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A new hypothesis on preventable neuropsychiatric illness in Africa
Medical Hypotheses 83 (2014) 16–20
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A new hypothesis on preventable neuropsychiatric illness in Africa Gregor Pollach ⇑, Kai Jung, Felix Namboya University of Malawi, College of Medicine, Department of Anaesthesia and Intensive Care, Malawi
a r t i c l e
i n f o
Article history: Received 13 February 2014 Accepted 13 April 2014
a b s t r a c t Background: Communicable diseases are still the most important public health challenge in Africa. Many of them such as malaria, schistosomiasis and pneumonia are frequently treated with quinoline derived substances, which are known to have neuropsychiatric side effects. Millions of Africans have to take two or three of them simultaneously (e.g. quinine and ciprofloxacin or praziquantel). Almost nothing is known about their additive effects or interactions. Hypothesis: We hypothesize, that a parallel therapy with quinoline derived antimicrobial substances leads to a preventable neuropsychiatric syndrome and suggest to find the joint pathobiochemical explanation for this condition in the l-Tryptophane–Kynurenine–Serotonine pathway. Discussion: Almost all intermediary substances of the Kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid and serotonin) are known to have neuropsychiatric properties on their own. Direct interactions between quinolines and the oxygenases of the pathway (especially with the indoleamine (2,3)-dioxygenase and kynurenine-monoxygenase) and indirect influences via the interferon-c induced breakdown of tryptophane are discussed, as well as the modifying effect of the already existing neurotoxicity of the single quinoline related drug used. Three different mechanisms were discovered which can influence the complex, well balanced biochemical equilibrium of the kynurenine pathway. Due to the complexity of the pathway and the fact that all substances have their own, even contradictory, neuropsychiatric properties, we do not argue that through a certain type of postulated metabolism a certain drug might have a specific effect, but we do hypothesize that it is the disturbance of a well balanced equilibrium which makes a neuropsychiatric effect of the parallel antimicrobial therapy with quinolines more than probable. Consequences: If confirmed, our hypothesis demonstrates that parallel therapy with quinoline antimicrobials constitutes an under addressed public health challenge in Africa with severe diagnostic, therapeutic and financial implications. The individual physician has to take a new entity into account for the neuropsychiatric differential diagnosis, especially in patients suffering from another neurological illness, being treated with efavirenz or belonging to high risk groups affecting the health of others like mini-bus drivers. Further direct consequences apply to physicians in the rich countries dealing with migrants, refugees, long term expats or professional groups in need of a high level of psychological stability, good judgement and fine motor skills. Conclusion: The hypothesis needs urgent confirmation in a randomized, prospective trial comparing levels of quinolinic acid etc., in patients on quinoline treatment versus a quinoline-naïve patients for several body fluids and ideally in the brain post-mortem. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Infectious diseases are a major public health concern in African countries. Several of the most important infectious diseases such as ⇑ Corresponding author. Address: University of Malawi, Department of Anaesthesia and Intensive Care, Blantyre 3, Chichiri, Blantyre, P.B.: 360, Malawi, Africa. Tel.: +265 999289570. E-mail addresses: [email protected], [email protected] (G. Pollach). http://dx.doi.org/10.1016/j.mehy.2014.04.018 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
malaria, schistosomiasis, cysticercosis, typhoid fever, pneumonia and sepsis are routinely treated by antimicrobial substances [1,2] known for neurotoxic or psychotoxic side effects. These unwanted effects include insomnia, anxiety, restlessness, mood imbalances, nausea, impaired vision, tinnitus or even convulsions, depression, hallucinations and psychosis or suicide [3]. Millions of patients in Africa take several of these common drugs simultaneously.
