Ischemic tolerance in chemical preconditioning: possible role of astrocytic glutamine synthetase buffering glutamate-mediated neurotoxicity.

Glutamine synthetase (GS), localized to astrocyte is a key enzyme in the glutamate-glutamine pathway in the brain. 3-Nitropropionic acid (3-NPA) is an irreversible inhibitor of succinate dehydrogenase in the tricarboxylic-acid cycle, and provides ischemic tolerance to the brain. So far, there have been no reports on the relationship of astrocytic GS and ischemic tolerance by chemical preconditioning. In order to test the hypothesis that astrocytes serve a pivotal role in 3-NPA-induced chemical preconditioning, we have investigated the temporal profile of GS expression in astrocyte parallel with those of glial fibrillary acidic protein and heat-shock protein 70 (HSP70). In our rat model of permanent focal ischemia, preconditioning with 3-NPA singnificantly reduced the subsequent neurological deficits and infarct volume within 24-72 hours after treatment. Immunohistochemically, protoplasmic astrocytes in the cortex and striatum were activated in terms of upregulation of GS and more abundant protoplasmic processes with 3-NPA preconditioning, however, HSP70 expression could not be induced. Thus, the activation of astrocytes and upregulation of GS play an important role in 3-NPA-induced preconditioning but HSP70 does not. In view of glutamate being imposed on the cerebral ischemic damage, the astrocytic GS may contribute to 3-NPA-induced ischemic tolerance.