4) (1998) 319–334. [2] B. Shukitt-Hale, et al., Hypobaric hypoxia impairs spatial memory in an elevationdependent fashion, Behav. Neural Biol. 62 (3) (1994) 244–252.
175
Life Sciences 203 (2018) 171–176
S. Paul et al.
[63] I. Baitharu, et al., Withania somnifera root extract ameliorates hypobaric hypoxia induced memory impairment in rats, J. Ethnopharmacol. 145 (2) (2013) 431–441. [64] A.K. Pandey, et al., Quercetin in hypoxia-induced oxidative stress: novel target for neuroprotection, Int. Rev. Neurobiol. 102 (2012) 107–146. [65] L. Karcher, P. Zagermann, J. Krieglstein, Effect of an extract of Ginkgo biloba on rat brain energy metabolism in hypoxia, Naunyn Schmiedeberg's Arch. Pharmacol. 327 (1) (1984) 31–35. [66] H. Oberpichler, et al., Effects of Ginkgo biloba constituents related to protection against brain damage caused by hypoxia, Pharmacol. Res. Commun. 20 (5) (1988) 349–368. [67] J.H. Gertsch, et al., Randomised, double blind, placebo controlled comparison of Ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT), BMJ 328 (7443) (2004) 797. [68] F.A. Moraga, et al., Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollagüe (3696 m) in northern Chile, Wilderness Environ. Med. 18 (4) (2007) 251–257. [69] S. Hoyer, et al., Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761), J. Neural Transm. 106 (11) (1999) 1171–1188. [70] S.K. Hota, et al., Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment, Neurobiol. Dis. 34 (1) (2009) 23–39. [71] J.G. Farias, et al., Oxidative stress in rat testis and epididymis under intermittent hypobaric hypoxia: protective role of ascorbate supplementation, J. Androl. 31 (3) (2010) 314–321. [72] S.A. Devi, et al., Intermittent hypobaric hypoxia-induced oxidative stress in rat erythrocytes: protective effects of vitamin E, vitamin C, and carnitine, Cell Biochem. Funct. 25 (2) (2007) 221–231. [73] K. Barhwal, et al., Acetyl-L-carnitine (ALCAR) prevents hypobaric hypoxia–induced spatial memory impairment through extracellular related kinase–mediated nuclear factor erythroid 2-related factor 2 phosphorylation, Neuroscience 161 (2) (2009) 501–514. [74] D.M. Bailey, B. Davies, Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude, High Alt. Med. Biol. 2 (1) (2001) 21–29. [75] H. Gatterer, et al., Short-term supplementation with alpha-ketoglutaric acid and 5hydroxymethylfurfural does not prevent the hypoxia induced decrease of exercise performance despite attenuation of oxidative stress, Int. J. Sports Med. 34 (01) (2013) 1–7. [76] J.-H. Zhang, et al., 5-HMF prevents against oxidative injury via APE/Ref-1, Free Radic. Res. 49 (1) (2015) 86–94. [77] S.K. Hota, et al., Ceftriaxone rescues hippocampal neurons from excitotoxicity and enhances memory retrieval in chronic hypobaric hypoxia, Neurobiol. Learn. Mem. 89 (4) (2008) 522–532. [78] S. Jafarian, et al., Gabapentin for prevention of hypobaric hypoxia-induced headache: randomized double-blind clinical trial, J. Neurol. Neurosurg. Psychiatry 79 (3) (2008) 321–323. [79] A. Kumar, R. Goyal, Gabapentin Attenuates Acute Hypoxic Stress–induced Behavioral Alterations and Oxidative Damage in Mice: Possible Involvement of GABAergic Mechanism, (2008). [80] N. Dixit, et al., Silymarin: a review of pharmacological aspects and bioavailability enhancement approaches, Indian J. Pharmacol. 39 (4) (2007) 172. [81] S. Paul, et al., Size restricted silymarin suspension evokes integrated adaptive response against acute hypoxia exposure in rat lung, Free Radic. Biol. Med. 96 (2016) 139–151.
[39] L. Guo, et al., Three plasma metabolite signatures for diagnosing high altitude pulmonary edema, Sci. Rep. 5 (2015) 15126. [41] Y. Ahmad, et al., The proteome of hypobaric induced hypoxic lung: insights from Temporal Proteomic Profiling for Biomarker Discovery, Sci. Rep. 5 (2015). [42] D. Woods, et al., Severe acute mountain sickness, brain natriuretic peptide and NTproBNP in humans, Acta Physiol. 205 (3) (2012) 349–355. [43] M.R. Toshner, et al., NT-proBNP does not rise on acute ascent to high altitude, High Alt. Med. Biol. 9 (4) (2008) 307–310. [44] D. Woods, et al., Brain natriuretic peptide and NT-proBNP levels reflect pulmonary artery systolic pressure in trekkers at high altitude, Physiol. Res. 62 (6) (2013) 597. [45] M. Gao, et al., NT-ProBNP levels are moderately increased in acute high-altitude pulmonary edema, Exp. Ther. Med. 5 (5) (2013) 1434–1438. [46] A. Mellor, et al., Cardiac biomarkers at high altitude, High Alt. Med. Biol. 15 (4) (2014) 452–458. [47] U. Scherrer, et al., New insights in the pathogenesis of high-altitude pulmonary edema, Prog. Cardiovasc. Dis. 52 (6) (2010) 485–492. [48] P. Bärtsch, et al., Physiological aspects of high-altitude pulmonary edema, J. Appl. Physiol. 98 (3) (2005) 1101–1110. [49] H. Lu, et al., In search for better pharmacological prophylaxis for acute mountain sickness: looking in other directions, Acta Physiol. 214 (1) (2015) 51–62. [50] C.G. Julian, et al., Exploratory proteomic analysis of hypobaric hypoxia and acute mountain sickness in humans, J. Appl. Physiol. 116 (7) (2014) 937–944. [51] Y. Ahmad, et al., An insight into the changes in human plasma proteome on adaptation to hypobaric hypoxia, PLoS One 8 (7) (2013) e67548. [52] C.M. Beall, Two routes to functional adaptation: Tibetan and Andean high-altitude natives, Proc. Natl. Acad. Sci. 104 (Suppl. 1) (2007) 8655–8660. [53] X. Yi, et al., Sequencing of 50 human exomes reveals adaptation to high altitude, Science 329 (5987) (2010) 75–78. [54] T. Simonson, et al., Adaptive genetic changes related to haemoglobin concentration in native high-altitude Tibetans, Exp. Physiol. 100 (11) (2015) 1263–1268. [55] A. Tomar, S. Malhotra, S. Sarkar, Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives, BMC Genet. 16 (1) (2015) 112. [56] A. Arya, et al., Cerium oxide nanoparticles protect rodent lungs from hypobaric hypoxia-induced oxidative stress and inflammation, Int. J. Nanomedicine 8 (2013) 4507. [57] A. Arya, et al., Cerium oxide nanoparticles prevent apoptosis in primary cortical culture by stabilizing mitochondrial membrane potential, Free Radic. Res. 48 (7) (2014) 784–793. [58] A. Arya, et al., Cerium oxide nanoparticles promote neurogenesis and abrogate hypoxia-induced memory impairment through AMPK–PKC–CBP signaling cascade, Int. J. Nanomedicine 11 (2016) 1159. [59] J. Yu, et al., Protective effects of vasonatrin peptide against hypobaric hypoxiainduced pulmonary hypertension in rats, Clin. Exp. Pharmacol. Physiol. 