Mefloquine Induces Dose-Related Neurological Effects in a Rat Model

Dow, Geoffrey S.; Bauman, Roc; Caridha, Diana; Cabezas, Manuel Castro; Du, Fuliang; Gomez-Lobo, R.; Park, M.; Smith, Kirsten S.; Cannard, K.

doi:10.1128/aac.50.3.1045-1053.2006

Cited by 61 publications

(67 citation statements)

References 31 publications

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“…These results indicate that at the given doses supporting glia cells were affected. The present study is similar to a previous reported effect of higher dose mefloquine on brain stem nuclei [16].…”

Section: Discussionsupporting

confidence: 82%

Hippocampal Glial Degenerative Potentials of Mefloquine and Artequin in Adult Wistar Rats

Udoh

Ekanem

Ekong

et al. 2014

International Journal of Brain Science

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Mefloquine and Artequin are two effective antimalarial drugs currently in use in the treatment of uncomplicated malaria. This study was to investigate the hippocampal glial degenerative potentials of these drugs in adult Wistar rats. Forty-nine adult Wistar rats weighing 200 g were divided into groups 1-7. Group 1 served as the control that received distilled water, while groups 2-7 received oral doses of 0.86/1.07 mg/kg, 1.71/2.14 mg/kg, and 3.24/4.28 mg/kg of Artequin and 1.07 mg/kg, 2.14 mg/kg, and 4.28 mg/kg of Mefloquine. The treatment lasted for three days, and on day 4 the animals were sacrificed. Their hippocampi were preserved in neutral formal saline and processed by silver impregnation method. The histomorphology of the hippocampal sections of rats in the groups treated with 2.14 mg/kg and 4.28 mg/kg of Mefloquine and 0.86/1.07 mg/kg, 1.71/2.14 mg/kg, and 3.24/4.28 mg/kg of Artequin showed large and dense populations of astrocytes and astrocytes' processes, with either loss or reduction in the population of oligodendrocytes. There was also loss in the population of pyramidal neurons all compared with the control group. In conclusion, Mefloquine and Artequin administration induced dose-dependent reactive astrocytes and astrocytes' processes formation in the hippocampus. This may impair the uptake of neurotransmitter and alter neuronal environment thus altering the hippocampal function.

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Section: Discussionsupporting

confidence: 82%

Hippocampal Glial Degenerative Potentials of Mefloquine and Artequin in Adult Wistar Rats

Udoh

Ekanem

Ekong

et al. 2014

International Journal of Brain Science

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“…These are dose related, since they occur at a higher frequency at doses used for the treatment of malaria (26). Recently, we observed that in rats mefloquine induces dose-related ataxia and histopathologic injuries to the brain stem nuclei that control proprioception (12). The threshold dose for this effect was approximately equivalent to the rat equivalent of the human treatment dose (12).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous putative CNS targets have been proposed (reviewed in reference 12) in either in vitro or ex vivo contexts. Recent studies in our laboratory demonstrated mefloquine induction of brain stem histopathology consistent with direct cellular neurotoxicity in rats (12) and disruption of neuronal calcium homeostasis in vitro (14). The latter effect involves discharge of the endoplasmic reticulum (ER) calcium store and induction of a subsequent influx of calcium into the cell from the extracellular space (14).…”

