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Effect of Boswellia serrata on cognitive impairment in multiple sclerosis patients
Accepted Manuscript Title: Effect of Boswellia serrata on cognitive impairment in multiple sclerosis patients Author: Nastaran Majdinasab Amir Siahpush Seyedeh Khatoon Mousavinejad Alireza Malayeri Seyed Aidin Sajedi Parisa Bizhanzadeh PII: DOI: Reference:
S2210-8033(16)30045-8 http://dx.doi.org/doi:10.1016/j.hermed.2016.05.003 HERMED 140
To appear in: Received date: Revised date: Accepted date:
2-6-2015 22-11-2015 23-5-2016
Please cite this article as: Majdinasab, Nastaran, Siahpush, Amir, Mousavinejad, Seyedeh Khatoon, Malayeri, Alireza, Sajedi, Seyed Aidin, Bizhanzadeh, Parisa, Effect of Boswellia serrata on cognitive impairment in multiple sclerosis patients.Journal of Herbal Medicine http://dx.doi.org/10.1016/j.hermed.2016.05.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effect of Boswellia Serrata on Cognitive impairment in Multiple Sclerosis patients Nastaran Majdinasab1, Amir Siahpush2, Seyedeh Khatoon Mousavinejad*1, Alireza Malayeri2, Seyed Aidin Sajedi1, Parisa Bizhanzadeh3 1. Department of Neurology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 2. Department of Pharmacognosy, Herbal Medicine & Natural Product Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 3. Department of Psychology and Educational Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran *Corresponding Author: Seyedeh Khatoon Mousavinejad Department of Neurology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Phone & Facsimile Numbers: 0098-61-33743092 Mobile Phone: 0098-917-373-6197 E-mail: [email protected]
Conflict of interest: No declared
Abstract Background: Boswellia Serrata (BS) has been shown to have anti-inflammatory effects and neuroprotective activity. OBJECTIVE: To determine whether BS improves cognitive performance among patients with multiple sclerosis (MS) related cognitive impairment (CI). Method: This was a double-blind, randomized, placebo-controlled study, in which 60 patients who had subjective cognitive complaints (according to multiple sclerosis neuropsychological questionnaire) were selected and categorized in two groups (each with 30 persons). These groups were compared on the basis of the effect of 450 mg of BS or placebo capsules twice a day. A series of MACFIMS (minimum assessment of cognitive function in MS) tests were conducted on the patients at the beginning of the treatment process and after 2 months of the study. Results of the mentioned tests were analyzed and recorded. Results: Considering changes in brief visuospatial memory test (BVMT) (p < 0.05) and the California verbal learning test (CVLT) second edition (p < 0.05), differences between the two groups were significant. But on the basis of paced auditory serial addition test, symbol digit modalities test, controlled oral word association test, judgment of line orientation test and Delis-Kaplan executive function system, differences between the two groups were negligible (p > 0.05). Conclusion: BS improved CVLT and BVMT in relapsing remitting (RR)MS patients without major depression who had subjective complaints of CI. Keywords: Multiple sclerosis, Relapsing-remitting, Cognitive impairment, Boswellia serrata, MACFIMS
Clinical trial registry number: IRCT2015042021862N1.
1. Introduction Multiple sclerosis (MS) is an inflammatory disease of the central nervous system and the most common cause of chronic neurologic disorders, which normally occurs when people are aged 20 to 40 years old (Hauser et al., 2006; Trapp et al., 2008; Messina et al., 2014). The cause of MS is not clearly known, but most likely demyelination and neurodegeneration via an autoimmune process could be the cause of disease (Hauser et al., 2006). Cognitive impairment (CI) is a major problem in MS patients (Browne et al., 2014) and in all subtypes of MS, it can be detected in the early stages of the disease (Robert et al., 2012; Messinis et al., 2010). Mild to moderate CI is observed in 40–60% of patients (Jongen et al., 2012). CI is associated with the disease type and duration, although disease duration and physical disability do not predict the presence of CI (Deluca et al., 2015; Shkil’niuk et al., 2013). Mood disorders such as depression can affect performance of CI measurement. Since depression disorder is common in MS patients (50%), depression needs to be measured in such patients. In addition, drugs, such as corticosteroids and particularly high-dose intravenous methylprednisolone used in new MS attacks, may have a negative impact on cognition (Sahraian and Etesam, 2014). CI can affect patients' quality of life (Akbar et al., 2010), decrease employment or cause unemployment and affects daily activities, general progress, coping, and rehabilitation progress (Langdon et al., 2012; Benedict et al., 2012). CI can lead to full disability and thus imposes heavy personal and social costs (Patti, 2009). In neuropsychological assessment of MS, the complex attention, information processing speed, episodic memory and executive function have typical changes, but language and general intelligence show no changes (Langdon et al., 2012). Clinical, radiographic, and pathological data suggests that both white matter and gray matter pathology play roles in the pathogenesis of MS-related CI (Deluca et al., 2015). Thus neurological assessment and cognitive screening for monitoring the cognitive impairments of patients are important (Sahraian et al., 2014). Boswellia serrata (BS) is a resinous extract from Boswellia species of Burceracea Boswellia genus trees (Archier et al., 2000). It has been used for thousands of years in traditional medicine in India, Italy, China, Greece and Iran (Behnamrasuli et al., 2001). It has been used for its anti- inflammatory, anti-nociceptive, anti-oxidant, anti-bacterial, cancer drug sensitizing, cardio-protective, insulin-resistance lowering and anti-arthritis properties (Jung et al., 2007; Mathe et al., 2004; Poeckel et al., 2006; Sunharsan et al., 2005; Syrovets et al., 2005). The most important pharmacological effect of BS is suppression of leukotriene from arachidonic acid by inhibition of 5-lipoxygenase which has anti-inflammatory properties (Ammon et al. 1991; Safayhi et al. 1992). Several studies have reported the antiinflammatory effects of BS in the management of inflammatory diseases such as ulcerative colitis, crohn’s disease, rheumatoid arthritis and asthma. In a study on a group of patients
with advanced ulcerative colitis, 6 weeks of supplementation with Boswellia gum resin extract (350 mg three times daily) showed significant improvements in stool properties, microscopic appearance of the bowel wall, and blood tests of inflammation (Moussaieff et al., 2008a; Omura et al., 2009; Ring et al., 2006; Glaser et al., 1999; Arnett and Strober, 2011; Moussaieff et al., 2008b; Ammon et al., 2006; Gupta et al., 1997). Boswellia also has neuroprotective activity and can increase structural formation of new nerve networks (Moussaieff et al., 2008a; Omura et al., 2009). It also inhibits degenerative changes in the hippocampus, which is one of the brain’s chief memory-processing areas (Ring et al., 2006). It should be noted that based on the toxicology studies of BS resin conducted on animals, significant pathological, hematologic and genotoxic changes were not observed at concentrations of up to 1000 mg/kg. In addition, the side effects are negligible in humans, and only in some cases have nausea, reflux and digestive disorders been reported in patients (Sharma et al. 2009; Singh et al. 1986). Treatment for patients with MS and cognitive impairment usually involves disease-modifying drugs (DMD) in combination with a pharmacological cognitive-enhancement strategy (Patti, 2012). Considering the above review of literature and anecdotes of traditional experiments, the aim of this paper is to compare therapeutic effects of BS with placebo in treatment of CI of MS patients.