37 (1) (2010) 69–74. [60] N.K. Sharma, et al., Activity-dependent neuroprotective protein (ADNP)-derived peptide (NAP) ameliorates hypobaric hypoxia induced oxidative stress in rat brain, Peptides 32 (6) (2011) 1217–1224. [61] A. Arya, et al., NAP (davunetide) protects primary hippocampus culture by modulating expression profile of antioxidant genes during limiting oxygen conditions, Free Radic. Res. 49 (4) (2015) 440–452. [62] S. Bhattacharya, A. Muruganandam, Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress, Pharmacol. Biochem. Behav. 75 (3) (2003) 547–555.
176
Contents lists available at ScienceDirect
Life Sciences journal homepage: www.elsevier.com/locate/lifescie
Review article
Diagnosis and prophylaxis for high-altitude acclimatization: Adherence to molecular rationale to evade high-altitude illnesses
T
⁎
Subhojit Paul, Anamika Gangwar, Kalpana Bhargava, Pankaj Khurana, Yasmin Ahmad
Peptide & Proteomics Division, Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India
A R T I C LE I N FO
A B S T R A C T
Keywords: High-altitude acclimatization Prophylactics Proteomics Biomarkers Proteins Redox homeostasis Energy homeostasis HAPE HACE AMS
Lack of zero side-effect, prescription-less prophylactics and diagnostic markers of acclimatization status lead to many suffering from high altitude illnesses. Although not fully translated to the clinical setting, many strategies and interventions are being developed that are aimed at providing an objective and tangible answer regarding the acclimatization status of an individual as well as zero side-effect prophylaxis that is cost-effective and does not require medical supervision. This short review brings together the twin problems associated with highaltitude acclimatization, i.e. acclimatization status and zero side-effect, easy-to-use prophylaxis, for the reader to comprehend as cogs of the same phenomenon. We describe current research aimed at preventing all the highaltitude illnesses by considering them an assault on redox and energy homeostasis at the molecular level. This review also entails some proteins capable of diagnosing either acclimatization or high-altitude illnesses. The future strategies based on bioinformatics and systems biology is also discussed.
1. Introduction High altitude areas have become focal for both leisure and adventure travel, attracting millions of visitors each year. Both the leisure and adventure travelers, as well as the deployed security forces in these areas, seek out uncharted pristine territory which requires high levels of cognitive and physical function. High-altitude areas are inversely related to high-level cognitive and physical performance [1,2]. High altitude areas, apart from the difficult terrain and uncomfortable weather conditions, also expose one to hypobaric hypoxia (HH). HH, on its own, can cause notable decreases in cognitive and physical functions. If unattended, these decreases become severe enough to cause maladies like Acute mountain sickness (AMS) and High altitude pulmonary/cerebral edema (HACE/HAPE), collectively referred to as High altitude illnesses (HAI). The preferred treatment for HAI is either immediate descent, supplemental oxygen or both [3,4]. But in practical life and death situations, both can be difficult to administer. Thus, to prevent such a situation from occurring many pharmacological interventions like nifedipine, dexamethasone and tadalafil have been advocated and marketed. Such interventions, although useful for most of the high-altitude visitors, are contra-indicated for individuals suffering from cardiac, renal and hepatic issues. Also, all such interventions require proper medical supervision for prescription and dosing with both over and under dosing causing harm [5]. Over the years, many solutions
⁎
Corresponding author. E-mail address: [email protected] (Y. Ahmad).
https://doi.org/10.1016/j.lfs.2018.04.040 Received 11 January 2018; Received in revised form 13 April 2018; Accepted 21 April 2018 Available online 23 April 2018 0024-3205/ © 2018 Elsevier Inc. All rights reserved.
have been proposed which circumvent the issues related to both faster acclimatization and better side-effect free prophylaxis. The treatment options mentioned above are useful only when there is quick and accurate detection of HAI, preferably before descent and oxygen are essential. As an aside, the incidence rates for AMS are reported to be 75% (Finnish Kilimanjaro trekkers, altitude attained 4730 m)-10% (Nepali Himalayas, 3000–4000 m group); with most studies showing AMS incidence increases with both high rate of ascent and the altitude obtained [6–12]. Mt. Kilimanjaro trekkers are reported to have a high incidence of AMS, with most researchers concurring that rapid ascent in this region due to socio-economic reasons is the culprit [6,9]. Basnyat has compiled various studies to give the range of HAPE/ HACE incidence as between 2% to 31% [13]. Currently, diagnosis is based generally on consensus clinical parameters, which maybe subjective to some extent, e.g. Lake Louise self-scoring criteria for AMS. The current impetus, thus, is also towards ensuring a more objective assessment of HAI and acclimatization, before clinical symptoms like pulmonary and cerebral edema manifest themselves. In this regard also, the authors' lab has made considerable progress towards blood plasma based diagnosis of acclimatization/HAI as well as providing a novel method for faster acclimatization [14]. This short review aims to present the notable advances made in the twin areas of biomarker discovery and prophylaxis/therapy for high-altitude. We first introduce the various HAI concisely, discussing their current diagnosis and treatment options. To conclude, we present the newer advances
