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

Neuroprotection exerted by 17 beta-estradiol (17 beta-E-2) has been widely investigated in animal models of acute cerebral ischemia. Estrogens interact with intracellular receptors (ER alpha and ER beta) 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 17 beta-E-2 in male rats subjected to transient (2 h) middle cerebral artery occlusion (tMCAo) involves modulation of interleukin-1 beta (IL-1 beta), a proinflammatory cytokine strongly implicated in the pathophysiology of ischemic stroke. Administration of 17 beta-E-2 (0.2 mg/kg, i.p., 1 h before tMCAo) results in significant reduction of brain infarct volume, and this is reverted by the ER antagonist ICI 182,780 (0.25 mg/kg, i.p.) administered I h before 17 beta-E-2. Two hours MCAo followed by 2-h reperfusion results in a significant, threefold increase of IL-1 beta levels in the cortical tissue ipsilateral to the ischemic damage. Interestingly, a pretreatment with a neuroprotective dose of 17 beta-E-2 attenuates the cytokine elevation and this appears to occur through ER activation. In addition, neuroprotection by 17 beta-E-2 is accompanied by reduced cytochrome c translocation both in the striatum and in the cortex as revealed by Western blotting 3 h after reperfusion. In conclusion, we report the original observation that neuroprotection exerted by 17 beta-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-1 beta production.