mentioning

confidence: 99%

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

Caridha

Yourick

Cabezas

et al. 2008

Antimicrob Agents Chemother

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In previous studies, we have shown that mefloquine disrupts calcium homeostasis in neurons by depletion of endoplasmic reticulum (ER) stores, followed by an influx of external calcium across the plasma membrane. In this study, we explore two hypotheses concerning the mechanism(s) of action of mefloquine. First, we investigated the possibility that mefloquine activates non-N-methyl-D-aspartic acid receptors and the inositol phosphate 3 (IP3) signaling cascade leading to ER calcium release. Second, we compared the disruptive effects of mefloquine on calcium homeostasis to those of ionomycin in neuronal and nonneuronal cells. Ionomycin is known to discharge the ER calcium store (through an undefined mechanism), which induces capacitative calcium entry (CCE). In radioligand binding assays, mefloquine showed no affinity for the known binding sites of several glutamate receptor subtypes. The pattern of neuroprotection induced by a panel of glutamate receptor antagonists was dissimilar to that of mefloquine. Both mefloquine and ionomycin exhibited doserelated and qualitatively similar disruptions of calcium homeostasis in both neurons and macrophages. The influx of external calcium was blocked by the inhibitors of CCE in a dose-related fashion. Both mefloquine and ionomycin upregulated the IP3 pathway in a manner that we interpret to be secondary to CCE. Collectively, these data suggest that mefloquine does not activate glutamate receptors and that it disrupts calcium homeostasis in mammalian cells in a manner similar to that of ionomycin.Mefloquine is an antimalarial with utility for chemoprophylaxis and treatment. The drug has been associated with adverse central nervous system (CNS) effects in a dose-related manner (reviewed in reference 14). As a consequence, its continued use in an otherwise healthy population for prophylaxis is controversial. The precise etiology of mefloquine-induced adverse effects is unknown. There is clinical evidence that P glycoprotein polymorphisms are associated with adverse neurological outcomes (1). Numerous putative CNS targets have been proposed (reviewed in reference 12) in either in vitro or ex vivo contexts. Recent studies in our laboratory demonstrated mefloquine induction of brain stem histopathology consistent with direct cellular neurotoxicity in rats (12) and disruption of neuronal calcium homeostasis in vitro (14). The latter effect involves discharge of the endoplasmic reticulum (ER) calcium store and induction of a subsequent influx of calcium into the cell from the extracellular space (14). Initially we suspected that this effect might occur as a consequence of the inhibition of the thapsigargin-sensitive sarcoplasmic reticulum/ER Ca 2ϩ -ATPase (SERCA), followed by subsequent triggering of capacitative calcium entry (CCE). However, in subsequent gene expression studies, we observed that mefloquine failed to induce the downstream stress responses typical of thapsigargininduced ER calcium depletion (13). These observations suggested either that the interaction of mefloquine ...

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“…It has been known for decades that this class of drugs can precipitate unwanted neuropsychiatric effects [5]. Mefloquine appears to be the most dangerous of these drugs, since it is neurotoxic in animal models [26], and has been associated with sudden and irrational acts of extreme violence in humans [27]; Case Study Three in our lay series typifies this. The pharmacology of mefloquine is imperfectly un-derstood [28].…”

Section: Discussionmentioning

confidence: 99%

Evidence for Neurotoxicity from Quinoline Antimalaria Drugs: Four Personal Accounts

Croft¹,

Mawson²

2017

OJAS

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Background: The adverse effects of mefloquine and other quinoline antimalaria drugs can be severe and long-lasting. We believe that the trigger for these effects may be drug-induced hepatocellular damage that causes, firstly, a spillage of retinoids into the circulation (and hence a direct toxic effect on the brain and other target organs), and secondly, disruption of the liver-thyroid axis (and hence a pattern of specific bipolar symptoms such as is often seen in thyroid disease). Methods: We sought recently-published lay accounts of adverse effects in users of quinoline antimalaria drugs, to test these lay descriptions against our hypothesis on the likely pathogenesis of these effects. Results: We found six lay accounts that described four different experiences of adverse effects arising from the prophylactic use of quinoline antimalaria drugs. All four travellers were healthy, at the start of travel. Two of the travellers experienced severe psychoses, and one had a mild psychosis. The fourth traveller, a serving US soldier, killed 16 unarmed Afghan civilians. Analysis of these accounts shows that, based on our hypothesis, all four travellers had at least one risk factor (most commonly, concurrent alcohol use), for developing a severe reaction to their quinoline antimalaria drug. Our hypothesis therefore predicted a severe adverse drug reaction in each of these four travellers. We also identified a hitherto unrecognized risk factor for developing a severe reaction to quinoline antimalaria drugs-namely, the concurrent use of anabolic steroids. Conclusions: Lay accounts of drug adverse effects can help initiate or further develop medical hypotheses of their pathogenesis. We advise that the quinoline class of antimalaria drugs should be prescribed cautiously, and that mefloquine should not now be prescribed for malaria prophylaxis, under any circumstances whatsoever. Where persistent adverse effects have resulted from the historical use of quinoline antimalaria drugs, we propose a five-point management strategy that we believe will in most cases cause symptoms to abate rapidly: 1) stop taking the quinoline drug; 2) stop alcohol, and stop all other liver-damaging drugs, including anabolic steroids, hormonal contraception, hormone replacement therapy, recreational drugs, antidepressants, anxiolytics and hypnotics; 3) maintain good hydration, using non-fluoridated drinking water; 4) temporarily eliminate die-

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Mefloquine Induces Dose-Related Neurological Effects in a Rat Model

Cited by 61 publications

References 31 publications

Hippocampal Glial Degenerative Potentials of Mefloquine and Artequin in Adult Wistar Rats

Hippocampal Glial Degenerative Potentials of Mefloquine and Artequin in Adult Wistar Rats

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

Evidence for Neurotoxicity from Quinoline Antimalaria Drugs: Four Personal Accounts

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