Life Sciences 203 (2018) 171–176
S. Paul et al.
combined with labored breathing are the hallmarks of HAPE accompanied by cough, dyspnea at rest, tachycardia and tachypnea. It usually occurs above 2500 m upon 1–3 days of arrival. Cold ambient temperatures, rapid ascent rate (> 500 m/day), vigorous physical exertion, hampered pulmonary system (due to pulmonary infection and hypertension) and being male with previous history of high altitude illness are considered pre-disposing factors for HAPE incidence [23]. HAPE incidence is reported to be between 6.4%–0.4% (based on individual's age being over or below 20 years) by none other than Hultgren himself [24]. Other authors have stated the same to be 5% [10]–1.9% [12]. Although descent, supplemental oxygen and rest thereafter are critical for resolving HAPE, the adjunctive interventions cannot be left out.
towards faster diagnosis based on molecular perturbations and sideeffect free methods of prophylaxis with smaller doses and shorter dosing regimens. An overriding insight across the various aspects of HAI and acclimatization is that managing redox and energy homeostasis is sufficient to prevent HAI and assure acclimatization. 2. Acute mountain sickness Acute mountain sickness (AMS) affects individuals above 2500 m elevation. Its symptoms include general fatigue, headache, nausea, vomiting, palpitations, persistent rapid pulse, loss of appetite, excessive flatulating, insomnia, dizziness, peripheral edema, pins and needles, nose bleeds and shortness of breath [15]. The pathophysiology of AMS remains unclear [16] and according to a popular theory of tight-fit hypothesis which suggests that increased brain volume with hypobaric hypoxia elevates intracranial pressure and, when accompanied by impaired or diminished intracranial buffering capacity, contributes to the development of the symptoms that define AMS [17]. The incidence and severity of AMS can be measured by Environmental Symptoms Questionnaire and the Lake Louise AMS symptom score [18]. Different individuals have different susceptibility to AMS. Some may not be highly affected by the primary symptoms while others may develop HAPE and HACE if left untreated.
4.1. Current prescribed treatment Nifedipine (30 mg PO every 12 h during ascent) is the most widely used intervention for preventing HAPE. Phosphodiesterase inhibitors like sildenafil and tadalafil are also used extensively and they are quite recent additions. Tadalafil with a longer half-life is more commonly used. Salmeterol, a new inhalable drug, is also being prescribed nowadays [25]. 5. From physiological to molecular: changing perspectives Physiologists approached high altitude illnesses via categorizing them between lung or brain. When viewed from the prism of molecular events, it is obvious that all these diseases may be linked to each other more than expected previously. All acute high-altitude illnesses show extravasation of fluids into the extracellular spaces, whether in brain or lung. Bao et al. reported that some Chronic Mountain Sickness (CMS) patients have deranged cerebral hemodynamics and cerebral edema linking CMS and HACE [26]. Bailey et al. report that AMS and HACE are better explained by the interactions between free radicals and the trigeminal system rather than classical edema of the brain [27]. Also, there is offset redox balance in above mentioned tissues evident from the increased levels of oxidative damage products (TBARS, 8-OHdG) and free radicals (ROS) upon exposure to hypobaric hypoxia [28–30]. Hultgren et al. reviewed the medical records of 150 HAPE patients in Colorado Rocky Mountain ski area and found that 14% had symptoms of cerebral edema [31]. Lt. Col. A. Chawla reported that 41% of HAPE patients in Western Himalayas had mild to severe AMS symptoms and though the two don't share a common pathophysiology, Lake Louise scores showed AMS co-existed with HAPE in these patients [32]. Further, oblique evidence can be derived from the efficacy of a common drug (e.g. dexamethasone) for all high-altitude illnesses [33]. Thus, future interventions will be targeted at overcoming the systemic molecular events that result in such pathophysiologies summarily rather than categorizing medicines to be effective against a single illness. The future may view AMS, HACE and HAPE through the lens of molecular/ omics data as branches of the same tree, i.e. systemic redox imbalance due to hypobaric hypoxia exposure. Notable advances have been made in providing proof-of-concept regarding agents and modalities for treating the redox imbalance caused due to hypobaric hypoxia. These may become future prescriptions for faster, safer acclimatization to high altitude. The next two sections will focus on: a) the probable biomarkers for hypobaric hypoxia and b) the prophylactics and therapeutics with potential to prevent HAI.
2.1. Current prescribed treatment Although immediate descent, supplemental oxygen and rest are still considered the best treatment, acetazolamide at 125 mg–250 mg twice daily starting from 24 h before ascent till few hours after descent to either prevent AMS is the most recommended [19]. Acetazolamide 750 mg has been proven effective for treating AMS. Also, 500 mg acetazolamide was categorically rejected as ineffective for treating AMS. Some reports suggest dexamethasone to be better at treating AMS. In the same study, dexamethasone 8–16 mg was found to be equally effective as 750 mg acetazolamide in treating AMS above 4000 m [20]. 3. High altitude cerebral edema High altitude cerebral edema (HACE) is considered the extreme escalation of pathological events that began during AMS. Extravascular fluid accumulation in the brain begins during AMS. Further ascent causes greater fluid accumulation leading to coma, ataxia, convulsions and death. Thus, apart from pharmacological interventions, the primary focus for anyone diagnosed with AMS should be either rest at that altitude or descent of at least 1000 m. Once HACE occurs, the only true treatment is rapid descent [21]. Maximal HACE incidence is reported to be 31%(Gosainkund, Nepal, 4300 m) by Basnyat et al. [10]. The pharmacological alternatives are just to help the person survive. Nonetheless, pharmacological alternatives should be provided immediately to either prevent or delay HACE symptoms, with focus being on prevention. 3.1. Current prescribed treatment The primary rescue medicine for HACE beyond 3000–4000 m is dexamethasone [22], when rapid descent is a difficulty due to weather and terrain during long excursions. Acetazolamide and nifedipine both are useful in preventing HACE, at concentrations similar to those taken for preventing AMS. Hyperbaric therapy, immediate descent and supplemental oxygen remain the mainstay in treating and resolving HACE cases.