2. Material and methods This is a single-center, randomized, double-blind and placebo-controlled study. 2.1. Patient selection The authors screened 125 clinically confirmed MS patients (MS diagnosis by revised McDonald criteria (Polman et al., 2011)) who were receiving care in the MS association of Khuzestan province Iran. Patients that had relapsing remitting (RR) MS and were relapse free for the last 6 weeks before the start of assessments were included in this study. Patients with current major depression, pre-existing medical or psychiatric disorders associated with cognitive dysfunction, developmental disease, drug or alcohol abuse, expanded disability status scale (EDSS) >3, new MS attacks and those who had received corticosteroids up to 6 weeks before the study or were pregnant or breastfeeding were excluded. First, Persian beck depression inventory-fast screen (BDI-FS) questionnaire (Ghassemzadeh et al., 2005) was given to patients (see Appendix). Patients with positive beck test results were omitted from this study. Remaining patients were given a multiple sclerosis neuropsychological questionnaire (MSNQ) to determine cognitively impaired participants in which score should be equal or higher than 22 (Akbar et al., 2010) – See Appendix
In this study 60 patients were finally selected; another 65 patients were excluded, among them 36 were without CI, 18 had depression, 8 were subtypes of MS (PP, PR and SP) and 3 had received corticosteroids.
2.2. Test procedure MACFIMS battery was carried out after obtaining informed consent. Various batteries to measure CI in MS patients such as the brief repeatable battery of neuropsychological tests (BRB-N) (Bever et al., 1995), the minimal assessment of cognitive function in MS (MACFIMS) (Benedit et al., 2002) and the brief international cognitive assessment for multiple sclerosis (BICAMS) were carried out (Longdon et al., 2012). MACFIMS proved to be more comprehensive in neuropsychological assessments in MS patients because the BRB-N did not have a measure of visual/spatial ability or executive function. (Deluca et al. 2015) (Table 1) MACFIMS is a battery of seven neuropsychological tests (Benedict et al., 2002). This battery is a collection of the paced auditory serial addition test (PASAT) (Gronwall, 1977), the symbol digit modalities test (SDMT) (Smith, 1982), the California verbal learning test second edition (CVLT-II) (Delis et al., 2000), the brief visuospatial memory test - revised (BVMT-R) (Benedict, 1977), the controlled oral word association test (COWAT) (Benton, 1994), the judgment of line orientation test (JLO) (Benton, 1994) and the Delis-Kaplan executive function system (D-KEFS) sorting test (Delis et al., 2001). It is worth mentioning that a standard Persian version of The MACFIMS which was validated by Arman Eshagh et al. in 2012 was used in this study (Eshaghi et al., 2012). In CVLT-II, there are five learning trials tests with 16 words that are read aloud for five consecutive trials, but participants are asked to recall after each trial. Then after 25 minutes they are asked to recall the list again. Total learning (TL) over five trials and number of correct recalls following the delay (DR) are measured. In the PASAT, single digits are presented at intervals of 3 second; the participant must add each new digit to the one immediately preceding. SDMT consists of nine target symbols paired with a number from 1 to 9 at the top of a page. The patient scans the symbol/number pairings and voices numbers as fast as possible in response to unpaired symbols below. After 90 seconds, the total correct number is recorded. In the BVMT-R, the participant is shown a page containing six geometric designs in a matrix and then asked to draw designs as possible from memory. BVMT-R consists of three learning trials (TL) and delayed recall (DR) of six designs. The range of scores is from 0 to 12 for each trial. D-KEFS have two parts, and in each part the participant is asked to sort six different cards into two groups with three cards per group in as many different categorizations as possible and to describe the concepts (he or she) used to generate each sort. Scores are measured for sorting and description. The second part of the test is carried out for another six cards. In the COWAT, the examiner asks the patient to express as many words as possible beginning with a specific letter in one minute. In the JLO, participants are presented a display of numbered visual angles to which two smaller lines are to be matched.
2.3. Treatment procedure The 60 patients were separated randomly into two groups of treatment and placebo according to a balanced 1:1 randomization in which a computer-generated randomization table was applied (each group included 30 persons). The treatment group received a capsule containing 450 mg powder of BS (plus excipients 50mg) twice a day for 2 months while placebo group received a capsule of the same size without BS (section 2.4). After 2 months, the MACFIMS battery was carried out and the results were documented. Except the team pharmacologist, the randomization was kept hidden from all clinical staff. Adverse events were monitored during this study (Figure 1). The study was approved by the medical ethics committee of Ahvaz Jundishapur University of Medical Sciences (registration number: MPRC-065) and it was registered in the Iranian Registry of Clinical Trials (IRCT). It is available at www.irct.ir under registration number: IRCT2015042021862N1. 2.4. Preparation of extract BS was purchased from Irandarouk Co. located in Tehran, Iran. The capsules were formulated and prepared by the Medicinal Plants Research center and Pharmacology Department of Ahvaz Jundishapur University of Medical Sciences. 1000 g of BS powder was placed in a clean 10-litre flask and macerated with 8000 mL of 70% ethanol for a period of 48 h at room temperature. The whole mixture was then filtered and evaporated with a rotary evaporator at a temperature not exceeding 50ºC until its volume decreased to 5% of its original volume (Siahposh et al., 2014). At the next stage, the moisture content was extracted and dried by mixing with lactose and starch (9:1) and powdered by experimental mill. The powder was consequently sieved with mesh number 16 and then filled into capsules using an automatic filling machine. Each capsule contained 450 mg BS plus 25 mg lactose/ 25 mg starch. Placebo capsules contained only lactose and starch. All capsules had the same shape and color. 2.5. Statistical analyses In order to describe the data, mean and standard deviation were used for quantitative variables, and percentage was applied for qualitative variables. T-test was used to evaluate the difference between age and disease duration in the mentioned two groups. T-test was also used to assess the baseline difference between dependent variables. To show the extent of medication effect on response variables, when controlling these variables at baseline, analysis of covariance (ANCOVA) was applied. All data were analyzed with SSPS 17 and a p-value less than 0.05 was considered as the level of significant difference in all tests.
3. Results 3.1. Patient demographics The final sample included 60 patients (treatment and placebo, 30 each). The patients’ mean age was 30.83±8.16 years, however the mean age of treatment groups was 30.17±8.68 (max.
