oxadiazoles and Cerebellar-Diseases

It has long been proposed that the excitatory and toxic properties of acidic amino acid receptor agonists are linked. To test this hypothesis, the depolarizing effects of quisqualate, kainate and N-methyl-D-aspartate in adult and immature rat cerebellar slices have been studied in relation to their neurotoxic effects in the same tissues (reported separately). A "grease-gap" method was used to measure the depolarizing responses of Purkinje cells and granule cells in lobule VI to the agonists. The depolarizing potencies of kainate and quisqualate were apparently similar on both cell types and at both ages studied although maximal responses to kainate were always larger. N-Methyl-D-aspartate was a very weak agonist in the adult slices but was much more effective in the immature tissues, apparently on both Purkinje cells and granule cells. Comparison of the depolarizing effects of the agonists with their neurotoxic effects on Purkinje cells and granule cells suggested that: (a) the ability to depolarize is a required condition for an agonist to be neurotoxic, (b) the magnitude of depolarization, rather than depolarizing potency, is the more pertinent determinant of neurotoxic potency and (c) resistance to the neurotoxicity of an agonist is not necessarily associated with resistance to its depolarizing actions. Histological studies indicated that the neurotoxicity of N-methyl-D-aspartate and kainate in immature cerebellar slices could largely not be replicated by veratridine (50 microM) or high extracellular K+ (124 mM) indicating that receptor-mediated ionic fluxes may be needed in addition to those caused by depolarization. Exposure of the slices to anoxia in the absence of glucose partially reproduced the toxicity of the receptor agonists. Application of ouabain for 30 min caused necrosis of all the cells which are vulnerable to the agonists but spared the cells which are not vulnerable. Profound ionic imbalance thus appears to be a sufficient explanation for amino acid neurotoxicity.

Topics: Age Factors; Animals; Aspartic Acid; Cerebellar Diseases; Female; In Vitro Techniques; Kainic Acid; Male; Membrane Potentials; N-Methylaspartate; Ouabain; Oxadiazoles; Purkinje Cells; Quisqualic Acid; Rats; Rats, Inbred Strains; Veratridine