6. Biomarkers reflecting high-altitude maladies and acclimatization status for high-altitude hypoxia The term biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” (NIH Biomarkers Definitions Working Group, 1998) [34].
4. High altitude pulmonary edema High altitude pulmonary edema (HAPE) is the extravascular fluid accumulation in alveolar airspaces of lung. Pink frothy sputum 172
Life Sciences 203 (2018) 171–176
S. Paul et al.
1Receptor Agonist (IL-1RA), Heat Shock Protein-70 (HSP-70), and adrenomedullin were lower in AMS-susceptible subjects as compared to control subjects throughout 10 h of hypobaric hypoxia [49]. The authors recently reported that glutathione peroxidase 3, SOD1, hemopexin, catalase, malate dehydrogenase 1, STAT-3, thioredoxin reductase 2, RXR, tubulin, phenol sulfotransferase and MCP-1 can provide a credible status of acclimatization when following a particular acclimatization strategy [14]. Julian et al. also suggest that although a major anti-inflammatory/anti-permeability response accompanies AMS-susceptibility, the converse isn't true [50]. Further, some authors have questioned cerebral edema being held as the cause of AMS and HACE, suggesting free radicals and their interaction with trigeminal nerve to be the cause [27]. An important mystery thus far, remains as to why the high-altitude natives (HAN) are not susceptible to the radicals and the subsequent inflammation caused by their excess generation. Among the plasma proteins of high altitude natives compared against normal control group, vitamin D-binding protein, hemopexin, alpha-1–antitrypsin, haptoglobin b-chain, apolipoprotein A1, transthyretin and hemoglobin beta chain were up-regulated. The down-regulated proteins were transferrin, complement C3, serum amyloid, complement C4A and plasma retinol binding protein. Ahmad et al. suggested a fine balance of inflammatory processes with anti-inflammatory proteins dominant in natives that prevented any altitude related patho-physiologies developing in HAN [51]. Other works elucidating adaptive mechanisms in HAN detail genetic polymorphisms related to erythropoiesis and hemostasis [52–55]. All such probable biomarkers will in the near future make the assessment of acclimatization status during ascent to high altitude much more objective and immediate, thus nullifying life and death situations to a great extent.
In case of high altitude associated hypobaric hypoxia, a biomarker thus should be any molecule derived from easily accessible tissue (blood) that can be measured and evaluated (plasma proteins) to indicate a patho-physiological response (systemic redox imbalance). Hence, this short review is focused on blood plasma derived proteins that have been shown to be putative biomarkers due to their significant differential expression levels either during hypobaric hypoxia exposure or in patients of HAI as compared to control groups. HAPE is known to be a life-threatening HAI. Its current diagnosis is completely dependent on chest X-rays showing edema in lungs [35]. But, Ahmad et al. showed distinct protein signatures in HAPE patients and healthy controls' plasma. 14 proteins were found to be differentially expressed in HAPE patients. Of these, haptoglobin and Apo A1 were observed to have the most significant (p < 0.05) differential expression between HAPE patients and controls after validation using immunoblots [36]. Related to edema are the aspects of thrombosis and inflammation. Tyagi et al. showed that platelet proteins and calpain activity can be a predictor of thrombosis, a major health risk in hypoxic environments [37]. Further, molecules like asymmetric dimethylarginine (ADMA), serotonin (5-HT), 8-isoprostaglandin F2α (8-isoPGF2α), endothelin-1 (ET-1), plasma renin activity (PRA), plasma aldosterone concentration (PAC), superoxide dismutase (SOD) and nitric oxide (NO) levels were estimated in HAPE patients, high altitude travelers and high-altitude natives. It was observed that ADMA, 5-HT, 8-isoPGF2α, ET-1 levels, and PAC were significantly higher (p < 0.0001, each), whereas SOD activity and NO level were significantly lower in HAPE patients than high altitude travelers(p ≤ 0.001) [38]. Metabolite signatures for HAPE (C8-ceramide, sphingosine and glutamine) have also been determined [39] but these are still at a very nascent stage to be used definitively among clinicians. This is due to the fact that the large datasets obtained are entangled in myriad pathways, which currently can't be quantified as either a susceptibility indicator or a consequence of HAPE. Among all these leads, a headline protein for diagnosing HAPE in plasma samples is sulfotransferase 1A1 (Sult 1A1). Sult 1A1, with no other known implications in cardiorespiratory insufficiencies, shows highly significant differential expression in HAPE patients as compared to control groups [41]. NT-proBNP, supposed to be a cardiac biomarker, has also gained a lot of attention and evidence recently to be counted as a probable biomarker for diagnosis of severe AMS and susceptible marker of HAPE [42–44]. But other studies have highlighted many contradictions and drawbacks also. As per the study of Toshner et al., there is no increase in NT-proBNP in healthy resting subjects after ascending to 5200 m despite a significant rise in pulmonary artery systolic pressure (PASP) [43]. Gao et al. have given rather confusing results and views regarding BNP and HAPE. They stated clearly that in high-altitude travelers, whether afflicted by HAPE or not, NT-proBNP levels are higher as compared to sea-level controls. HAPE treatment lowered the levels of NT-proBNP in patients. But then they contradict their own findings and state that BNP can be a marker for HAPE [45]. Woods et al. have reported that severe AMS has better correlation with both BNP and NT-proBNP [42]. Mellor et al. have reported that hs-cTnT and natriuretic peptides are associated with high PASP and AMS [46]. Thus, in view of the tangential findings, one can conclude two things. First, BNP/NT-proBNP are associated with high PASP (which may or may not develop into HAI/HAPE as other related mechanisms are involved [47,48]) and secondly, one molecule alone is not a good way to demarcate HAI from normal stress responses at high altitude. AMS and HACE, observed to be related to increasing degrees of blood-brain-barrier (BBB) disruption, are currently dependent on a scoring system scored by the patient and MRI scans of brain to ascertain fluid accumulation, respectively. Lake Louise is completely subjective while MRI scans (MRI equipment mostly not available in remote highaltitude areas) show the end-stage of disease making immediate descent and oxygen inevitable. Although not as many molecules have been identified decisively as in HAPE, important molecules like Interleukin-
7. Prophylactics and therapeutics: without side-effects and contra-indications Coming back to ascent and acclimatization to high-altitude, its crystal clear that better prophylactics and therapeutics are still required to treat those who can't acclimatize or need to ascend rapidly. The current pharmaceuticals available for this purpose require extensive medical supervision, monitoring the side-effects of doses as well as the periodicity and quantity of these doses and are contra-indicated in people with cardiac, renal and hepatic ailments. Thus, this aspect is being looked at thoroughly to find such prophylactics/therapeutics that have least or no side-effects and are not contra-indicated in people suffering from any other ailments. Also, these newer alternatives should require minimal repeated dosing and prescription may not be essential. These are discussed below. 8. Nano-cerium particles (CNPs) In case of molecular advances in life sciences too, nano-materials have opened up new domains whether it be cancer or wound healing. To prevent or nullify the negative effects of hypobaric hypoxia, cerium nanoparticles (CNPs) have been employed. CNPs do not require mammoth quantities in terms of dosing. They are till now considered sideeffect free at the prescribed doses. The only two drawbacks are they require specific modes and strategies of dosing with the dose being a very minute quantity. The authors' lab has been a major proponent of CNPs and their efficacy in combating hypobaric hypoxia associated maladies. Arya et al. have shown the efficacy of CNPs against hypobaric hypoxia. They have shown that CNPs protects the lungs and brain against hypobaric hypoxia induced oxidative stress, inflammation, loss of mitochondrial membrane potential and memory impairment, respectively [56,57]. An important feature was the ability of CNPs to promote neurogenesis. Arya et al. elucidated the neuro-protective mechanism of CNPs in brain as being through the 5′-adenine 173