G. Pollach et al. / Medical Hypotheses 83 (2014) 16–20
Even when each single antimicrobial therapy usually is of short duration, we deal with a medium to long term application of these drugs because of their overlapping and recurrent application. Malaria is treated e.g. in Malawi (14 million inhabitants) more than 7 million times – meaning several times per year for the patients living in the endemic areas. Pupils are mass-treated against bilharzias various times during their time in school and sepis or pneumonia are treated around the year by quinolines, because no modern antibiotics are available [5a–c] A closer look shows, that most of these substances belong to the chemical class of the quinolines (for malaria: quinine, chloroquine, lumefantrine, mefloquine; for schistosomiasis and cysticercosis: praziquantel; for the bacterial diseases: ciprofloxacin, norfloxacin, levofloxacin; and also hydroxychloroquine [4]). Despite their abundant parallel use and their well known neurological side effects, almost nothing is known concerning their possible additive or synergistic neuropsychological drug interactions [5]. The hypothesis We hypothesize, that a parallel therapy with several common quinoline derived antimicrobial substances in Africa leads, to defined, preventable, neuropsychiatric conditions in the resource poor countries of the continent. We suggest, that the patho-biochemical explanation for this condition, can be found in the L-Tryptophane–Kynurenine–Serotonine pathway. Three different mechanisms which influence the complex, well balanced biochemical equilibrium of the pathway are evaluated. The basis of the hypothesis In recent years evidence has evolved that the tryptophan–kynurenine–serotonin pathway is involved in the development of several neuropsychiatric disorders like fear [6], depression [7,8], schizophrenia [9], AIDS–dementia complex [10] or Parkinsons disease [10a]. Kynurenic acid [7,14], kynurenine [8], quinolinic acid [15–17], tryptophan [18], 5-HTP [19], 3-OH-kynurenine [7] and serotonin [20,21] – all have neuropsychological effects. It is not always clear whether these effects are beneficial or detrimental as reports in the literature describe contradictory effects. For example, kynurenic acid has been described as neuroprotective in the case of depression [7] and as detrimental in the case of cognitive function [44] or schizophrenia [22,23]. Moreover not only chronic diseases are affected via this pathway, but even conditions, which are known to last only a short period of time like cerebral malaria [10b], postpartum depression [7] or a short therapy of depression through amantadine [10c] and ketamine [10d] (NMDA-receptor antagonists like kynurenic acid) are probably influenced. Considering the neuropsychological situation we obviously deal with a highly complex, very well balanced equilibrium. We postulate that the application of quinoline-derived antiinfectious substances will disturb this balance and will lead to neurological or psychological symptoms for the patient, especially when he is treated simultaneously with several substances of this group. We evaluate three mechanisms to provide a biochemical explanation. For a better biochemical understanding please see Figs. 1 and 2. Evaluation of the hypothesis Indirect influences We influence the different enzymes involved in the pathway and so indirectly disturb the equilibrium of the enzyme products.
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There is growing evidence that these substances and their immunmodulatory action influences the activity of the rate-limiting enzymatic step in the extrahepatic, cytokine inducible, conversion from tryptophane into kynurenine [24] through the indoleamine (2,3)dioxygenase (IDO) [7,25] and the kynurenin-monoxygenase KMO [22]. (a). Chloroquine reduces the activity in human mononuclear blood cells and suppresses, by a lower interferon-c (IFN-c) production, the IFN-c induced tryptophane breakdown [26]. This leads to more tryptophan and less kynurenine. (b). Hydroxychloroquine affects peripheral mononuclear blood cells through a reduction of IFN-c and influences so IDO and KMO [22], leading again to more tryptophan and less kynurenine. (c). Fluorquinolones (like ciprofloxacin, norfloxacin, levofloxacin) show agonist activity at the NMDA receptor [27], like quinolinic acid at the end of the pathway. The same was suggested for mefloquine [28]. (d). Praziquantel enhances the IFN-c production of CD8+ T Cells (Tc1) after DNA vaccination in mice [29], which would result in more products downstream from IDO and KMO. (e). Quinine treatment in severe malaria showed, in a randomised trial in Vietnam, a trend towards a higher concentration of quinolinic acid than arthemeter treatment [43]. (f). Enhanced metabolic function of IDO, KMO and Kinurenine hydroxilase through IF-c [7], will lead (due to the fact that more than 95% of trypthophane is metabolized this way) to a reduced amount of Serotonin. (g). In recent years the influence of the proinflammatory cytokines on the kynurenine pathway and the NMDA receptors is considered, in psychiatric research, as important enough to partly explain major depression. We should consider it relevant enough to explain temporary psychological imbalances through quinolines disturbing the balance of the pathway [lit.iIn 7]. Direct influences Quinolinic acid is considered to have considerable neurotoxic potential and is sometimes even called the ‘‘enemy at home’’ [42]. Nevertheless it is an important step in the end of the kynurenine pathway for the creation of niacin. We postulate, that during therapy with various quinolines there will be interaction between the quinolines and the almost ubiquitous IDO. This may result in a direct enhancement of the production of the NMDA agonist, quinolinic acid [7,30]. Even when there is no proof of the direct chemical conversion of a quinoline drug in the kynurenine pathway, there are, to the best of our knowledge, no studies showing the contrary in astrocytes and microglia cells, which are the cellular focus of the described hypothesis. There are different explanations for the neurotoxic side effects of the anti-infectious drugs used against malaria, schistosomiasis and bacterial infections in Africa, but there is no unifying theory available. This is especially surprising when we realize that many of the drugs known for neuropsychiatric side effects can be chemically identified as quinolines. At the same time the kynurenine pathway shows various biochemical features necessary to metabolize and degredate quinolines and related substances. (a). The chemical structure of quinolinic acid strikingly resembles a quinoline with a cleavaged pyrimidine ring [4]. The usual degredation process of quinolines is oxidation and we know that Praziquantel and Mefloquine are partially
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G. Pollach et al. / Medical Hypotheses 83 (2014) 16–20
Fig. 1. The kynurenine pathway (adapted after [12] from [13]).
