Role of glia in ischemia-induced and MPTP-induced neuronal deaths

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The purpose of this study was to clarify the role of glial cells in the development of ischemia-induced and MPTP-induced neuronal deaths. (1) Cerebral ischemia (10 min) was induced by the 2-vessel occlusion method in rats, which were sacrificed after 1 day, 2 days, and 7 days for double label immunohistochemistry. Expression of cell cycle proteins occurred prior to CAI neuronal death, and played a role in microglial proliferation. Proliferating cell nuclear antigen (PCNA) was expressed in 83% of microglial cells in CAI after 2 days. The number of microglial cells increased by 7.6-fold after 7 days CAI neurons were depleted. Cell cycle proteins, cyclin D1 and cdk4, were induced in microglia in a similar fashion. PCNA was expressed only in 6% of astrocytes in CAI after 7 days, when astroglial proliferation was only 1.8-fold. We observed no cell cycle protein expression in neurons. (2) MPTP (20 mg/kg) was injected i.p. 4 times 2 hr apart to mice. The content of dopamine in striatum was reduced to 16% of control after 1 day, and was remained as low as 22% after 14 days. ONO-2506, an astroglial function modulating agent, administered immediately, 6 hr, 24 hrs, 48 hrs, and 72 hrs after MPTP injection prevented the dopamine depletion, and led to better performance in behavioral tests. Astrocytes in striatum were activated markedly after 7 days, and ONO-2506 treatment resulted in earlier activation of asrtrocytes. The findings suggest that astrocytes may be a target for neuroprotection in MPTP induced neuronal death, and possibly in Parkinson's disease.