Life Sciences 203 (2018) 171–176
S. Paul et al.
for renal or cardiac insufficiencies [80]. The stable aqueous solution tides over the cost hurdle and increases bio-availability making the requirement of multiple daily doses (common with complex formulations available) redundant. SMN was observed to protect the rodent lung from HH-induced oxidative stress and inflammation at 50 mg/kg/ day single oral doses repeated over 5 days [81]. With all the known benefits and proven efficacy against HH-induced oxidative stress and inflammation, the authors are of the view that SMN is a ready to market alternative to current pharmacological interventions particularly in individuals suffering from renal and hepatic ailments.
monophosphate-activated protein kinase–protein kinase C–cyclic adenosine monophosphate response element-binding protein binding (AMPK-PKC-CBP). They also used PEG(polyethylene glycol)-ylation to localize the CNPs in rodent brain tissue in vivo [58]. 9. Peptides/peptide mimetics of biological proteins and antioxidant substances as interventions against hypobaric hypoxia Since the proteome shows significant perturbations upon exposure to hypobaric hypoxia, it makes sense to designate the affected proteins and sort them based on functions. The proteins with proven beneficial effects against hypobaric hypoxia can be further checked for functional domains. Such functional domain-specific peptides can then be synthesized as therapeutic peptides to be used as therapies/prophylactics. The positive aspect of such a strategy is the high efficacy, minimal chances of side-effects, requirement of minute doses and specific profile of effects. However, the high cost of production both economically and technically remains a hurdle to mass-production. Nonetheless, two proteins have shown significant efficacy against hypobaric hypoxia. Vasonatrin peptide (VNP) treatment for a week at 50 μg/kg/day i.p. was shown to have significantly reduced mean pulmonary arterial pressure, pulmonary vascular resistance, right ventricular hypertrophy and muscularization of the pulmonary arteries. Blood flow was also increased in this group. In addition, significantly lower levels of plasma Endothelin-1 and Angiotensin II and cardiac natriuretic peptide receptor-C mRNA expression were observed in VNP-treated as compared with saline-treated HH-induced pulmonary hypertension rats. Yu et al. summarized that VNP has therapeutic effects against pulmonary hypertension caused by hypobaric hypoxia exposure [59]. The authors lab has put in considerable effort in this domain with NAP. NAP peptide at 2 μg/kg/day (intranasal) was shown to protect the rodent brain against chronic and acute HH lasting to a maximum of 28 days (simulated altitude of 25,000 ft.) [60]. In primary culture of hippocampal region cells, only 15fM of NAP provided sufficient protection against severe hypoxia for 72 h [61]. In all the above articles, NAP was elucidated to have mechanistic effects on antioxidant proteins (Nrf2 mediated oxidative stress response, HO-1, SOD), energy production pathways (AMPK signaling) and Rho family GTPases pathway. NAP, thus has significant effects on antioxidant and signaling proteins in the rodent brain causing a prophylactic response against hypobaric hypoxia. In terms of antioxidants used against hypobaric hypoxia to attenuate oxidative stress caused by it, phyto-extracts have been in the limelight for long. Natural origins reducing the need for synthesis, biocompatibility without requirement of much safety testing at fairly high doses, non-requirement of medical supervision in most cases and easy availability make them a favorite of the research community. Notable phyto-extracts with considerable effects on redox stress during hypobaric hypoxia exposure include, but are not limited to, Withania somnifera extracts [62,63], quercetin [64], Ginkgo biloba extracts [65–69] and Bacopa monniera extracts [70]. Other substances of natural/synthetic origin found to be effective against hypobaric hypoxia induced oxidative stress are ascorbic acid [71], acetyl-L-carnitine [72,73], alphalipoic acid, alpha-ketoglutaric acid [74], 5-hydroxymethylfurfural [75,76], Ceftriaxone [77] and Gabapentin [78,79]. The authors have also dabbled with phyto-extracts to overcome the problems with current pharmacological interventions like cost, sideeffects, contra-indications in individuals with existing renal, cardiac and hepatic conditions, risks of over-dosing and medical supervision for use. The efforts have culminated with the development of a novel stable aqueous suspension of micronized silymarin (SMN). SMN has no known severe side-effects, has tolerance values approaching or even higher than 10 g/kg (oral; dogs) and 300 mg/kg (single IV bolus; dogs) [61], is already proven safe for humans with over 35 formulations already marketed (formulations are complex thereby increasing cost) as a hepatoprotective oral supplement with no known complications observed
10. Conclusion When looked through the prism of physiology, high altitude and the resulting hypobaric hypoxia assumes multiple forms as various HAI. Each HAI has its own set of symptoms, affecting a different organ. Also, by the time indisputable symptoms of any HAI whether AMS, HACE, HAPE or CMS emerge, the situation is already out of hand causing emergency descent and oxygen supplementation. In context of security forces and their style of functioning, it means that a single troop afflicted by HAI will require between two to six other fit troops to descent and survive depending on the prevailing situation. This can be catastrophic during their large-scale mobilization. Also, as is obvious, it becomes a logistical and medical burden to help such a troop recover knowing that he may not be able to re-ascend immediately and be deployed. In case of the numerous leisure/adventure travelers, they may not be capable of performing rescue descents in all terrain, thus either perishing or calling in emergency services wherever possible. This will also hamper the eco-tourism vistas as they place a socioeconomic burden on the native populace during such incidents. Thus, the requirement of finding statistically significant biomarkers in plasma which can be used to quickly and objectively monitor the acclimatization status of individuals before any severe symptoms of HAI develop is paramount. In the same vein, we must acknowledge that with or without biomarkers, HAI are a clear and present danger to all sojourners stationed at high-altitude. The current crop of interventions, although effective, remains ridden with contra-indications and sideeffects. Thus, a new set of prophylactics, based more on natural sources (our own physiology and plant extracts) is required which can show greater efficacy at lower doses and need not be prescription medicines. Also, all these measures need to be cost-effective enough to be employed at a huge scale. The authors, based on published data, have firm belief that the biomarkers as well as the prophylactic/therapeutics listed here (Table 1) will be able to solve the majority of current issues related to prognosis and prophylaxis at high altitude thereby reducing the occurrence of sudden emergency descent. It goes without saying that such an improvement will not only improve the quality of life and travel at high altitude but also provide a safer experience to all at high altitude. In the near future, authors speculate that systems biology and bioinformatics as well as patient repositories with genetic details, lifestyle choices, hereditary factors and other medical history will play decisive roles in high altitude environment.