Fig. 2. The quinoline structure [4,11].
eliminated through CYP P450, an non specific monoxygenase system [31]. In the kynurenine pathway we encounter several oxygenases. The elimination of tryptophan requires the opening of both aromatic rings through three oxygenases. The tryptophan2,3-dioxygenase, the kynurenin-3-monooxygenase and the 3-hydroxyanthranilat-3,4-dioxygenase. These are not very specific oxygenases and should be able to degredate at least a fraction of the appearing quinolines. (b). Furthermore we know that the pathway is able to reconstruct a real quinoline (kynurenic acid) [4] and to degrade it again to quinolinic acid [13]. The kynurenine pathway opens and closes a pyrimidine and an indol-ring. This suggests a 5-ring system containing a ‘‘N’’-atom like trypthophan and a 6-ring system with an ‘‘N’’-atom like quinolinic acid or kinurenic acid might be converted into each other [4,12]. (c). It is known that some cells can metabolize at least one quinoline–kynurenic acid. Astrocytes are unable to produce quinolinic acid (and via this way niacin for NAD), so that
the produced kynurenic acid (a quinoline) has to be channelled to the microglia, where it can be metabolized to quinolinic acid [34]. (d). Depending on the additional amount of metabolites and quinolinic acid [32,33] produced under the influence of quinoline related antimicrobial substances, the capacity of the enzymatic reactions might be overloaded, so that there will be a blockage in the capacity of KMO, KAT or IDO. This would lead to an enhanced production of 5-hydroxy-tryptophane in and outside the brain. 5-HPT can freely pass the blood brain barrier, as suggested by Fukuda 2013 in his 5-HTP-Schizophrenia Hypothesis [9]. This might enhance intracerebral serotonin with its typical influences on mood, sleep, cognition and memory. On the other hand the contrary might happen and a lack of serotonin might arise, because it is known that an enhanced provision with L-Tryptophan leads to an overproportional activity of the tryptophan-2,3-dioxygenase. This again demonstrates how delicate the system is balanced. We would like to stress the point again, that our hypothesis does not define the adverse effect of a specific substance, but the fact that the complex balance of the pathway´s equilibrium can be disturbed at various levels through the direct chemical processes proposed here, leading to unpredictable, but clinically important symptoms. Underlying influences The indirect and direct effects on the kynurenin pathway by the quinolines have to be evaluated in the light of the already known
G. Pollach et al. / Medical Hypotheses 83 (2014) 16–20
neuropsychiatric side effects of each single substance. Arguably the most challenging of them is mefloquine. It interacts with a whole number of receptor systems in our nervous system. Mefloquine influences the adenosine 2A receptor [35], inhibits acetylcholinesterase [36], enhances striatal GABA release [37] and blocks SERCA [38]. This suggests, that even minor additional influences through our hypothesis might have a considerable influence on a patients mental health. In a study by Gostner et al. the ratio Kynurenin/Trypthophan was increased approximately 100-fold through chloroquine in stimulated human blood cells [26], which shows that we have reason to believe that these effects are not negligible or minor. Summary of the hypothesis The L-Trypthophan–Kynurenine–Serotonin pathway provides us with a new view on neuropsychiatric side effects and interactions which may occur during simultaneous therapy with multiple quinolines. Three effects are of special interest: The pathway´s possible interactions with quinolines are complex and partly contradictory, so that a neurotoxic effect is made probable, but its clinical nature will be difficult to predict. Secondly, the most interesting substance to justify further efforts in research should be quinolinic acid and its ratio to kynurenic acid. Lastly, but most importantly it is the disturbance of a well balanced neuropsychological equilibrium which matters and leads to clinical effects and not so much a single substance which might be singled out. Consequences of the hypothesis If the proposed hypothesis is confirmed, then it suggests that parallel therapy with quinoline derived anti-infective substances is an under addressed public health challenge in tropical countries. This has important diagnostic, therapeutic and financial implications for the treatment of some of the most prevalent diseases in resource poor countries. Nevertheless some might even proof to ease financial pressures like a possible reduction of extensive neurological evaluations (CT scans and MRIs) through a thoroughly conducted anamnestic evaluation. On the individual level of the patient, doctors have to take a new diagnostic entity into account concerning their neuropsychiatric differential diagnoses. In order to avoid this preventable iatrogenic condition, physicians have to carefully consider alternative treatment options to avoid parallel quinoline therapy, especially in patients presenting with any other kind of neuropsychological illness. This is not only true for the typical poor, African with multiple diseases, but also for the travel medicine physician, in richer countries, where they may be dealing with migrants, refugees, long term expatriate or professional groups needing a high level of psychological stability, good judgement and fine motor skill. The diagnosis of quinoline related neurotoxicity might prove beneficial to both patients suffering from HIV receiving a therapeutic regime containing drugs with neuropsychological side effects such as efavirenz [39] and the wider public. There is a very high incidence of morbidity and mortality associated with motor vehicle accidents in most African countries; countries endemic for infectious diseases treated with quinolines [40]. The addition of quinoline related neurotoxicity might further enhance the risk for accidents in a high risk group of patients where HIV, high risk taking behaviour and alcohol use is already prevalent, namely the African minibus driver. Professional drivers should be worthy of a specially cautious evaluation when treated with quinolines.
