Involvement of N-methyl-D-aspartate receptor in the delayed transneuronal regression of substantia nigra neurons in rats.

Abstract

The substantia nigra pars reticulata (SNr) receives both inhibitory GABAergic and excitatory glutamatergic afferents from diverse origins. Ischemic injury to the striatum and/or the globus pallidus causes delayed transneuronal death of the SNr neurons, in the course of which neuronal disinhibition induced by loss of GABAergic inputs is supposed to trigger a lethal hypermetabolic process. In the in vivo experiment presented herein, we clarified the role of glutamatergic action via the N-methyl-D-aspartate receptor in this cell death process. Continuous intraventricular infusion (0.5 microliter/h) of the N-methyl-D-aspartate receptor antagonist MK-801 (1000 micrograms/ml), or of saline (control group) was initiated 24 h after 2 h of transient middle cerebral artery (MCA) occlusion in rats, by which massive ischemic injury was produced in the striatopallidal regions. The measured rectal temperature was not significantly altered in the MK-801-infused and in the control rats throughout the time period examined. The rats were killed at 15 days after MCA occlusion. The volume of the focal ischemic infarction of the MK-801-infused group did not significantly differ from that of controls. Also, MK-801-infusion did not significantly ameliorate the nigral atrophy subsequent to MCA occlusion. In association with a marked depletion of GABAergic afferent fibers, neuronal cell number in the ipsilateral SNr was significantly decreased in the control group. In contrast, the neuronal cell loss in the nucleus was completely prevented in the MK-801-infusion group. The data suggested that withdrawal of GABAergic inputs may cause a severe imbalance between excitation and inhibition of the SNr neurons and may eventually result in neurotoxicity mediated by the N-methyl-D-aspartate receptor. Suppression of glutamatergic excitatory effects by suitable drugs may be a reasonable therapy for the transneuronal death of the SNr neurons.

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@article{Yamada1996InvolvementON, title={Involvement of N-methyl-D-aspartate receptor in the delayed transneuronal regression of substantia nigra neurons in rats.}, author={K Yamada and Shinichi Goto and Masayuki Yoshikawa and Atsushi Okamura and Yukitaka Ushio}, journal={Brain research}, year={1996}, volume={743 1-2}, pages={233-9} }