53 and min. 16 years) and for the placebo group was 31.50±7.69 (max. 47 and min. 17 years). 73.3% (n=43) of patients were female. The mean duration of the disease (calculated from the onset of diagnosis confirmation) was 4.33±2.66 years with 4.23±2.39 and 4.43±2.92 years in treatment and placebo groups, respectively. There was no significant difference in demographic between the two groups and the groups were matched in terms of age (p=0.531), duration of disease (p=0.773) and gender (p=0.774). The baseline characteristics of the two groups are shown in Table 2. Similarly, in the results of MACFIMS battery tests there was no significant difference between the two groups at baseline (p>0.05). 3.2. Results of treatment efficacy The change for CVLTII-TL score between the treatment and placebo groups was noticed to be significant when performance was compared with baseline (p<0.01). Comparing with the baseline (p<0.01), the change for BVMTR-TL score between the two groups was also important. Therefore the covariance analysis showed that in day 60, the treatment group had superior performance in CVLTII-TL and BVMTR-TL (Figures 2 and 3). In contrast, the difference in PASAT was found to be insignificant when performance was compared with the baseline (P=0.601). On the basis of comparison with the baseline, the score of other tests such as SDMT (P=0.283), COWAT (P=0.900), D-KEFS (P=0.506), and JLO (P=0.607) showed significant changes (Table 3). There were no serious adverse events reported during this study.
4. Discussion Damage to white matter tracts and neuronal degeneration in gray matter in MS causes the significant prevalence of CI in patients and is due to changes in pro-inflammatory agents such as tumour necrosis factor (TNF)α, interferon (IFN), interleukin (IL), monocyte and macrophage. These agents are increased in MS patients (Rowland et al., 2010). There are no approved drugs for CI treatment in MS patients. Donepezil was the first drug to be studied in MS patients. Primary studies showed some positive responses to this drug in neuropsychological tests; nevertheless, two recent studies have not confirmed its impact on improving CI (Amato and Portaccio, 2011; Krupp et al., 2011). In studies by Lovera et al. and Villoslada et al. the efficacy of memantine on CI was examined, but differences between studied groups (memantine and placebo) were not significant (Villoslada et al., 2009; Lovera et al., 2010). The results of our randomized clinical trial showed significant improvement on auditory/verbal and visual/spatial memory (CVLT-TL and BVMTR-TL) in MS patients who suffer from CI. One possible explanation for the observed effect of BS on auditory/verbal and visual/spatial memory could be the mechanisms that are induced by BS.
Boswellia species resin is a major anti-inflammatory natural product that has been used for centuries. More than 200 compounds have been identified in the Boswellia resin (Ammon, 2006). Some compounds of Boswellia affect the immune system in different ways. The major constituents of BS are boswellic acids (Jauch and Bergmann, 2004). The four major pentacyclic triterpenic acids present are β-boswellic acid (BA), 3-acetyl-β-boswellic acid (ABA), 11-keto-boswellic acid (KBA) and 3-acetyl-11-keto-β-boswellic (AKBA) (Figure 4) (Safayhi et al., 1992; Rall et al. 1996). AKBA is the most potent anti-inflammatory fraction of boswellic acids, with 5-lipoxygenase enzyme inhibitory activity. Therefore, the suppression of leukotriene biosynthesis has been observed (Figure 5) (Robbins et al., 2005). It has been reported that BA can decrease IL-1, IL-2, IL-4, IL-6, IL-10, IL-12 and IFN, cause down regulation of TNFα, and suppress white blood cell migration, mast cell degranulation, monocyte and macrophage induction and inhibition of direct and indirect pathways of complement (Ammon, 2010). AKBA is able to pass the blood brain barrier (Kruger et al., 2008). These substances lead to synaptic plasticity in the hippocampus by activating protein kinase-C (PKC) and protein kinase-A (PKA) signaling pathways. There is strong evidence that PKC signaling pathways are causally involved in memory storage. PKA has been strongly implicated in the expression of a specific form of hippocampal long-term memory (Alkon et al., 2007; Nguyen et al., 2003). Nuclear factor- B (NF-B) is a prerequisite for the formation/action of cytokines/chemokines and thus any inhibitor of NFB will result in decrease of cellular defense and inflammatory reactions. However, inhibition of NF-B is not only related to the action of BA (Ammon, 2010). Another effective compound in Boswellia resin is incensole-acetate (IA), which inhibits NFB activation. IA also shows anti-inflammatory effects on the CNS and has shown antianxiety as well as anti-depression effects. Activating TRPV3 canal and thus increasing calcium (Ca) influx, BS (IA) also inhibits degenerative changes in the hippocampus, which is one of the brain’s chief memory-processing areas. Thus, calcium plays a role in the synaptic enhancement in hippocampus and molecule mechanisms of memory by releasing neurotransmitters. Anti-inflammatory and neuroprotective effects of IA may serve as a novel therapeutic treatment for neurological disorders and CI (Moussaieff et al. 2008a; Guyton et al., 2011). This study has not found noticeable effect of BS on processing speed (auditory) , processing speed (visual), verbal fluency, spatial processing and executive function (PASAT, SDMT, COWAT, DKEFS and JLO) in MS patients with CI. It can be said that, the relationship between these cases is not well understood. Furthermore, impacts that are induced by BS on memory storage and hippocampal long-term memory as well as the anatomical region of damage may play a role in improvement of neuropsychological impairment. In several studies relations are found between damage of the corpus callosum and cognitive functions such as processing speed, rapid problem solving, and dichotic listening tasks. Also there is a relationship between executive function impairment and damage in pre-frontal cortex and cognitive functions such as immediate recall (after repeated trial five) which is correlated with both medial temporal lobes. Hippocampal lesion number was related to visuospatial memory (Mclaughlin et al. 2012; Engel et al. 2007; Roosendaal et al. 2009; Rao et al. 1989).
Several studies have been carried out to show the effect of Boswellia species on CI. Mousavi et al. examined the efficacy of Memoral Herbal (Boswellia resin) in prevention of electroconvulsive therapy (ECT)-induced memory impairment in mood disorder patients. It was an effective choice in prevention of ECT-induced CI (Mousavi et al., 2012). Also, results of a study by Moin et al. suggest BS resin may enhance the cognitive outcome of patient following diffuse axonal injury of brain (Moein et al., 2013). Other studies investigated vision spatial memory retention in rats (Mahmoudi et al., 2011), fatigue due to MS (Majdinassab et al., 2013) and CI of MS (Sedighi et al., 2014). All studies showed therapeutically effective treatment with Boswellia species. The authors could not find any studies whereby the effect of Boswellia on CI of MS patients had been investigated in Iran by using MACFIMS battery of tests. However, Sedighi et al. reported the significant effect of Boswellia by BICAMS battery in just a BVMT test. There were no significant changes in SDMT and CVLT in MS patients (Sedighi et al., 2014). In the aforementioned study, patients who received Boswellia experienced a significant improvement in visional spatial memory as measured by BVMT. This confirms previous results (Sedighi et al., 2014, Mahmoudi et al., 2011 and Farshchi et al., 2010). All studies have shown that Boswellia has a noticeable effect on improvement of the spatial memory in rats. Rahmani and Hedayati reported that in healthy people, verbal learning and logical memory are improved by using Boswellia (Hedayati et al., 2010). This is in contrast with our study in which improvement is not seen in logical memory. Another finding of the present study is improvement in CVLTII-TR. This confirms previous results obtained by Hedayati et al., in which considerable improvement was seen in verbal learning memory. It should be pointed out that work of Hedayati et al. was conducted on healthy participants and this is in contrast with results of Sedighi et al. The reason that Boswellia improved analyzed cognitive skill in MS patients in the auditory verbal learning test (CVLTII-TR) might be due to its dose-dependent effect. Our results are also confirmed by Farshchi et al. and Mahmudi et al. Their study showed that the effect of Boswellia on rats’ visual memory was dose dependent. Since we have used 450 mg capsule (twice a day) in the present study, significant changes observed in CVLTII-TR might be due to increasing dosage of Boswellia. This is contrary to the findings of Sedighi et al. More studies are recommended with more patients, longer use and higher dosage of Boswellia, to assess the effect of Boswellia by other tests and to recognize the mechanism of its effect.
