Estradiol rescues neurons from global ischemia-induced cell death: Multiple cellular pathways of neuroprotection

Abstract

The potential neuroprotective role of sex hormones in chronic neurodegenerative disorders and acute brain ischemia following cardiac arrest and stroke is of a great therapeutic interest. Longterm pretreatment with estradiol and other estrogens affords robust neuroprotection in male and female rodents subjected to focal and global ischemia. However, the receptors (e.g., cell surface or nuclear), intracellular signaling pathways and networks of estrogen-regulated genes that intervene in neuronal apoptosis are as yet unclear. We have shown that estradiol administered at physiological levels for two weeks before ischemia rescues neurons destined to die in the hippocampal CA1 and ameliorates ischemia-induced cognitive deficits in ovariectomized female rats. This regimen of estradiol treatment involves classical intracellular estrogen receptors, transactivation of IGF-1 receptors and stimulation of the ERK/MAPK signaling pathway, which in turn maintains CREB activity in the ischemic CA1. We also find that a single, acute injection of estradiol administrated into the brain ventricle immediately after an ischemic event reduces both neuronal death and cognitive deficits. Because these findings suggest that hormones could be used to treat patients when given after brain ischemia, it is critical to determine whether the same or different pathways mediate this form of neuroprotection. We find that an agonist of the membrane estrogen receptor GPR30 mimics short latency estradiol facilitation of synaptic transmission in the hippocampus. Therefore, we are testing the hypothesis that GPR30 may act together with intracellular estrogen receptors to activate cell signaling pathways to promote neuron survival after global ischemia.

ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning

“…For example, estrogen activated ERK1/2 signaling pathway in global ischemia-induced hypoxia, and the MEK (upstream activator kinase for ERK) inhibitor PD98059 blocked the neuroprotection by estrogen (Lebesgue et al 2009). However, such studies used pharmacological inhibitors for MEK, including PD98059 or U0126, which inhibit both MEK1 and MEK5, the upstream activator of ERK1/2 and ERK5, respectively (Davies et al 2000).…”

Estrogen and Brain Protection

“…Estrogen also protects neurons from ischemia (Petito et al, 1987). Estrogen administered at physiological levels for two weeks before ischemia rescued the hippocampal neurons and ameliorated ischemia-induced cognitive deficits in female rats (Lebesgue, 2009). This study provides direct evidence that estrogen is neuroprotective against ischemia.…”

“…In addition, ICI 182780, a competitive antagonist for both estrogen receptors-and -, completely blocked estrogen's protection against post-ischemic stress (Miller et al, 2005). On the other hand, Lebesgue et al (2009) found that a single injection of estrogen into the brain ventricle immediately after an ischemic event reduced both neuronal death and cognitive deficits. The genomic mechanism of estrogen is typically a slow process because it involves estrogen's receptors in the nuclei, affecting protein synthesis.…”

Neuroprotection in Animal Models of Global Cerebral Ischemia

“…Besides, the opportunity time window may be further extended when it is expected that neuroprotective procedures act through promotion of cellular processes of neuronal repair and plasticity. In view of the multiple pathophysiological processes occurring both in sequence and simultaneously after ischemia and reperfusion, it is considered as an advantage for presumptive neuroprotective drugs to have multiple cellular or molecular mechanisms of action, as occurring with some originally endogenous compounds, namely melatonin, estradiol and progesterone (El-Abhar et al, 2002;Hurn et al, 1995;Jover-Mengual et al, 2010;Lebesgue et al, 2009;Reiter et al, 2005;Wang et al, 2008). By contrast, most synthetic drugs only have one mechanism of action accounting for neuroprotection.…”