Author contribution SP and AG wrote the review. YA developed the whole conception of the review. KB and PK substantially contributed to the editing of the final version. Acknowledgement The authors acknowledge Aditya Arya for valuable inputs in designing artwork. Subhojit Paul is recipient of CSIR fellowship. Anamika Gangwar is a recipient of DST-INSPIRE fellowship. 174
Life Sciences 203 (2018) 171–176
S. Paul et al.
Table 1 List of future prophylactic interventions (Table1.a) and putative protein biomarkers (Table1.b) for facilitating and monitoring high-altitude acclimatization.
[3] P. Bärtsch, High altitude pulmonary edema, Respiration 64 (6) (1997) 435–443. [4] G.W. Rodway, L.A. Hoffman, M.H. Sanders, High-altitude-related disorders—part I: pathophysiology, differential diagnosis, and treatment, Heart Lung 32 (6) (2003) 353–359. [5] A.M. Luks, E.R. Swenson, Medication and dosage considerations in the prophylaxis and treatment of high-altitude illness, Chest 133 (3) (March 2008) 744–755. [6] H. Karinen, J. Peltonen, H. Tikkanen, Prevalence of acute mountain sickness among Finnish trekkers on Mount Kilimanjaro, Tanzania: an observational study, High Alt. Med. Biol. 9 (4) (2008) 301–306. [7] S.A. Gallagher, P.H. Hackett, High-altitude illness, Emerg. Med. Clin. 22 (2) (2004) 329–355. [8] J. Vardy, J. Vardy, K. Judge, Acute mountain sickness and ascent rates in trekkers above 2500 m in the Nepali Himalaya, Aviat. Space Environ. Med. 77 (7) (2006) 742–744. [9] S.J. Jackson, et al., Incidence and predictors of acute mountain sickness among trekkers on Mount Kilimanjaro, High Alt. Med. Biol. 11 (3) (2010) 217–222. [10] B. Basnyat, et al., Disoriented and ataxic pilgrims: an epidemiological study of acute mountain sickness and high-altitude cerebral edema at a sacred lake at 4300 m in the Nepal Himalayas, Wilderness Environ. Med. 11 (2) (2000) 89–93. [11] C.S. Houston, Incidence of acute mountain sickness: a study of winter visitors to six Colorado resorts, Am. Alpine J. 27 (1985) 162–165. [12] Y. Ren, et al., Incidence of high altitude illnesses among unacclimatized persons who acutely ascended to Tibet, High Alt. Med. Biol. 11 (1) (2010) 39–42. [13] B. Basnyat, High altitude cerebral and pulmonary edema, Travel Med. Infect. Dis. 3 (4) (2005) 199–211. [14] S. Paul, et al., STAT3-RXR-Nrf2 activates systemic redox and energy homeostasis upon steep decline in pO2 gradient, Redox Biol. 14 (2018) 423–438. [15] R.C. Roach, J.A. Loeppky, M.V. Icenogle, Acute mountain sickness: increased severity during simulated altitude compared with normobaric hypoxia, J. Appl. Physiol. 81 (5) (1996) 1908–1910. [16] K. Kallenberg, et al., Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness, J. Cereb. Blood Flow Metab. 27 (5) (2007) 1064–1071. [17] M.H. Wilson, J. Milledge, Direct measurement of intracranial pressure at high altitude and correlation of ventricular size with acute mountain sickness: Brian Cummins' results from the 1985 Kishtwar expedition, Neurosurgery 63 (5) (2008) 970–975. [18] R. Roach, et al., The Lake Louise acute mountain sickness scoring system, Hypoxia Mol. Med. 272 (1993) 4. [19] L.P. Queiroz, A.M. Rapoport, High-altitude headache, Curr. Pain Headache Rep. 11 (4) (2007) 293–296. [20] L. Dumont, C. Mardirosoff, M.R. Tramèr, Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review, BMJ 321 (7256) (2000) 267. [21] P.H. Hackett, High altitude cerebral edema and acute mountain sickness, Hypoxia, Springer, 1999, pp. 23–45. [22] M.B. Rabold, Dexamethasone for prophylaxis and treatment of acute mountain sickness, J. Wilderness Med. 3 (1) (1992) 54–60. [23] H. Lobenhoffer, R. Zink, W. Brendel, High altitude pulmonary edema: analysis of 166 cases, High Alt. Physiol. Med. (1982) 219–231. [24] H. Hultgren, High altitude pulmonary