5. Conclusion BS improves CVLT and BVMT in RRMS patients without major depression who had subjective complaints of CI. It does not improve processing speed (auditory and visual), verbal fluency, spatial processing and executive function.
6. Acknowledgement
This study was supported by the deputy of research of Ahvaz Jundishapur University of Medical Sciences. We would like to express our gratitude to the staffs of MS Association of Khuzestan province as well as pharmacological research center of medicinal plants in the faculty of Pharmacy of Ahvaz Jundishapur University of Medical Sciences. Also the authors would like to thank all colleagues who contributed to this study and the Golestan clinical research development unit.
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Tables and Figures: Table 1. Neuropsychometric batteries commonly used to measure CI in MS. Domain
MACFIMS
BICAMS
PASAT
1
PASAT
-
Processing speed (visual)
SDMT
2
SDMT
SDMT
Verbal memory (learning and recall)
SRT 3
Processing speed (auditory) and working memory
BRN-B
5
Visual/spatial memory (learning and recall)
SPART
Verbal fluency
COWAT 7
CVLT-II 4
CVLT-II
6
BVMT-R
BVMT-R COWAT 8
Spatial processing
-
JLO
Executive function
-
D-KEFS 9
-
BVMT-R, brief visuospatial memory test – revised; COWAT, controlled oral word association test; CVLT-II, California verbal learning test second edition; D-KEFS, Delis- Kaplan executive function system; JLO, judgment of line orientation test; PASAT, paced auditory serial addition test; SDMT, symbol digit modalities test; SPART, spatial recall test; SRT, selective reminding test.
Table 2. Characteristics of participants demographics at baseline (day 0). Characteristic Age (years) Mean±SD
Treatment (n=30)
Placebo (n=30)
0.531 30.17±8.68
31.5±7.69 0.774
Gender, n (%) Male Female
8 (26.7%) 22 (73.3%)
9 (30%) 21 (70%) 0.773
Disease Duration Mean±SD
p value
4.23±2.39
4.43±2.92
Table 3. Neuropsychological test scores at baseline and on day 60 of the study. Neuropsychological test SDMT Drug Placebo
Day 0 (baseline)
Day 60
P value (ANCOVA)
39.67±12.94 41.33±11.10
42.60±13.84 43.77±12.42
0.283
44.70±11.38 45.10±10.32
49.34±10.61 46.16±10.63
<0.01
Drug Placebo
11.63±5.60 11.80±6.21
14.23±6.43 14.14±5.73
0.506
BVMTR-TL Drug Placebo
17.1±7.5 16.44±8.4
21.36±6.34 18.25±7.9
<0.01
Drug Placebo
23.67±10.53 21.80±10.94
25.20±10.30 23.47±1o.64
0.900
Drug Placebo
36.60±16.37 37.82±15.85
37.87±15.89 39.25±13.71
0.601
Drug Placebo
18.30±6.30 17.90±5.14
19.03±6.13 18.67±5.69
0.607
CVLT2-TL Drug Placebo D-KEFS
COWAT
PASAT
JLO
Persian beck test and MSNQ questionnaire
Assessed for eligibility (n=125)
Excluded: (n=65) Not Cognitively Impaired (n=36) Depression (n=18) Other subtypes of MS (n=8) Receiving Corticosteroid (n=3) Included: (n=60)
Randomized
MACFIMS test
Boswellia Serrata treatment (n=30) After 2 months
Placebo treatment (n=30)
After 2 months
MACFIMS test
MACFIMS test
Analyzed (n=30)
Analyzed (n=30)
Figure 1. Study flowchart (Consort format). MACFIMS, minimum assessment of cognitive function in multiple sclerosis; MS, multiple sclerosis; MSNQ, MS neuropsychological questionnaire.
Figure 2. Mean values for CVLTII-TL test before and after treatment.
Figure 3. Mean values for BVMTR-TL test before and after treatment.
HO HOOC 1
H 3CCOO HOOC 2
O
O
H 3CCOO HOOC
HO HOOC 3
4
Figure 4. The four major pentacyclic triterpenic acids present in BA (Β-Boswellic Acid (1), Acetyl-β-Boswellic Acid (2), 11-keto-β-Boswellic Acid (3), Acetyl-11-keto-β-Boswellic Acid (4) (Rall et al., 1996).
Figure 5. The role of the 5-LO pathway in the generation of leukotrienes (LT’s) (Robbins et al., 2005)
Appendix: Questionnaires
Multiple Sclerosis Neuropsychological screening Questionnaire (MSNQ) Name: Date: Sex (circle one): Male / Female Very often. Very disruptive (4) 1. Are you easily distracted? 2. Do you lose your thoughts while listening to somebody speaks? 3. Are you slow when trying to solve problems? 4. Do you forget appointments? 5. Dou you forget what you read? 6. Do you have trouble describing shows or programs recently watched? 7. Do you need to have instructions repeated? 8. Do you have to be reminded to do tasks? 9. Do you forget errands that were planned? 10. Do you have difficulty answering questions? 11. Do you have difficulty keeping track of two things at once? 12. Do you miss the point of what someone is trying to say? 13. Do you have difficulty controlling impulses? 14. Do you laugh or cry with little cause? 15. Do you talk excessively or focus too much on your own interests?
Quite often. Interferes with life (3)
Occasionally. Seldom a problem (2)
Very rarely. No problem (1)
Never. Does not occur (0)
Persian beck depression inventory-fast screen (BDI-FS) questionnaire 1. Sadness 0 I do not feel sad. 1 I feel sad much of the time. 2 I am sad all time. 3 I am so sad or unhappy that I can't 2. Pessimism 0 I am not discouraged about my future. 1 I feel more discouraged about my future than I used to be. 2 I do not expect things to work out for me. 3 I feel my future in hopeless and will only get worse. 3. Past Failure 0 I do feel like a failure. 1 I have failed more than I should have. 2 As I look back, I see a lot of failure. 3 I feel I am a total failure as a person. 4. Loss of pleasure 0 I get as much pleasure as I ever did from the things I enjoy. 1 I don't enjoy things as much as I used to. 2 I get very little pleasure from the things I used to enjoy. 3 I can't get any pleasure from the things I used to enjoy. 5. Punishment Feeling 0 I don't feel I am being punished. 1 I feel I may be punished. 2 I expect to be punished. 3 I feel I am being punished. 6. Self- Dislike 0 I feel the same about myself as ever. 1 I have lost confidence in myself. 2 I am disappointed in myself. 3 I dislike myself. 7. Suicidal thoughts or Wishes 0 I don't have any thoughts of killing myself. 1 I have thoughts of killing myself, but I would not carry them out. 2 I would like to kill myself. 3 I would kill myself if I had the chance.
