Evidence to implicate early modulation of interleukin-1beta expression in the neuroprotection afforded by 17beta-estradiol in male rats undergone transient middle cerebral artery occlusion.

Neuroprotection exerted by 17beta-estradiol (17beta-E(2)) has been widely investigated in animal models of acute cerebral ischemia. Estrogens interact with intracellular receptors (ERalpha and ERbeta) to modulate the transcription of target genes, including those implicated in neuronal survival. Neuroprotection may also occur via interaction with ER-like membrane receptors mediating rapid, non-genomic, actions or via receptor-independent mechanisms. There is also evidence that blockade of inflammatory factors may represent an important mechanism involved in estrogenic neuroprotection. Here we investigate whether reduced brain damage by acute pharmacological treatment with 17beta-E(2) in male rats subjected to transient (2h) middle cerebral artery occlusion (tMCAo) involves modulation of interleukin-1beta (IL-1beta), a proinflammatory cytokine strongly implicated in the pathophysiology of ischemic stroke. Administration of 17beta-E(2) (0.2mg/kg, i.p., 1h before tMCAo) results in significant reduction of brain infarct volume, and this is reverted by the ER antagonist ICI 182,780 (0.25mg/kg, i.p.) administered 1h before 17beta-E(2). Two hours MCAo followed by 2-h reperfusion results in a significant, threefold increase of IL-1beta levels in the cortical tissue ipsilateral to the ischemic damage. Interestingly, a pretreatment with a neuroprotective dose of 17beta-E(2) attenuates the cytokine elevation and this appears to occur through ER activation. In addition, neuroprotection by 17beta-E(2) is accompanied by reduced cytochrome c translocation both in the striatum and in the cortex as revealed by Western blotting 3h after reperfusion. In conclusion, we report the original observation that neuroprotection exerted by 17beta-E(2) in a rat model of transient focal brain ischemia is accompanied by reduced cytochrome c translocation to the cytosol and involves early modulation of IL-1beta production.

Estradiol reduces cytochrome c translocation and minimizes hippocampal damage caused by transient global ischemia in rat.

It is well-established that 17beta-estradiol (17beta-E(2)) confers neuroprotection to male and female rats exposed to focal cerebral ischemia, while less is known about the effects of the hormone under conditions of transient global ischemia. Since translocation of cytochrome c from the mitochondria to the cytosol is a critical step in apoptotic cell death after cerebral ischemia, we have investigated whether 17beta-E(2) interferes with such mechanism to exert neuroprotection. Global ischemia, induced in male Wistar rats by 5-min 4 vessel occlusion (4VO), resulted in a significant increase of cytosolic cytochrome c (cyt-c) levels as detected by Western blotting at 6h after reperfusion. 17beta-E(2) (0.2mg/kg, i.p.) given 1h before ischemia minimized cytochrome c translocation and the latter effect was partially reversed by tamoxifen (0.25mg/kg, i.p.). Bilateral cell counting revealed that delayed hippocampal damage typically caused by 4VO was abolished by 17beta-E(2) and this was partially reversed by tamoxifen in the CA3 subregion, but not in CA1/CA2 or CA4. These findings provide the original observation that 17beta-E(2) reduces delayed hippocampal damage caused by 4VO in male rats and blocks cytochrome c translocation during the early stages of neuronal death, thus providing an important mechanism involved in estrogen-mediated neuroprotection.