Trialkylglycines: a new family of compounds with in vivo neuroprotective activity.

Glutamate neurotoxicity is involved in the pathogenesis of neurodegenerative disorders such as Huntington's, Parkinson's and Alzheimer's diseases. It plays also a major role in the neuronal damage that occurs in brain ischemia and head trauma. Finding molecules that prevent or reverse glutamate neurotoxicity (excitotoxicity) is, therefore, of great interest. Strategies aimed at this end include the screening of libraries of compounds synthesized by combinatorial chemistry to find molecules that prevent neuronal death in vitro and in vivo. A library of trialkylglycines was screened to assess whether they prevent glutamate-induced neuronal death in primary cultures of cerebellar neurons. Two types of trialkylglycines have been found that significantly reduce the incidence of glutamate-induced neuronal death. The first type includes two compounds (referred to as 6-1-2 and 6-1-10) that efficiently prevent glutamate or NMDA-induced neuronal death. They also prevent excitotoxicity in vivo as assessed by using two animal models of excitotoxicity: acute intoxication with ammonia and a model of cerebral ischemia in rats. Trialkylglycines 6-1-2 and 6-1-10 prevent ammonia-induced (NMDA receptor-mediated) death of mice and neuronal degeneration in the model of cerebral ischemia. The trialkylglycines of the second type act as open channel blockers of the NMDA receptor. The first group of trialkylglycines does not block NMDA receptor channels and does not affect the glutamate-nitric oxide-cGMP pathway. Their molecular target has not yet been identified. These two types of trialkylglycines (especially those that do not affect NMDA receptor function) might represent effective drugs for the treatment of neurodegeneration. They are likely to be well tolerated and have fewer side effects than NMDA receptor antagonists.