S2210-8033(16)30045-8 http://dx.doi.org/doi:10.1016/j.hermed.2016.05.003 HERMED 140
To appear in: Received date: Revised date: Accepted date:
2-6-2015 22-11-2015 23-5-2016
Please cite this article as: Majdinasab, Nastaran, Siahpush, Amir, Mousavinejad, Seyedeh Khatoon, Malayeri, Alireza, Sajedi, Seyed Aidin, Bizhanzadeh, Parisa, Effect of Boswellia serrata on cognitive impairment in multiple sclerosis patients.Journal of Herbal Medicine http://dx.doi.org/10.1016/j.hermed.2016.05.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Effect of Boswellia Serrata on Cognitive impairment in Multiple Sclerosis patients Nastaran Majdinasab1, Amir Siahpush2, Seyedeh Khatoon Mousavinejad*1, Alireza Malayeri2, Seyed Aidin Sajedi1, Parisa Bizhanzadeh3 1. Department of Neurology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 2. Department of Pharmacognosy, Herbal Medicine & Natural Product Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 3. Department of Psychology and Educational Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran *Corresponding Author: Seyedeh Khatoon Mousavinejad Department of Neurology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Phone & Facsimile Numbers: 0098-61-33743092 Mobile Phone: 0098-917-373-6197 E-mail: [email protected]
Conflict of interest: No declared
Abstract Background: Boswellia Serrata (BS) has been shown to have anti-inflammatory effects and neuroprotective activity. OBJECTIVE: To determine whether BS improves cognitive performance among patients with multiple sclerosis (MS) related cognitive impairment (CI). Method: This was a double-blind, randomized, placebo-controlled study, in which 60 patients who had subjective cognitive complaints (according to multiple sclerosis neuropsychological questionnaire) were selected and categorized in two groups (each with 30 persons). These groups were compared on the basis of the effect of 450 mg of BS or placebo capsules twice a day. A series of MACFIMS (minimum assessment of cognitive function in MS) tests were conducted on the patients at the beginning of the treatment process and after 2 months of the study. Results of the mentioned tests were analyzed and recorded. Results: Considering changes in brief visuospatial memory test (BVMT) (p < 0.05) and the California verbal learning test (CVLT) second edition (p < 0.05), differences between the two groups were significant. But on the basis of paced auditory serial addition test, symbol digit modalities test, controlled oral word association test, judgment of line orientation test and Delis-Kaplan executive function system, differences between the two groups were negligible (p > 0.05). Conclusion: BS improved CVLT and BVMT in relapsing remitting (RR)MS patients without major depression who had subjective complaints of CI. Keywords: Multiple sclerosis, Relapsing-remitting, Cognitive impairment, Boswellia serrata, MACFIMS
Clinical trial registry number: IRCT2015042021862N1.
1. Introduction Multiple sclerosis (MS) is an inflammatory disease of the central nervous system and the most common cause of chronic neurologic disorders, which normally occurs when people are aged 20 to 40 years old (Hauser et al., 2006; Trapp et al., 2008; Messina et al., 2014). The cause of MS is not clearly known, but most likely demyelination and neurodegeneration via an autoimmune process could be the cause of disease (Hauser et al., 2006). Cognitive impairment (CI) is a major problem in MS patients (Browne et al., 2014) and in all subtypes of MS, it can be detected in the early stages of the disease (Robert et al., 2012; Messinis et al., 2010). Mild to moderate CI is observed in 40–60% of patients (Jongen et al., 2012). CI is associated with the disease type and duration, although disease duration and physical disability do not predict the presence of CI (Deluca et al., 2015; Shkil’niuk et al., 2013). Mood disorders such as depression can affect performance of CI measurement. Since depression disorder is common in MS patients (50%), depression needs to be measured in such patients. In addition, drugs, such as corticosteroids and particularly high-dose intravenous methylprednisolone used in new MS attacks, may have a negative impact on cognition (Sahraian and Etesam, 2014). CI can affect patients' quality of life (Akbar et al., 2010), decrease employment or cause unemployment and affects daily activities, general progress, coping, and rehabilitation progress (Langdon et al., 2012; Benedict et al., 2012). CI can lead to full disability and thus imposes heavy personal and social costs (Patti, 2009). In neuropsychological assessment of MS, the complex attention, information processing speed, episodic memory and executive function have typical changes, but language and general intelligence show no changes (Langdon et al., 2012). Clinical, radiographic, and pathological data suggests that both white matter and gray matter pathology play roles in the pathogenesis of MS-related CI (Deluca et al., 2015). Thus neurological assessment and cognitive screening for monitoring the cognitive impairments of patients are important (Sahraian et al., 2014). Boswellia serrata (BS) is a resinous extract from Boswellia species of Burceracea Boswellia genus trees (Archier et al., 2000). It has been used for thousands of years in traditional medicine in India, Italy, China, Greece and Iran (Behnamrasuli et al., 2001). It has been used for its anti- inflammatory, anti-nociceptive, anti-oxidant, anti-bacterial, cancer drug sensitizing, cardio-protective, insulin-resistance lowering and anti-arthritis properties (Jung et al., 2007; Mathe et al., 2004; Poeckel et al., 2006; Sunharsan et al., 2005; Syrovets et al., 2005). The most important pharmacological effect of BS is suppression of leukotriene from arachidonic acid by inhibition of 5-lipoxygenase which has anti-inflammatory properties (Ammon et al. 1991; Safayhi et al. 1992). Several studies have reported the antiinflammatory effects of BS in the management of inflammatory diseases such as ulcerative colitis, crohn’s disease, rheumatoid arthritis and asthma. In a study on a group of patients
with advanced ulcerative colitis, 6 weeks of supplementation with Boswellia gum resin extract (350 mg three times daily) showed significant improvements in stool properties, microscopic appearance of the bowel wall, and blood tests of inflammation (Moussaieff et al., 2008a; Omura et al., 2009; Ring et al., 2006; Glaser et al., 1999; Arnett and Strober, 2011; Moussaieff et al., 2008b; Ammon et al., 2006; Gupta et al., 1997). Boswellia also has neuroprotective activity and can increase structural formation of new nerve networks (Moussaieff et al., 2008a; Omura et al., 2009). It also inhibits degenerative changes in the hippocampus, which is one of the brain’s chief memory-processing areas (Ring et al., 2006). It should be noted that based on the toxicology studies of BS resin conducted on animals, significant pathological, hematologic and genotoxic changes were not observed at concentrations of up to 1000 mg/kg. In addition, the side effects are negligible in humans, and only in some cases have nausea, reflux and digestive disorders been reported in patients (Sharma et al. 2009; Singh et al. 1986). Treatment for patients with MS and cognitive impairment usually involves disease-modifying drugs (DMD) in combination with a pharmacological cognitive-enhancement strategy (Patti, 2012). Considering the above review of literature and anecdotes of traditional experiments, the aim of this paper is to compare therapeutic effects of BS with placebo in treatment of CI of MS patients.