edema, Hypoxia, High Altitude and the Heart, Karger Publishers, 1970, pp. 24–31. [25] A. Pennardt, High-altitude pulmonary edema: diagnosis, prevention, and treatment, Curr. Sports Med. Rep. 12 (2) (2013) 115–119. [26] H. Bao, et al., Cerebral edema in chronic mountain sickness: a new finding, Sci. Rep. 7 (2017) 43224. [27] D.M. Bailey, et al., Emerging concepts in acute mountain sickness and high-altitude cerebral edema: from the molecular to the morphological, Cell. Mol. Life Sci. 66 (22) (2009) 3583–3594. [28] P. Maiti, et al., Hypobaric hypoxia induces oxidative stress in rat brain, Neurochem. Int. 49 (8) (2006) 709–716. [29] J. Magalhães, et al., Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle, J. Appl. Physiol. 99 (4) (2005) 1247–1253. [30] J. Magalhaes, et al., Acute and severe hypobaric hypoxia-induced muscle oxidative stress in mice: the role of glutathione against oxidative damage, Eur. J. Appl. Physiol. 91 (2–3) (2004) 185–191. [31] H.N. Hultgren, et al., High-altitude pulmonary edema at a ski resort, West. J. Med. 164 (3) (1996) 222–227. [32] A. Chawla, Incidence of acute mountain sickness in patients of high altitude pulmonary edema: is the Lake Louise scoring accurate, Ind. J. Aerospace Med. 53 (1) (2009) 1–5. [33] A.M. Luks, et al., Wilderness Medical Society consensus guidelines for the prevention and treatment of acute altitude illness, Wilderness Environ. Med. 21 (2) (2010) 146–155. [34] Biomedical, F., NIH definition of biomarker, Clin. Pharmacol. Ther. 69 (2001) 89–95. [35] A.M. Sophocles, High-altitude pulmonary edema in Vail, Colorado, 1975–1982, West. J. Med. 144 (5) (1986) 569–573. [36] Y. Ahmad, et al., Identification of haptoglobin and apolipoprotein AI as biomarkers for high altitude pulmonary edema, Funct. Integr. Genomics 11 (3) (2011) 407. [37] T. Tyagi, et al., Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype, Blood 123 (8) (2014) 1250–1260. [38] Z. Ali, et al., Interactions among vascular-tone modulators contribute to high altitude pulmonary edema and augmented vasoreactivity in highlanders, PLoS One 7 (9) (2012) e44049.
Table 1.a S.NO.
Prophylactic
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
NAP peptide Vasonatrin peptide Gabapentin Silymarin Ceftriaxone 5-Hydroxymethylfurfural Alpha-ketoglutaric acid Alpha-lipoic acid Acetyl-L-carnitine Ascorbic acid Bacopa monnieri extracts Ginkgo biloba extracts Quercetin Withania somnifera extracts Cerium nanoparticles
Table 1.b S.No.
Putative biomarkers
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.
Haptoglobin Apolipoprotein A1 Calpain Asymmetric dimethylarginine (ADMA) Serotonin (5-HT) 8-Iso-prostaglandin F2α (8-isoPGF2α) Endothelin-1 (ET-1) Plasma renin activity (PRA) Plasma aldosterone Nitric oxide C8-ceramide Sphingosine Glutamine Sult 1A1 (PST) hs-cTnT BNP/NT-proBNP Interleukin-1Receptor Agonist (IL-1RA) Heat Shock Protein-70 (HSP-70) Glutathione peroxidase 3 (GPx3) Superoxide dismutase 1 (SOD1) Hemopexin Catalase Malate dehydrogenase 1 (MDH-1) Signal transducer and activator of Transcription 3 (STAT-3) Thioredoxin reductase 2 (TR2) Retinoid X receptor (RXR) Tubulin Monocyte chemo-attractant protein-1(MCP-1) Vitamin D-binding protein (VDBP) Alpha-1–antitrypsin Transthyretin Hemoglobin beta chain Transferrin Complement C3, C4A Serum amyloid protein Plasma retinol binding protein (RBP)
Competing interests The authors have no conflicts of interest or financial ties to disclose. References [1] B. Shukitt-Hale, L.E. Banderet, H.R. Lieberman, Elevation-dependent symptom, mood, and performance changes produced by exposure to hypobaric hypoxia, Int. J. Aviat. Psychol. 8 (4) (1998) 319–334. [2] B. Shukitt-Hale, et al., Hypobaric hypoxia impairs spatial memory in an elevationdependent fashion, Behav. Neural Biol. 62 (3) (1994) 244–252.