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Testing the hypothesis We would suggest the following experimental approach to confirm our hypothesis. 1. A randomized, prospective study should be carried out for patients receiving quinoline treatment versus a quinoline-naïve control group in a country which provides a high number of patients with parallel treatment for malaria, schistosomiasis, typhoid fever, pneumonia and sepsis (e.g. Malawi). Measurements for quinolinic acid, kynurenic acid, Kynurenine, tryptophane, serotonin and IDO, should be obtained from specimens of csf, blood, urine and bowel lumen contents. In the second, and probably more important group, measurements should be taken from the brain (microglia and astrocytes of non-survivors) at a post-mortem. 2. In parallel an evaluated neuropsychological test tool (e.g. a questionnaire) should be filled out to correlate the neuropsychiatric situation with the amount of excreted metabolites. A subgroup here could be established for HIV reactive patients with and without efavirenz treatment. 3. All surviving patients showing neurotoxic side effects can then be treated with COX-2-Inhibitors (with a repetition of all measurements) in order to counteract the effect of quinolinic acid [7,41]. 4. Together this would give a good indication as to whether the hypothesis is worthy of further scrutiny. Conflict of interest/funding disclosure There is no conflict of interest concerning the above presented hypothesis and there was no funding for its development. Acknowledgement To the late Dr.rer. nat. Walter Bubeck, who taught me to see the beauty and function behind chemical formalisms. References [1] Ministry of Health. Malawi Standard Treatment Guidelines (MSTG). Ministry of Health, 2009; 4th Edition. [2] Cook GC, Zumla A (ed.), Manson’s Tropical Diseases. 21 ed. Saunders; 2003: 1291. [3] British National Formulary. 55, Informations on praziquantel, mefloquin, ciprofloxacin, efavirenz. Ed.: 2009. [4] Moss GP, Powell WH. Revision of the extended Hantzsch–Widmann system of nomenclature for Heteromonocycles. Pure Appl Chem 1983;55:409–16. [5] (a) Pollach G. Neurotoxicity of quinoline-related anti-infectives an underestimated burden of the health care systems in Africa? e-first publication Gesundheitsökonomie Qualitätsmanagement 2013. http:// dx.doi.org/10.1055/s-0033-1335753; (b) Ministry of Health; Malawi Standard Treatment Guidelines, ((MSTG), Ministry of, Health, 2009, 4th Edition.; (c) Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world role in the treatment of malaria. Malaria 2013. [6] Lapin IP. Neurokynurenines (NEKY) as com mon neurochemical links of stress and anxiety. Adv Exp Med Biol 2003;527:121–5. [7] Müller N, Schwarz MJ. Immunological aspects of depressive disorders. Nervenarzt 2007;78:1261–73. [8] Wichers MC, Koek GH, Robaeys G, et al. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 2005;10:538–44. [9] Fukuda K. 5-HTP hypothesis of schizophrenia. Med Hypothesis 2014;82:20–3. [10] (a) Cotton P. AIDS dementia may be linked to metabolite of tryptophan. JAMA 1990;264:305–6; (b) Szabó N, Kincses ZT, Toldi J, Vécsei L. Altered tryptophan metabolism in Parkinson’s disease a possible novel therapeutic approach. J Neurol Sci 2011;310(1–2):256–60; (c) Idro R, Marsh K, John CC, Newton CRJ. Cerebral malaria; mechanisms of brain injury and strategies for improved neuro-cognitive outcome. Pediatr Res 2010;68(4):267–74; (d) Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry 1999;32:47–55;
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A new hypothesis on preventable neuropsychiatric illness in Africa Gregor Pollach ⇑, Kai Jung, Felix Namboya University of Malawi, College of Medicine, Department of Anaesthesia and Intensive Care, Malawi
a r t i c l e
i n f o
Article history: Received 13 February 2014 Accepted 13 April 2014