2. Material and methods This is a single-center, randomized, double-blind and placebo-controlled study. 2.1. Patient selection The authors screened 125 clinically confirmed MS patients (MS diagnosis by revised McDonald criteria (Polman et al., 2011)) who were receiving care in the MS association of Khuzestan province Iran. Patients that had relapsing remitting (RR) MS and were relapse free for the last 6 weeks before the start of assessments were included in this study. Patients with current major depression, pre-existing medical or psychiatric disorders associated with cognitive dysfunction, developmental disease, drug or alcohol abuse, expanded disability status scale (EDSS) >3, new MS attacks and those who had received corticosteroids up to 6 weeks before the study or were pregnant or breastfeeding were excluded. First, Persian beck depression inventory-fast screen (BDI-FS) questionnaire (Ghassemzadeh et al., 2005) was given to patients (see Appendix). Patients with positive beck test results were omitted from this study. Remaining patients were given a multiple sclerosis neuropsychological questionnaire (MSNQ) to determine cognitively impaired participants in which score should be equal or higher than 22 (Akbar et al., 2010) – See Appendix
In this study 60 patients were finally selected; another 65 patients were excluded, among them 36 were without CI, 18 had depression, 8 were subtypes of MS (PP, PR and SP) and 3 had received corticosteroids.
2.2. Test procedure MACFIMS battery was carried out after obtaining informed consent. Various batteries to measure CI in MS patients such as the brief repeatable battery of neuropsychological tests (BRB-N) (Bever et al., 1995), the minimal assessment of cognitive function in MS (MACFIMS) (Benedit et al., 2002) and the brief international cognitive assessment for multiple sclerosis (BICAMS) were carried out (Longdon et al., 2012). MACFIMS proved to be more comprehensive in neuropsychological assessments in MS patients because the BRB-N did not have a measure of visual/spatial ability or executive function. (Deluca et al. 2015) (Table 1) MACFIMS is a battery of seven neuropsychological tests (Benedict et al., 2002). This battery is a collection of the paced auditory serial addition test (PASAT) (Gronwall, 1977), the symbol digit modalities test (SDMT) (Smith, 1982), the California verbal learning test second edition (CVLT-II) (Delis et al., 2000), the brief visuospatial memory test - revised (BVMT-R) (Benedict, 1977), the controlled oral word association test (COWAT) (Benton, 1994), the judgment of line orientation test (JLO) (Benton, 1994) and the Delis-Kaplan executive function system (D-KEFS) sorting test (Delis et al., 2001). It is worth mentioning that a standard Persian version of The MACFIMS which was validated by Arman Eshagh et al. in 2012 was used in this study (Eshaghi et al., 2012). In CVLT-II, there are five learning trials tests with 16 words that are read aloud for five consecutive trials, but participants are asked to recall after each trial. Then after 25 minutes they are asked to recall the list again. Total learning (TL) over five trials and number of correct recalls following the delay (DR) are measured. In the PASAT, single digits are presented at intervals of 3 second; the participant must add each new digit to the one immediately preceding. SDMT consists of nine target symbols paired with a number from 1 to 9 at the top of a page. The patient scans the symbol/number pairings and voices numbers as fast as possible in response to unpaired symbols below. After 90 seconds, the total correct number is recorded. In the BVMT-R, the participant is shown a page containing six geometric designs in a matrix and then asked to draw designs as possible from memory. BVMT-R consists of three learning trials (TL) and delayed recall (DR) of six designs. The range of scores is from 0 to 12 for each trial. D-KEFS have two parts, and in each part the participant is asked to sort six different cards into two groups with three cards per group in as many different categorizations as possible and to describe the concepts (he or she) used to generate each sort. Scores are measured for sorting and description. The second part of the test is carried out for another six cards. In the COWAT, the examiner asks the patient to express as many words as possible beginning with a specific letter in one minute. In the JLO, participants are presented a display of numbered visual angles to which two smaller lines are to be matched.
2.3. Treatment procedure The 60 patients were separated randomly into two groups of treatment and placebo according to a balanced 1:1 randomization in which a computer-generated randomization table was applied (each group included 30 persons). The treatment group received a capsule containing 450 mg powder of BS (plus excipients 50mg) twice a day for 2 months while placebo group received a capsule of the same size without BS (section 2.4). After 2 months, the MACFIMS battery was carried out and the results were documented. Except the team pharmacologist, the randomization was kept hidden from all clinical staff. Adverse events were monitored during this study (Figure 1). The study was approved by the medical ethics committee of Ahvaz Jundishapur University of Medical Sciences (registration number: MPRC-065) and it was registered in the Iranian Registry of Clinical Trials (IRCT). It is available at www.irct.ir under registration number: IRCT2015042021862N1. 2.4. Preparation of extract BS was purchased from Irandarouk Co. located in Tehran, Iran. The capsules were formulated and prepared by the Medicinal Plants Research center and Pharmacology Department of Ahvaz Jundishapur University of Medical Sciences. 1000 g of BS powder was placed in a clean 10-litre flask and macerated with 8000 mL of 70% ethanol for a period of 48 h at room temperature. The whole mixture was then filtered and evaporated with a rotary evaporator at a temperature not exceeding 50ºC until its volume decreased to 5% of its original volume (Siahposh et al., 2014). At the next stage, the moisture content was extracted and dried by mixing with lactose and starch (9:1) and powdered by experimental mill. The powder was consequently sieved with mesh number 16 and then filled into capsules using an automatic filling machine. Each capsule contained 450 mg BS plus 25 mg lactose/ 25 mg starch. Placebo capsules contained only lactose and starch. All capsules had the same shape and color. 2.5. Statistical analyses In order to describe the data, mean and standard deviation were used for quantitative variables, and percentage was applied for qualitative variables. T-test was used to evaluate the difference between age and disease duration in the mentioned two groups. T-test was also used to assess the baseline difference between dependent variables. To show the extent of medication effect on response variables, when controlling these variables at baseline, analysis of covariance (ANCOVA) was applied. All data were analyzed with SSPS 17 and a p-value less than 0.05 was considered as the level of significant difference in all tests.
3. Results 3.1. Patient demographics The final sample included 60 patients (treatment and placebo, 30 each). The patients’ mean age was 30.83±8.16 years, however the mean age of treatment groups was 30.17±8.68 (max.
53 and min. 16 years) and for the placebo group was 31.50±7.69 (max. 47 and min. 17 years). 73.3% (n=43) of patients were female. The mean duration of the disease (calculated from the onset of diagnosis confirmation) was 4.33±2.66 years with 4.23±2.39 and 4.43±2.92 years in treatment and placebo groups, respectively. There was no significant difference in demographic between the two groups and the groups were matched in terms of age (p=0.531), duration of disease (p=0.773) and gender (p=0.774). The baseline characteristics of the two groups are shown in Table 2. Similarly, in the results of MACFIMS battery tests there was no significant difference between the two groups at baseline (p>0.05). 3.2. Results of treatment efficacy The change for CVLTII-TL score between the treatment and placebo groups was noticed to be significant when performance was compared with baseline (p<0.01). Comparing with the baseline (p<0.01), the change for BVMTR-TL score between the two groups was also important. Therefore the covariance analysis showed that in day 60, the treatment group had superior performance in CVLTII-TL and BVMTR-TL (Figures 2 and 3). In contrast, the difference in PASAT was found to be insignificant when performance was compared with the baseline (P=0.601). On the basis of comparison with the baseline, the score of other tests such as SDMT (P=0.283), COWAT (P=0.900), D-KEFS (P=0.506), and JLO (P=0.607) showed significant changes (Table 3). There were no serious adverse events reported during this study.
