Neuroprotection by Ovarian Hormones in Animal Models of Neurological Disease

Abstract

Ovarian hormones can protect against brain injury, neurodegeneration, and cognitive decline. Most attention has focused on estrogens and accumulating data demonstrate that estrogen seems to specifically protect cortical and hippocampal neurons from ischemic injury and from damage due to severe seizures. Although multiple studies demonstrate protection by estrogen, in only a few instances is the issue of how the steroid confers protection known. Here, we first review data evaluating the neuroprotective effects of estrogens, a selective estrogen receptor modulator (SERM), and estrogen receptor alpha- and beta-selective ligands in animal models of focal and global ischemia. Using focal ischemia in ovariectomized ERalphaKO, ERbetaKO, and wild-type mice, we clearly established that the ERalpha subtype is the critical ER mediating neuroprotection in mouse focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke, while in gerbils the two-vessel occlusion model, representing global ischemia, was used. The gerbil global ischemia model was used to evaluate the neuroprotective effects of estrogen, SERMs, and ERalpha- and ERbeta-selective compounds in the hippocampus. Analysis of neurogranin mRNA, a marker of viability of hippocampal neurons, with in situ hybridization, revealed that estrogen treatment protected the dorsal CA1 regions not only when administered before, but also when given 1 h after occlusion. Estrogen rarely is secreted alone and studies of neuroprotection have been less extensive for a second key ovarian hormone progesterone. In the second half of this review, we present data on neuroprotection by estrogen and progesterone in animal model of epilepsy followed by exploration into ovarian steroid effects on neuronal damage in models of multiple sclerosis and traumatic brain injury.

Tanshinone IIA attenuates the cerebral ischemic injury-induced increase in levels of GFAP and of caspases-3 and -8

“…Middle cerebral artery occlusion is a generally accepted model of cerebral ischemia (Hoffman et al, 2006). The findings presented suggest that indices of apoptosis in rat brain induced by I/R can be considerably reduced (but not totally prevented) by TSA.…”

The spinal nucleus of the bulbocavernosus: Firsts in androgen-dependent neural sex differences

“…Thus, the SNB stands in contrast to some other areas in the nervous system, where estradiol has powerful neuroprotective effects (Henderson and Reynolds, 2002;Hoffman et al, 2006).…”

Estrogen Receptor Alpha Inhibits the Estrogen-Mediated Suppression of HIV Transcription in Astrocytes: Implications for Estrogen Neuroprotection in HIV Dementia

“…22,35,45,46 ERa expression increases in reactive astrocytes in the rodent, primate, and human brain, 24,27 and In the absence of viral infection no HIV protein is found. As shown, the HIV þ brain contains 35 reactive astrocytes, 10 of which express ERa.…”