175
Life Sciences 203 (2018) 171–176
S. Paul et al.
[63] I. Baitharu, et al., Withania somnifera root extract ameliorates hypobaric hypoxia induced memory impairment in rats, J. Ethnopharmacol. 145 (2) (2013) 431–441. [64] A.K. Pandey, et al., Quercetin in hypoxia-induced oxidative stress: novel target for neuroprotection, Int. Rev. Neurobiol. 102 (2012) 107–146. [65] L. Karcher, P. Zagermann, J. Krieglstein, Effect of an extract of Ginkgo biloba on rat brain energy metabolism in hypoxia, Naunyn Schmiedeberg's Arch. Pharmacol. 327 (1) (1984) 31–35. [66] H. Oberpichler, et al., Effects of Ginkgo biloba constituents related to protection against brain damage caused by hypoxia, Pharmacol. Res. Commun. 20 (5) (1988) 349–368. [67] J.H. Gertsch, et al., Randomised, double blind, placebo controlled comparison of Ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT), BMJ 328 (7443) (2004) 797. [68] F.A. Moraga, et al., Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollagüe (3696 m) in northern Chile, Wilderness Environ. Med. 18 (4) (2007) 251–257. [69] S. Hoyer, et al., Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761), J. Neural Transm. 106 (11) (1999) 1171–1188. [70] S.K. Hota, et al., Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment, Neurobiol. Dis. 34 (1) (2009) 23–39. [71] J.G. Farias, et al., Oxidative stress in rat testis and epididymis under intermittent hypobaric hypoxia: protective role of ascorbate supplementation, J. Androl. 31 (3) (2010) 314–321. [72] S.A. Devi, et al., Intermittent hypobaric hypoxia-induced oxidative stress in rat erythrocytes: protective effects of vitamin E, vitamin C, and carnitine, Cell Biochem. Funct. 25 (2) (2007) 221–231. [73] K. Barhwal, et al., Acetyl-L-carnitine (ALCAR) prevents hypobaric hypoxia–induced spatial memory impairment through extracellular related kinase–mediated nuclear factor erythroid 2-related factor 2 phosphorylation, Neuroscience 161 (2) (2009) 501–514. [74] D.M. Bailey, B. Davies, Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude, High Alt. Med. Biol. 2 (1) (2001) 21–29. [75] H. Gatterer, et al., Short-term supplementation with alpha-ketoglutaric acid and 5hydroxymethylfurfural does not prevent the hypoxia induced decrease of exercise performance despite attenuation of oxidative stress, Int. J. Sports Med. 34 (01) (2013) 1–7. [76] J.-H. Zhang, et al., 5-HMF prevents against oxidative injury via APE/Ref-1, Free Radic. Res. 49 (1) (2015) 86–94. [77] S.K. Hota, et al., Ceftriaxone rescues hippocampal neurons from excitotoxicity and enhances memory retrieval in chronic hypobaric hypoxia, Neurobiol. Learn. Mem. 89 (4) (2008) 522–532. [78] S. Jafarian, et al., Gabapentin for prevention of hypobaric hypoxia-induced headache: randomized double-blind clinical trial, J. Neurol. Neurosurg. Psychiatry 79 (3) (2008) 321–323. [79] A. Kumar, R. Goyal, Gabapentin Attenuates Acute Hypoxic Stress–induced Behavioral Alterations and Oxidative Damage in Mice: Possible Involvement of GABAergic Mechanism, (2008). [80] N. Dixit, et al., Silymarin: a review of pharmacological aspects and bioavailability enhancement approaches, Indian J. Pharmacol. 39 (4) (2007) 172. [81] S. Paul, et al., Size restricted silymarin suspension evokes integrated adaptive response against acute hypoxia exposure in rat lung, Free Radic. Biol. Med. 96 (2016) 139–151.
[39] L. Guo, et al., Three plasma metabolite signatures for diagnosing high altitude pulmonary edema, Sci. Rep. 5 (2015) 15126. [41] Y. Ahmad, et al., The proteome of hypobaric induced hypoxic lung: insights from Temporal Proteomic Profiling for Biomarker Discovery, Sci. Rep. 5 (2015). [42] D. Woods, et al., Severe acute mountain sickness, brain natriuretic peptide and NTproBNP in humans, Acta Physiol. 205 (3) (2012) 349–355. [43] M.R. Toshner, et al., NT-proBNP does not rise on acute ascent to high altitude, High Alt. Med. Biol. 9 (4) (2008) 307–310. [44] D. Woods, et al., Brain natriuretic peptide and NT-proBNP levels reflect pulmonary artery systolic pressure in trekkers at high altitude, Physiol. Res. 62 (6) (2013) 597. [45] M. Gao, et al., NT-ProBNP levels are moderately increased in acute high-altitude pulmonary edema, Exp. Ther. Med. 5 (5) (2013) 1434–1438. [46] A. Mellor, et al., Cardiac biomarkers at high altitude, High Alt. Med. Biol. 15 (4) (2014) 452–458. [47] U. Scherrer, et al., New insights in the pathogenesis of high-altitude pulmonary edema, Prog. Cardiovasc. Dis. 52 (6) (2010) 485–492. [48] P. Bärtsch, et al., Physiological aspects of high-altitude pulmonary edema, J. Appl. Physiol. 98 (3) (2005) 1101–1110. [49] H. Lu, et al., In search for better pharmacological prophylaxis for acute mountain sickness: looking in other directions, Acta Physiol. 214 (1) (2015) 51–62. [50] C.G. Julian, et al., Exploratory proteomic analysis of hypobaric hypoxia and acute mountain sickness in humans, J. Appl. Physiol. 116 (7) (2014) 937–944. [51] Y. Ahmad, et al., An insight into the changes in human plasma proteome on adaptation to hypobaric hypoxia, PLoS One 8 (7) (2013) e67548. [52] C.M. Beall, Two routes to functional adaptation: Tibetan and Andean high-altitude natives, Proc. Natl. Acad. Sci. 104 (Suppl. 1) (2007) 8655–8660. [53] X. Yi, et al., Sequencing of 50 human exomes reveals adaptation to high altitude, Science 329 (5987) (2010) 75–78. [54] T. Simonson, et al., Adaptive genetic changes related to haemoglobin concentration in native high-altitude Tibetans, Exp. Physiol. 100 (11) (2015) 1263–1268. [55] A. Tomar, S. Malhotra, S. Sarkar, Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives, BMC Genet. 16 (1) (2015) 112. [56] A. Arya, et al., Cerium oxide nanoparticles protect rodent lungs from hypobaric hypoxia-induced oxidative stress and inflammation, Int. J. Nanomedicine 8 (2013) 4507. [57] A. Arya, et al., Cerium oxide nanoparticles prevent apoptosis in primary cortical culture by stabilizing mitochondrial membrane potential, Free Radic. Res. 48 (7) (2014) 784–793. [58] A. Arya, et al., Cerium oxide nanoparticles promote neurogenesis and abrogate hypoxia-induced memory impairment through AMPK–PKC–CBP signaling cascade, Int. J. Nanomedicine 11 (2016) 1159. [59] J. Yu, et al., Protective effects of vasonatrin peptide against hypobaric hypoxiainduced pulmonary hypertension in rats, Clin. Exp. Pharmacol. Physiol. 37 (1) (2010) 69–74. [60] N.K. Sharma, et al., Activity-dependent neuroprotective protein (ADNP)-derived peptide (NAP) ameliorates hypobaric hypoxia induced oxidative stress in rat brain, Peptides 32 (6) (2011) 1217–1224. [61] A. Arya, et al., NAP (davunetide) protects primary hippocampus culture by modulating expression profile of antioxidant genes during limiting oxygen conditions, Free Radic. Res. 49 (4) (2015) 440–452. [62] S. Bhattacharya, A. Muruganandam, Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress, Pharmacol. Biochem. Behav. 75 (3) (2003) 547–555.
176