Neurotoxicity Associated with Mefloquine, an Anti-Malarial Drug

The objective of this proposal is to demonstrate that mitochondrial oxidative phosphorylation (OXPHOS) impairment is critical to development of mefloquine neurotoxicity and to develop a test that can screen for susceptibility to mefloquine neurotoxicity. The interaction between mefloquine and the endoplasmic reticulum (ER) induces a cascade of events leading to OXPHOS dysfunction. Mefloquine disrupts neuronal calcium homeostasis via liberation of the endoplasmic reticulum (ER) store and induction of calcium influx across the plasma membrane. Mitochondrial dysfunction is mediated by a variety of mechanism including increased calcium in mitochondria derived from ER. Once ATP synthesis by oxidative phosphorylation is impaired, the cellular toxicity of mefloquine is enhanced by mechanisms discussed below. We propose to test this hypothesis and develop testing that quantitates an individual’s cellular ATP generation in response to mefloquine. Given the complex nature of the neurotoxicity to mefloquine and the high frequency of adverse effects in the population, it is unlikely that a simple approach using single nucleotide polymorphisms will predict an individual’s susceptibility to neurotoxicity. Establishing a physiological assay that predicts mefloquine toxicity is more practical and has a higher likelihood of success and rapid implementation.