a b s t r a c t Background: Communicable diseases are still the most important public health challenge in Africa. Many of them such as malaria, schistosomiasis and pneumonia are frequently treated with quinoline derived substances, which are known to have neuropsychiatric side effects. Millions of Africans have to take two or three of them simultaneously (e.g. quinine and ciprofloxacin or praziquantel). Almost nothing is known about their additive effects or interactions. Hypothesis: We hypothesize, that a parallel therapy with quinoline derived antimicrobial substances leads to a preventable neuropsychiatric syndrome and suggest to find the joint pathobiochemical explanation for this condition in the l-Tryptophane–Kynurenine–Serotonine pathway. Discussion: Almost all intermediary substances of the Kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid and serotonin) are known to have neuropsychiatric properties on their own. Direct interactions between quinolines and the oxygenases of the pathway (especially with the indoleamine (2,3)-dioxygenase and kynurenine-monoxygenase) and indirect influences via the interferon-c induced breakdown of tryptophane are discussed, as well as the modifying effect of the already existing neurotoxicity of the single quinoline related drug used. Three different mechanisms were discovered which can influence the complex, well balanced biochemical equilibrium of the kynurenine pathway. Due to the complexity of the pathway and the fact that all substances have their own, even contradictory, neuropsychiatric properties, we do not argue that through a certain type of postulated metabolism a certain drug might have a specific effect, but we do hypothesize that it is the disturbance of a well balanced equilibrium which makes a neuropsychiatric effect of the parallel antimicrobial therapy with quinolines more than probable. Consequences: If confirmed, our hypothesis demonstrates that parallel therapy with quinoline antimicrobials constitutes an under addressed public health challenge in Africa with severe diagnostic, therapeutic and financial implications. The individual physician has to take a new entity into account for the neuropsychiatric differential diagnosis, especially in patients suffering from another neurological illness, being treated with efavirenz or belonging to high risk groups affecting the health of others like mini-bus drivers. Further direct consequences apply to physicians in the rich countries dealing with migrants, refugees, long term expats or professional groups in need of a high level of psychological stability, good judgement and fine motor skills. Conclusion: The hypothesis needs urgent confirmation in a randomized, prospective trial comparing levels of quinolinic acid etc., in patients on quinoline treatment versus a quinoline-naïve patients for several body fluids and ideally in the brain post-mortem. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Infectious diseases are a major public health concern in African countries. Several of the most important infectious diseases such as ⇑ Corresponding author. Address: University of Malawi, Department of Anaesthesia and Intensive Care, Blantyre 3, Chichiri, Blantyre, P.B.: 360, Malawi, Africa. Tel.: +265 999289570. E-mail addresses: [email protected], [email protected] (G. Pollach). http://dx.doi.org/10.1016/j.mehy.2014.04.018 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
malaria, schistosomiasis, cysticercosis, typhoid fever, pneumonia and sepsis are routinely treated by antimicrobial substances [1,2] known for neurotoxic or psychotoxic side effects. These unwanted effects include insomnia, anxiety, restlessness, mood imbalances, nausea, impaired vision, tinnitus or even convulsions, depression, hallucinations and psychosis or suicide [3]. Millions of patients in Africa take several of these common drugs simultaneously.