4. Discussion Damage to white matter tracts and neuronal degeneration in gray matter in MS causes the significant prevalence of CI in patients and is due to changes in pro-inflammatory agents such as tumour necrosis factor (TNF)α, interferon (IFN), interleukin (IL), monocyte and macrophage. These agents are increased in MS patients (Rowland et al., 2010). There are no approved drugs for CI treatment in MS patients. Donepezil was the first drug to be studied in MS patients. Primary studies showed some positive responses to this drug in neuropsychological tests; nevertheless, two recent studies have not confirmed its impact on improving CI (Amato and Portaccio, 2011; Krupp et al., 2011). In studies by Lovera et al. and Villoslada et al. the efficacy of memantine on CI was examined, but differences between studied groups (memantine and placebo) were not significant (Villoslada et al., 2009; Lovera et al., 2010). The results of our randomized clinical trial showed significant improvement on auditory/verbal and visual/spatial memory (CVLT-TL and BVMTR-TL) in MS patients who suffer from CI. One possible explanation for the observed effect of BS on auditory/verbal and visual/spatial memory could be the mechanisms that are induced by BS.
Boswellia species resin is a major anti-inflammatory natural product that has been used for centuries. More than 200 compounds have been identified in the Boswellia resin (Ammon, 2006). Some compounds of Boswellia affect the immune system in different ways. The major constituents of BS are boswellic acids (Jauch and Bergmann, 2004). The four major pentacyclic triterpenic acids present are β-boswellic acid (BA), 3-acetyl-β-boswellic acid (ABA), 11-keto-boswellic acid (KBA) and 3-acetyl-11-keto-β-boswellic (AKBA) (Figure 4) (Safayhi et al., 1992; Rall et al. 1996). AKBA is the most potent anti-inflammatory fraction of boswellic acids, with 5-lipoxygenase enzyme inhibitory activity. Therefore, the suppression of leukotriene biosynthesis has been observed (Figure 5) (Robbins et al., 2005). It has been reported that BA can decrease IL-1, IL-2, IL-4, IL-6, IL-10, IL-12 and IFN, cause down regulation of TNFα, and suppress white blood cell migration, mast cell degranulation, monocyte and macrophage induction and inhibition of direct and indirect pathways of complement (Ammon, 2010). AKBA is able to pass the blood brain barrier (Kruger et al., 2008). These substances lead to synaptic plasticity in the hippocampus by activating protein kinase-C (PKC) and protein kinase-A (PKA) signaling pathways. There is strong evidence that PKC signaling pathways are causally involved in memory storage. PKA has been strongly implicated in the expression of a specific form of hippocampal long-term memory (Alkon et al., 2007; Nguyen et al., 2003). Nuclear factor- B (NF-B) is a prerequisite for the formation/action of cytokines/chemokines and thus any inhibitor of NFB will result in decrease of cellular defense and inflammatory reactions. However, inhibition of NF-B is not only related to the action of BA (Ammon, 2010). Another effective compound in Boswellia resin is incensole-acetate (IA), which inhibits NFB activation. IA also shows anti-inflammatory effects on the CNS and has shown antianxiety as well as anti-depression effects. Activating TRPV3 canal and thus increasing calcium (Ca) influx, BS (IA) also inhibits degenerative changes in the hippocampus, which is one of the brain’s chief memory-processing areas. Thus, calcium plays a role in the synaptic enhancement in hippocampus and molecule mechanisms of memory by releasing neurotransmitters. Anti-inflammatory and neuroprotective effects of IA may serve as a novel therapeutic treatment for neurological disorders and CI (Moussaieff et al. 2008a; Guyton et al., 2011). This study has not found noticeable effect of BS on processing speed (auditory) , processing speed (visual), verbal fluency, spatial processing and executive function (PASAT, SDMT, COWAT, DKEFS and JLO) in MS patients with CI. It can be said that, the relationship between these cases is not well understood. Furthermore, impacts that are induced by BS on memory storage and hippocampal long-term memory as well as the anatomical region of damage may play a role in improvement of neuropsychological impairment. In several studies relations are found between damage of the corpus callosum and cognitive functions such as processing speed, rapid problem solving, and dichotic listening tasks. Also there is a relationship between executive function impairment and damage in pre-frontal cortex and cognitive functions such as immediate recall (after repeated trial five) which is correlated with both medial temporal lobes. Hippocampal lesion number was related to visuospatial memory (Mclaughlin et al. 2012; Engel et al. 2007; Roosendaal et al. 2009; Rao et al. 1989).
Several studies have been carried out to show the effect of Boswellia species on CI. Mousavi et al. examined the efficacy of Memoral Herbal (Boswellia resin) in prevention of electroconvulsive therapy (ECT)-induced memory impairment in mood disorder patients. It was an effective choice in prevention of ECT-induced CI (Mousavi et al., 2012). Also, results of a study by Moin et al. suggest BS resin may enhance the cognitive outcome of patient following diffuse axonal injury of brain (Moein et al., 2013). Other studies investigated vision spatial memory retention in rats (Mahmoudi et al., 2011), fatigue due to MS (Majdinassab et al., 2013) and CI of MS (Sedighi et al., 2014). All studies showed therapeutically effective treatment with Boswellia species. The authors could not find any studies whereby the effect of Boswellia on CI of MS patients had been investigated in Iran by using MACFIMS battery of tests. However, Sedighi et al. reported the significant effect of Boswellia by BICAMS battery in just a BVMT test. There were no significant changes in SDMT and CVLT in MS patients (Sedighi et al., 2014). In the aforementioned study, patients who received Boswellia experienced a significant improvement in visional spatial memory as measured by BVMT. This confirms previous results (Sedighi et al., 2014, Mahmoudi et al., 2011 and Farshchi et al., 2010). All studies have shown that Boswellia has a noticeable effect on improvement of the spatial memory in rats. Rahmani and Hedayati reported that in healthy people, verbal learning and logical memory are improved by using Boswellia (Hedayati et al., 2010). This is in contrast with our study in which improvement is not seen in logical memory. Another finding of the present study is improvement in CVLTII-TR. This confirms previous results obtained by Hedayati et al., in which considerable improvement was seen in verbal learning memory. It should be pointed out that work of Hedayati et al. was conducted on healthy participants and this is in contrast with results of Sedighi et al. The reason that Boswellia improved analyzed cognitive skill in MS patients in the auditory verbal learning test (CVLTII-TR) might be due to its dose-dependent effect. Our results are also confirmed by Farshchi et al. and Mahmudi et al. Their study showed that the effect of Boswellia on rats’ visual memory was dose dependent. Since we have used 450 mg capsule (twice a day) in the present study, significant changes observed in CVLTII-TR might be due to increasing dosage of Boswellia. This is contrary to the findings of Sedighi et al. More studies are recommended with more patients, longer use and higher dosage of Boswellia, to assess the effect of Boswellia by other tests and to recognize the mechanism of its effect.
