Upregulation of bcl2 Expression

The antiapoptotic protein bcl-2 is a product of a proto-oncogene originally identified in human B-cell lymphomas.123 Bcl-2 is a survival factor that can block both necrotic and apoptotic cell death124 and promotes cell survival in a variety of tissues including brain. For example, overexpression of bcl-2 in neurons inhibits death in response to deprivation of serum, glucose or growth factors, and exposure to the calcium ionophore A23187.125-127 Bcl-2 overexpression protects neurons from glutamate tox-icity as well.127,128 Bcl-2 has multiple neuroprotective actions including prevention of the activation of capases, inhibition of free radical formation, and regulation of calcium sequestration.129

Estrogen upregulates bcl-2 expression in various tissues including brain. Garcia-Segura et al.,130 for example, showed that bcl-2 was increased in the arcuate nucleus of rats on the day of estrus (i.e., peak estrogen levels) compared to other days, was decreased by ovariectomy, and was increased with 17P-estradiol treatment of ovariectomized rats. Bcl-2 induction may therefore be a mediator of estrogen's neuroprotection. Consistent with this concept, Singer et al.128 showed that 24 h of 17P-estradiol pretreatment significantly increased bcl-2 levels and enhanced survival of NT neurons in vitro after exposure to H2O2 or glutamate. This effect was blocked by the antiestrogen, ICI 182,780, suggesting a mechanistic role of the estrogen receptor.

Two in vivo studies further support the hypothesis that bcl-2 is a mediator of estrogen's neuroprotection. Alkayed et al.18 compared bcl-2 expression and infarct size in male, female, ovariectomized, and estrogen-treated ovariectomized female rats after a 2-h MCAO/22-h reperfusion ischemic injury. The bcl-2 signal was concentrated primarily in the ischemic penumbra and was higher in female and estrogen-treated ovariectomized rats compared to male and nontreated ovariectomized rats. The bcl-2 levels correlated negatively with infarct size. In a similar study, Dubal et al.30 found that after unilateral MCAO, the brains of female ovariectomized rats treated with 17P-estradiol showed more bcl-2 expression on the injured side of the brain and smaller infarct size compared to nontreated, ovariectomized female rats. Figure 1.6 summarizes the various neuroprotective actions of 17P-estradiol and their interactions.

figure 1.6 Mechanisms by which 17P-estradiol may exert its neuroprotective effects. PCS = prostacyclin synthetase.

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