G. Pollach et al. / Medical Hypotheses 83 (2014) 16–20
Even when each single antimicrobial therapy usually is of short duration, we deal with a medium to long term application of these drugs because of their overlapping and recurrent application. Malaria is treated e.g. in Malawi (14 million inhabitants) more than 7 million times – meaning several times per year for the patients living in the endemic areas. Pupils are mass-treated against bilharzias various times during their time in school and sepis or pneumonia are treated around the year by quinolines, because no modern antibiotics are available [5a–c] A closer look shows, that most of these substances belong to the chemical class of the quinolines (for malaria: quinine, chloroquine, lumefantrine, mefloquine; for schistosomiasis and cysticercosis: praziquantel; for the bacterial diseases: ciprofloxacin, norfloxacin, levofloxacin; and also hydroxychloroquine [4]). Despite their abundant parallel use and their well known neurological side effects, almost nothing is known concerning their possible additive or synergistic neuropsychological drug interactions [5]. The hypothesis We hypothesize, that a parallel therapy with several common quinoline derived antimicrobial substances in Africa leads, to defined, preventable, neuropsychiatric conditions in the resource poor countries of the continent. We suggest, that the patho-biochemical explanation for this condition, can be found in the L-Tryptophane–Kynurenine–Serotonine pathway. Three different mechanisms which influence the complex, well balanced biochemical equilibrium of the pathway are evaluated. The basis of the hypothesis In recent years evidence has evolved that the tryptophan–kynurenine–serotonin pathway is involved in the development of several neuropsychiatric disorders like fear [6], depression [7,8], schizophrenia [9], AIDS–dementia complex [10] or Parkinsons disease [10a]. Kynurenic acid [7,14], kynurenine [8], quinolinic acid [15–17], tryptophan [18], 5-HTP [19], 3-OH-kynurenine [7] and serotonin [20,21] – all have neuropsychological effects. It is not always clear whether these effects are beneficial or detrimental as reports in the literature describe contradictory effects. For example, kynurenic acid has been described as neuroprotective in the case of depression [7] and as detrimental in the case of cognitive function [44] or schizophrenia [22,23]. Moreover not only chronic diseases are affected via this pathway, but even conditions, which are known to last only a short period of time like cerebral malaria [10b], postpartum depression [7] or a short therapy of depression through amantadine [10c] and ketamine [10d] (NMDA-receptor antagonists like kynurenic acid) are probably influenced. Considering the neuropsychological situation we obviously deal with a highly complex, very well balanced equilibrium. We postulate that the application of quinoline-derived antiinfectious substances will disturb this balance and will lead to neurological or psychological symptoms for the patient, especially when he is treated simultaneously with several substances of this group. We evaluate three mechanisms to provide a biochemical explanation. For a better biochemical understanding please see Figs. 1 and 2. Evaluation of the hypothesis Indirect influences We influence the different enzymes involved in the pathway and so indirectly disturb the equilibrium of the enzyme products.
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There is growing evidence that these substances and their immunmodulatory action influences the activity of the rate-limiting enzymatic step in the extrahepatic, cytokine inducible, conversion from tryptophane into kynurenine [24] through the indoleamine (2,3)dioxygenase (IDO) [7,25] and the kynurenin-monoxygenase KMO [22]. (a). Chloroquine reduces the activity in human mononuclear blood cells and suppresses, by a lower interferon-c (IFN-c) production, the IFN-c induced tryptophane breakdown [26]. This leads to more tryptophan and less kynurenine. (b). Hydroxychloroquine affects peripheral mononuclear blood cells through a reduction of IFN-c and influences so IDO and KMO [22], leading again to more tryptophan and less kynurenine. (c). Fluorquinolones (like ciprofloxacin, norfloxacin, levofloxacin) show agonist activity at the NMDA receptor [27], like quinolinic acid at the end of the pathway. The same was suggested for mefloquine [28]. (d). Praziquantel enhances the IFN-c production of CD8+ T Cells (Tc1) after DNA vaccination in mice [29], which would result in more products downstream from IDO and KMO. (e). Quinine treatment in severe malaria showed, in a randomised trial in Vietnam, a trend towards a higher concentration of quinolinic acid than arthemeter treatment [43]. (f). Enhanced metabolic function of IDO, KMO and Kinurenine hydroxilase through IF-c [7], will lead (due to the fact that more than 95% of trypthophane is metabolized this way) to a reduced amount of Serotonin. (g). In recent years the influence of the proinflammatory cytokines on the kynurenine pathway and the NMDA receptors is considered, in psychiatric research, as important enough to partly explain major depression. We should consider it relevant enough to explain temporary psychological imbalances through quinolines disturbing the balance of the pathway [lit.iIn 7]. Direct influences Quinolinic acid is considered to have considerable neurotoxic potential and is sometimes even called the ‘‘enemy at home’’ [42]. Nevertheless it is an important step in the end of the kynurenine pathway for the creation of niacin. We postulate, that during therapy with various quinolines there will be interaction between the quinolines and the almost ubiquitous IDO. This may result in a direct enhancement of the production of the NMDA agonist, quinolinic acid [7,30]. Even when there is no proof of the direct chemical conversion of a quinoline drug in the kynurenine pathway, there are, to the best of our knowledge, no studies showing the contrary in astrocytes and microglia cells, which are the cellular focus of the described hypothesis. There are different explanations for the neurotoxic side effects of the anti-infectious drugs used against malaria, schistosomiasis and bacterial infections in Africa, but there is no unifying theory available. This is especially surprising when we realize that many of the drugs known for neuropsychiatric side effects can be chemically identified as quinolines. At the same time the kynurenine pathway shows various biochemical features necessary to metabolize and degredate quinolines and related substances. (a). The chemical structure of quinolinic acid strikingly resembles a quinoline with a cleavaged pyrimidine ring [4]. The usual degredation process of quinolines is oxidation and we know that Praziquantel and Mefloquine are partially
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G. Pollach et al. / Medical Hypotheses 83 (2014) 16–20
Fig. 1. The kynurenine pathway (adapted after [12] from [13]).