5. Conclusion BS improves CVLT and BVMT in RRMS patients without major depression who had subjective complaints of CI. It does not improve processing speed (auditory and visual), verbal fluency, spatial processing and executive function.
6. Acknowledgement
This study was supported by the deputy of research of Ahvaz Jundishapur University of Medical Sciences. We would like to express our gratitude to the staffs of MS Association of Khuzestan province as well as pharmacological research center of medicinal plants in the faculty of Pharmacy of Ahvaz Jundishapur University of Medical Sciences. Also the authors would like to thank all colleagues who contributed to this study and the Golestan clinical research development unit.
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Tables and Figures: Table 1. Neuropsychometric batteries commonly used to measure CI in MS. Domain
MACFIMS
BICAMS
PASAT
1
PASAT
-
Processing speed (visual)
SDMT
2
SDMT
SDMT
Verbal memory (learning and recall)
SRT 3
Processing speed (auditory) and working memory
BRN-B
5
Visual/spatial memory (learning and recall)
SPART
Verbal fluency
COWAT 7
CVLT-II 4
CVLT-II
6
BVMT-R
BVMT-R COWAT 8
Spatial processing
-
JLO
Executive function
-
D-KEFS 9
-
BVMT-R, brief visuospatial memory test – revised; COWAT, controlled oral word association test; CVLT-II, California verbal learning test second edition; D-KEFS, Delis- Kaplan executive function system; JLO, judgment of line orientation test; PASAT, paced auditory serial addition test; SDMT, symbol digit modalities test; SPART, spatial recall test; SRT, selective reminding test.
Table 2. Characteristics of participants demographics at baseline (day 0). Characteristic Age (years) Mean±SD
Treatment (n=30)
Placebo (n=30)
0.531 30.17±8.68
31.5±7.69 0.774
Gender, n (%) Male Female
8 (26.7%) 22 (73.3%)
9 (30%) 21 (70%) 0.773
Disease Duration Mean±SD
p value
4.23±2.39
4.43±2.92
Table 3. Neuropsychological test scores at baseline and on day 60 of the study. Neuropsychological test SDMT Drug Placebo
Day 0 (baseline)
Day 60
P value (ANCOVA)
39.67±12.94 41.33±11.10
42.60±13.84 43.77±12.42
0.283
44.70±11.38 45.10±10.32
49.34±10.61 46.16±10.63
<0.01
Drug Placebo
11.63±5.60 11.80±6.21
14.23±6.43 14.14±5.73
0.506
BVMTR-TL Drug Placebo
17.1±7.5 16.44±8.4
21.36±6.34 18.25±7.9
<0.01
Drug Placebo
23.67±10.53 21.80±10.94
25.20±10.30 23.47±1o.64
0.900
Drug Placebo
36.60±16.37 37.82±15.85
37.87±15.89 39.25±13.71
0.601
Drug Placebo
18.30±6.30 17.90±5.14
19.03±6.13 18.67±5.69
0.607
CVLT2-TL Drug Placebo D-KEFS
COWAT
PASAT
JLO
Persian beck test and MSNQ questionnaire
Assessed for eligibility (n=125)
Excluded: (n=65) Not Cognitively Impaired (n=36) Depression (n=18) Other subtypes of MS (n=8) Receiving Corticosteroid (n=3) Included: (n=60)
Randomized
MACFIMS test
Boswellia Serrata treatment (n=30) After 2 months
Placebo treatment (n=30)
After 2 months
MACFIMS test
MACFIMS test
Analyzed (n=30)
Analyzed (n=30)
Figure 1. Study flowchart (Consort format). MACFIMS, minimum assessment of cognitive function in multiple sclerosis; MS, multiple sclerosis; MSNQ, MS neuropsychological questionnaire.
Figure 2. Mean values for CVLTII-TL test before and after treatment.
Figure 3. Mean values for BVMTR-TL test before and after treatment.
HO HOOC 1
H 3CCOO HOOC 2
O
O
H 3CCOO HOOC
HO HOOC 3
4
Figure 4. The four major pentacyclic triterpenic acids present in BA (Β-Boswellic Acid (1), Acetyl-β-Boswellic Acid (2), 11-keto-β-Boswellic Acid (3), Acetyl-11-keto-β-Boswellic Acid (4) (Rall et al., 1996).
Figure 5. The role of the 5-LO pathway in the generation of leukotrienes (LT’s) (Robbins et al., 2005)
Appendix: Questionnaires
Multiple Sclerosis Neuropsychological screening Questionnaire (MSNQ) Name: Date: Sex (circle one): Male / Female Very often. Very disruptive (4) 1. Are you easily distracted? 2. Do you lose your thoughts while listening to somebody speaks? 3. Are you slow when trying to solve problems? 4. Do you forget appointments? 5. Dou you forget what you read? 6. Do you have trouble describing shows or programs recently watched? 7. Do you need to have instructions repeated? 8. Do you have to be reminded to do tasks? 9. Do you forget errands that were planned? 10. Do you have difficulty answering questions? 11. Do you have difficulty keeping track of two things at once? 12. Do you miss the point of what someone is trying to say? 13. Do you have difficulty controlling impulses? 14. Do you laugh or cry with little cause? 15. Do you talk excessively or focus too much on your own interests?
Quite often. Interferes with life (3)
Occasionally. Seldom a problem (2)
Very rarely. No problem (1)
Never. Does not occur (0)
Persian beck depression inventory-fast screen (BDI-FS) questionnaire 1. Sadness 0 I do not feel sad. 1 I feel sad much of the time. 2 I am sad all time. 3 I am so sad or unhappy that I can't 2. Pessimism 0 I am not discouraged about my future. 1 I feel more discouraged about my future than I used to be. 2 I do not expect things to work out for me. 3 I feel my future in hopeless and will only get worse. 3. Past Failure 0 I do feel like a failure. 1 I have failed more than I should have. 2 As I look back, I see a lot of failure. 3 I feel I am a total failure as a person. 4. Loss of pleasure 0 I get as much pleasure as I ever did from the things I enjoy. 1 I don't enjoy things as much as I used to. 2 I get very little pleasure from the things I used to enjoy. 3 I can't get any pleasure from the things I used to enjoy. 5. Punishment Feeling 0 I don't feel I am being punished. 1 I feel I may be punished. 2 I expect to be punished. 3 I feel I am being punished. 6. Self- Dislike 0 I feel the same about myself as ever. 1 I have lost confidence in myself. 2 I am disappointed in myself. 3 I dislike myself. 7. Suicidal thoughts or Wishes 0 I don't have any thoughts of killing myself. 1 I have thoughts of killing myself, but I would not carry them out. 2 I would like to kill myself. 3 I would kill myself if I had the chance.