There is strong evidence that the 'excitotoxic' action resulting from the excessive accumulation of L-glutamate plays a prominent role in human epilepsy and brain ischemial stroke, leading to neuronal dysfunction and cell death. The triazolines (TRs). One group of novel anticonvulsants discovered in the principal investigator's laboratories, 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 TRs may evince beneficial therapeutic potential in cerebral ischemia resulting from stroke. In extensive preliminary studies, the ability of seven TRs to reduce or prevent neuronal damage was assessed in the gerbil model of global ischemia and the MCAO rat model of focal ischemia Out of the seven TRs tested, five afforded protection well over 60 percent, with four of the TRs showing protective effect in the range of 77-96 percent. Testing was done at three doses and in all cases; the protective ability of the TRs was clearly dose dependent. Evaluation of locomotor activity tests indicated no undue toxicity. The most active TR showed significant protective effect in postischemic treatments in the MCAO rat model, up to 50 percent, at a dose of 30 mg/kg x 3, one at the beginning, then 1 hr and 2 hrs of reperfusion. The objectives of Phase I of this Fast Track proposal are to test eight other selected structural analogues and establish antiischemic activity in the TRs as a class. Initially the TRs will be tested in the gerbil model and the most promising compound will be tested further for its protective effects, in both pre- and post-treatment studies, in the MCAO rat model of focal ischemia, a clinically relevant model that mimics human stroke. All compounds will be assessed by behavioral and histopathological tests. Active compounds, including those from the preliminary tests, will be the subject of intense study in the MCAO rat model, in both pre- and post-treatments in Phase II. PROPOSED COMMERCIAL APPLICATION: Currently there is a definite need for clinically effective drugs in the treatment of cerebral ischemia/stroke that afflict more than a million Americans annually. The TR anticonvulsants to be evaluated in this proposal are lipid soluble and orally effective with good therapeutic indices and seem to act by impairing the excessive glutamate neurotransmission, the primary cause of neuronal cell death in epilepsy and stroke. Thus the TRs have good commercial potential as clinically effective drugs in the management of cerebral ischemia/stroke.