Fig. 2. The quinoline structure [4,11].
eliminated through CYP P450, an non specific monoxygenase system [31]. In the kynurenine pathway we encounter several oxygenases. The elimination of tryptophan requires the opening of both aromatic rings through three oxygenases. The tryptophan2,3-dioxygenase, the kynurenin-3-monooxygenase and the 3-hydroxyanthranilat-3,4-dioxygenase. These are not very specific oxygenases and should be able to degredate at least a fraction of the appearing quinolines. (b). Furthermore we know that the pathway is able to reconstruct a real quinoline (kynurenic acid) [4] and to degrade it again to quinolinic acid [13]. The kynurenine pathway opens and closes a pyrimidine and an indol-ring. This suggests a 5-ring system containing a ‘‘N’’-atom like trypthophan and a 6-ring system with an ‘‘N’’-atom like quinolinic acid or kinurenic acid might be converted into each other [4,12]. (c). It is known that some cells can metabolize at least one quinoline–kynurenic acid. Astrocytes are unable to produce quinolinic acid (and via this way niacin for NAD), so that
the produced kynurenic acid (a quinoline) has to be channelled to the microglia, where it can be metabolized to quinolinic acid [34]. (d). Depending on the additional amount of metabolites and quinolinic acid [32,33] produced under the influence of quinoline related antimicrobial substances, the capacity of the enzymatic reactions might be overloaded, so that there will be a blockage in the capacity of KMO, KAT or IDO. This would lead to an enhanced production of 5-hydroxy-tryptophane in and outside the brain. 5-HPT can freely pass the blood brain barrier, as suggested by Fukuda 2013 in his 5-HTP-Schizophrenia Hypothesis [9]. This might enhance intracerebral serotonin with its typical influences on mood, sleep, cognition and memory. On the other hand the contrary might happen and a lack of serotonin might arise, because it is known that an enhanced provision with L-Tryptophan leads to an overproportional activity of the tryptophan-2,3-dioxygenase. This again demonstrates how delicate the system is balanced. We would like to stress the point again, that our hypothesis does not define the adverse effect of a specific substance, but the fact that the complex balance of the pathway´s equilibrium can be disturbed at various levels through the direct chemical processes proposed here, leading to unpredictable, but clinically important symptoms. Underlying influences The indirect and direct effects on the kynurenin pathway by the quinolines have to be evaluated in the light of the already known
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neuropsychiatric side effects of each single substance. Arguably the most challenging of them is mefloquine. It interacts with a whole number of receptor systems in our nervous system. Mefloquine influences the adenosine 2A receptor [35], inhibits acetylcholinesterase [36], enhances striatal GABA release [37] and blocks SERCA [38]. This suggests, that even minor additional influences through our hypothesis might have a considerable influence on a patients mental health. In a study by Gostner et al. the ratio Kynurenin/Trypthophan was increased approximately 100-fold through chloroquine in stimulated human blood cells [26], which shows that we have reason to believe that these effects are not negligible or minor. Summary of the hypothesis The L-Trypthophan–Kynurenine–Serotonin pathway provides us with a new view on neuropsychiatric side effects and interactions which may occur during simultaneous therapy with multiple quinolines. Three effects are of special interest: The pathway´s possible interactions with quinolines are complex and partly contradictory, so that a neurotoxic effect is made probable, but its clinical nature will be difficult to predict. Secondly, the most interesting substance to justify further efforts in research should be quinolinic acid and its ratio to kynurenic acid. Lastly, but most importantly it is the disturbance of a well balanced neuropsychological equilibrium which matters and leads to clinical effects and not so much a single substance which might be singled out. Consequences of the hypothesis If the proposed hypothesis is confirmed, then it suggests that parallel therapy with quinoline derived anti-infective substances is an under addressed public health challenge in tropical countries. This has important diagnostic, therapeutic and financial implications for the treatment of some of the most prevalent diseases in resource poor countries. Nevertheless some might even proof to ease financial pressures like a possible reduction of extensive neurological evaluations (CT scans and MRIs) through a thoroughly conducted anamnestic evaluation. On the individual level of the patient, doctors have to take a new diagnostic entity into account concerning their neuropsychiatric differential diagnoses. In order to avoid this preventable iatrogenic condition, physicians have to carefully consider alternative treatment options to avoid parallel quinoline therapy, especially in patients presenting with any other kind of neuropsychological illness. This is not only true for the typical poor, African with multiple diseases, but also for the travel medicine physician, in richer countries, where they may be dealing with migrants, refugees, long term expatriate or professional groups needing a high level of psychological stability, good judgement and fine motor skill. The diagnosis of quinoline related neurotoxicity might prove beneficial to both patients suffering from HIV receiving a therapeutic regime containing drugs with neuropsychological side effects such as efavirenz [39] and the wider public. There is a very high incidence of morbidity and mortality associated with motor vehicle accidents in most African countries; countries endemic for infectious diseases treated with quinolines [40]. The addition of quinoline related neurotoxicity might further enhance the risk for accidents in a high risk group of patients where HIV, high risk taking behaviour and alcohol use is already prevalent, namely the African minibus driver. Professional drivers should be worthy of a specially cautious evaluation when treated with quinolines.
