SBIR-STTR Award

There is evidence that the excitotoxic action resulting from excessive accumulation of L-glutamate plays a prominent role in human epilepsy and brain ischemia/stroke, leading to neuronal dysfunction and cell death. The triazolines and the aminoalkylpyridine metabolite analogues are a group of novel anticonvulsants; they are be effective in the kindling and in the maximal electroshock seizure models of epilepsy, the best analogies to human partial seizures, and work by impairing excitatory amino acid neurotransmission at both post and presynaptic sites. Thus, it appears logical to expect that the anticonvulsant triazolines and metabolite analogues may have some beneficial therapeutic potential in cerebral ischemia. Our objective is to assess the ability of these anticonvulsants to reduce or prevent neuronal damage utilizing the bilateral carotid occlusion model in unanesthetized gerbil, which eliminates the protective effect of anesthesia as a variable. The gerbils undergo a predictable pattern of behavioral changes; the effects of drugs on these changes in producing alterations in this pattern will be monitored by determining the postischemic changes in spontaneous locomotor activity as well as by changes in radial arm maze performance. The postischemic changes in locomotor activity provide a reliable and reproducible first assessment data on neurological status. The applicant provides fairly extensive review of the triazohne anticonvulsants and their possible dual action mechanism for impairing excitatory amino acid neurotransmission. Basically, there is some evidence that suggests that the triazolines affect the post synaptic excitatory amino acid receptor as well as the presynaptic release of L- glutamate. This dual action mechanism may make these compounds rather potent in combating the neurotoxic effects of excessive excitatory amino acid release following injury and/or epilepsy. The applicant also cites evidence suggesting that the triazolines are lipophilic and can cross the blood brain barrier where the prodrug form enters the brain and then is metabolized within it. Most NMDA antagonists which are potent anticonvulsants and neuroprotective agents in a variety of tests must be administered into the ventricles because their activity is compromised when administered systemically. The basic protocols to be used include the measurement of locomotor activity following acute doses to determine direct behavioral effects of these drugs. Then the effects of pre-treatment doses on the outcome of a five minute period of bilateral carotid occlusion will be tested, and finally the effects of administration of these compounds after an ischemic attack where treatment has been initiated. These appear to be fairly simple types of approaches.Awardee's statement of the potential commercial applications of the research: 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 anticonvulsant agents to be evaluated in this proposal are orally effective with high therapeutic indices and act by impairing excessive glutamate neurotransmission, the primary cause of neuronal cell death in epilepsy and stroke. Thus, they have good commercial potential as safer, clinically useful, orally active drugs in the management of cerebral ischemia/stroke.National Institute of Neurological Disorders and Stroke (NINDS)

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.