Drug Potential of Anticonvulsants in Stroke Therapy

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Department of Health and Human Services
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Phase I
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Environmental Health Research
2514 Regency Road, Lexington, KY, 40503
Hubzone Owned:
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Socially and Economically Disadvantaged:
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 Pankaja K. Kadaba
 (606) 276-1436
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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 triazoline 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.

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