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Testing the hypothesis We would suggest the following experimental approach to confirm our hypothesis. 1. A randomized, prospective study should be carried out for patients receiving quinoline treatment versus a quinoline-naïve control group in a country which provides a high number of patients with parallel treatment for malaria, schistosomiasis, typhoid fever, pneumonia and sepsis (e.g. Malawi). Measurements for quinolinic acid, kynurenic acid, Kynurenine, tryptophane, serotonin and IDO, should be obtained from specimens of csf, blood, urine and bowel lumen contents. In the second, and probably more important group, measurements should be taken from the brain (microglia and astrocytes of non-survivors) at a post-mortem. 2. In parallel an evaluated neuropsychological test tool (e.g. a questionnaire) should be filled out to correlate the neuropsychiatric situation with the amount of excreted metabolites. A subgroup here could be established for HIV reactive patients with and without efavirenz treatment. 3. All surviving patients showing neurotoxic side effects can then be treated with COX-2-Inhibitors (with a repetition of all measurements) in order to counteract the effect of quinolinic acid [7,41]. 4. Together this would give a good indication as to whether the hypothesis is worthy of further scrutiny. Conflict of interest/funding disclosure There is no conflict of interest concerning the above presented hypothesis and there was no funding for its development. Acknowledgement To the late Dr.rer. nat. Walter Bubeck, who taught me to see the beauty and function behind chemical formalisms. References [1] Ministry of Health. Malawi Standard Treatment Guidelines (MSTG). Ministry of Health, 2009; 4th Edition. [2] Cook GC, Zumla A (ed.), Manson’s Tropical Diseases. 21 ed. Saunders; 2003: 1291. [3] British National Formulary. 55, Informations on praziquantel, mefloquin, ciprofloxacin, efavirenz. Ed.: 2009. [4] Moss GP, Powell WH. Revision of the extended Hantzsch–Widmann system of nomenclature for Heteromonocycles. Pure Appl Chem 1983;55:409–16. [5] (a) Pollach G. Neurotoxicity of quinoline-related anti-infectives an underestimated burden of the health care systems in Africa? e-first publication Gesundheitsökonomie Qualitätsmanagement 2013. http:// dx.doi.org/10.1055/s-0033-1335753; (b) Ministry of Health; Malawi Standard Treatment Guidelines, ((MSTG), Ministry of, Health, 2009, 4th Edition.; (c) Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world role in the treatment of malaria. Malaria 2013. [6] Lapin IP. Neurokynurenines (NEKY) as com mon neurochemical links of stress and anxiety. Adv Exp Med Biol 2003;527:121–5. [7] Müller N, Schwarz MJ. Immunological aspects of depressive disorders. Nervenarzt 2007;78:1261–73. [8] Wichers MC, Koek GH, Robaeys G, et al. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 2005;10:538–44. [9] Fukuda K. 5-HTP hypothesis of schizophrenia. Med Hypothesis 2014;82:20–3. [10] (a) Cotton P. AIDS dementia may be linked to metabolite of tryptophan. JAMA 1990;264:305–6; (b) Szabó N, Kincses ZT, Toldi J, Vécsei L. Altered tryptophan metabolism in Parkinson’s disease a possible novel therapeutic approach. J Neurol Sci 2011;310(1–2):256–60; (c) Idro R, Marsh K, John CC, Newton CRJ. Cerebral malaria; mechanisms of brain injury and strategies for improved neuro-cognitive outcome. Pediatr Res 2010;68(4):267–74; (d) Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry 1999;32:47–55;
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