Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats

The neuroprotective effects of menopausal hormonal therapy in Parkinson's disease have not yet been clarified, and it is not known whether there is a critical period. Estrogen induced significant protection against 6-hydroxydopamine-induced dopaminergic degeneration when administered immediately or 6 weeks, but not 20 weeks after ovariectomy. In the substantia nigra, ovariectomy induced a decrease in levels of estrogen receptor-α and increased angiotensin activity, NADPH-oxidase activity, and expression of neuroinflammatory markers, which were regulated by estrogen administered immediately or 6 weeks but not 20 weeks after ovariectomy. Interestingly, treatment with angiotensin receptor antagonists after the critical period induced a significant level of neuroprotection. In cultures, treatment with 1-methyl-4-phenylpyridinium induced an increase in astrocyte-derived angiotensinogen and dopaminergic neuron death, which were inhibited by estrogen receptor α agonists. In microglial cells, estrogen receptor β agonists inhibited the angiotensin-induced increase in inflammatory markers. The results suggest that there is a critical period for the neuroprotective effect of estrogen against dopaminergic cell death, and local estrogen receptor α and renin-angiotensin system play a major role.