Date of Award

1987

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

George M. Strain

Second Advisor

Phillip F. Von Voigtlander

Abstract

The mechanism underlying the anticonvulsant and cerebroprotective activity of U-50488H was evaluated using $\sp{45}$Ca$\sp{++}$ uptake in rat Ficoll purified synaptosomes, ($\sp3$H)-2-deoxyglucose uptake in selected mouse brain regions, ($\sp3$H)kainic acid binding to mouse forebrain synaptic membranes and incidence of KA-induced lesions in the CA3 region of the mouse hippocampus. U-50488H causes reduction in K$\sp+$-evoked $\sp{45}$Ca$\sp{++}$ uptake. These effects are comparable to those of the calcium channel blockers verapamil and nifedipine and seem to be related to calcium dependent mechanisms. Changes in saturability, specificity and dissociation constant values of kainic acid receptor binding were demonstrated in the presence of U-50488H at concentrations similar to those used in $\sp{45}$Ca$\sp{++}$ uptake studies and in the presence of calcium and chloride ions. The ability of U-50488H to block kainic acid binding was more pronounced on total specific binding than on high affinity binding. The effects of U-50488H on neuronal metabolism in areas associated with generation of seizures was evaluated. The kappa opiate anticonvulsant did not have pronounced inhibitory effects on cerebral metabolism and it did not block the activation of metabolism induced by the stimulation of kainic acid receptors. Significant differences were observed in the mean area of vacuolization induced by kainic acid in the CA3 area of the mouse hippocampus when comparing the U-50488H treated versus the neurotoxin treated group when assessed with parametric and non-parametric methods. The absence of kainic acid-induced vacuolization in the CA3 region of the hippocampus in the presence of U-50488H, and the requirement of calcium and chloride ions for U-50488H-increased affinity of KA at excitatory receptors and decreased B$\sb{\rm max}$ suggest that U-50488H interfered with a sequence of events induced by excitatory amino acids during the course of the neurodegenerative effects induced by seizures. U-50488H may be of potential value in the elucidation of the mechanisms underlying neuronal cell death after intense depolarization.

Pages

164

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