Abstract
In rodents, transient forebrain ischemia causes preferentially neuron death in small and medium size neurons of the striatum and hilar neurons in the hippocampus within 24 h, and CA1 hippocampal neurons within 72 h. The temporal unfolding of pathological processes after longer time intervals between reperfusion and sacrifice now includes delayed degeneration of the substantia nigra reticulata (SNr). Animals were exposed to 20 min of transient forebrain ischemia and sacrificed within 7 days, or at least 3 weeks after reperfusion. Histological examination and quantitative morphometrics revealed that the degree of volume loss and neuron loss in the SNr depended on the initial ischemic injury. Initial ischemic injury confined to the caudate nucleus produced volume loss but not neuron loss in the SNr. However, initial ischemic injury that included the caudate nucleus and the globus pallidus produced not only greater volume loss but also neuron loss in the SNr. SNr neuron loss was restricted to the medial dorsal area, occurred in animals that survived at least 3 weeks after perfusion, and did not occur in animals that survived 7 days after perfusion, and was accompanied by increased staining of antibody to glial fibrillary acidic protein. The topographic specificity and delayed time course suggest that the mechanism for SNr neuron loss depends on transneuronal events initiated by ischemia but evolving over a longer time period. In situ hybridization with a cDNA probe for glutamic acid decar☐ylase (GAD) mRNA demonstrated increased GAD signal in the remaining SNr neurons of animals with CN and GP damage compared to animals with CN damage. The significant increase in GAD mRNA may indicate compensation at the level of gene expression for the loss of GABAergic neurons. This rodent model offers new in vivo opportunities to elucidate the requirements for neuronal viability, and phenotypic expression, and suggests that the current notions of windows of opportunity for therapeutic intervention may be expanded from hours to days to weeks.
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