There is strong evidence that the """"""""excitotoxic"""""""" action resulting from the excessive accumulation of L-glutamate play a prominent role in human epilepsy and brain ischemia/stroke, leading to neuronal dysfunction and cell death. The triazolines and the aminoalkylpyridines (AAPs), two group of novel anticonvulsants discovered in the P.I.'s labs, are very effective in the kindling and in the maximal electroshock seizure models of epilepsy, the best analogies to human partial seizures, where excitatory amino acids play an important role, and appear to work by impairing glutamate neurotransmission. Thus it is logical to expect that the anticonvulsant triazolines and AAPs may evince beneficial therapeutic potential in cerebral ischemia. In Phase-I, the ability of two triazolines and three AAPs to reduce or prevent neuronal damage was assessed utilizing the gerbil model of global ischemia and the MCAO mouse model of focal ischemia. One triazoline prevented neuronal damage in both models as well as in the MCAO rat model as seen from preliminary studies, while on AAP was effective in gerbil model. The objectives of Phase-II are to test the antiischemic activity of additional structural analogues with significant anticonvulsant activity including AAP enantiomers. Initial testing will be done in the gerbil model, and the more promising compounds will be tested further for their protective effects in pretreatment studies in the rat MCAO (middle cerebral artery) model of the reversible focal ischemia, a clinically relevant model that mimics human stroke. Most active compounds will be the subject of post treatment studies. All compounds will be assessed by behavioral and histopathological tests. Active compounds will be patented and the most active will be developed to the IND status in collaboration with major a pharmaceutical company.
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