A new anti-obesity drug treatment: First clinical evidence that, antagonising glutamate-gated Ca 2+ ion channels with memantine normalises binge-eating disorders

Abstract

The regulation of appetite relies on complex hypothalamic neurocircuitry of which the arcuate nucleus, and the hormone leptin play important roles. Arcuate nucleus neurones are essential for the regulation of eating behaviour, but they can be intoxicated by elevated serum levels of the amino acid glutamate (GLU). Neurotoxic effects of GLU are mediated by the N-methyl- d-aspartate receptor (NMDA-R). But the neurotoxic effects of GLU can be prevented. Concurrent administration of dizocilpine maleate (MK-801), a selective and highly potent non-competitive NMDA-R antagonist, antagonises GLU-gated Ca 2+ ion channels and completely prevents the adverse effects of GLU. Also the non-competitive NMDA-R antagonist memantine displays neuroprotective properties. In view of a previously published hypothesis that human obesity results from chronic over-consumption of GLU, we performed a therapeutic trial in five obese, but otherwise healthy women. Memantine treatment markedly decreased appetite within few hours and complete suppressed the binge-eating disorder within 24 h. Body weight decreased markedly within a few days. The findings strongly support the hypothesis that elevated levels of nutritional GLU play an important role in the pathomechanism of human obesity. We suggest to treat human obesity by protecting the hypothalamic signalling cascade of leptin action with low to moderate affinity, non-competitive NMDA-R antagonists that selectively block the GLU-gated Ca 2+ ion channels.