Nowoslawski Lisa, Klocke Barbara J, Roth Kevin A
Department of Pathology, Division of Neuropathology University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
J Neuropathol Exp Neurol. 2005 Jun;64(6):490-7. doi: 10.1093/jnen/64.6.490.
Ethanol is a potent neurotoxin particularly for the developing nervous system. Intrauterine exposure to ethanol during the last trimester of human gestation can produce a broad spectrum of neuropathologic consequences. This period of human brain development is roughly equivalent to the first week of rodent postnatal life and acute exposure of neonatal mice to ethanol produces massive neuronal apoptosis throughout the brain. We have previously demonstrated that ethanol-induced neuron apoptosis is critically dependent on expression of Bax, a proapoptotic member of the Bcl-2 family. To further define the molecular pathway regulating ethanol-induced neuron apoptosis, we analyzed the effects of acute ethanol exposure on cerebellar internal granule cell neurons both in vivo and in vitro. Ethanol produced extensive Bax-dependent caspase-3 activation and neuron apoptosis in the cerebellar internal granule cell layer, which was maximal at approximately 6 hours postadministration. This effect was recapitulated in vitro and required new gene transcription, protein translation, Bax expression, and caspase activation. Ethanol-induced neuron death was independent of p53 expression and was unaffected by deficiency in the proapoptotic Bcl-2 family members Bid or Bad. These studies indicate that ethanol activates an intrinsic apoptotic death program in neurons that is likely to contribute to the neuropathologic effects of human fetal alcohol exposure.
乙醇是一种强效神经毒素，对发育中的神经系统尤其如此。在人类妊娠期的最后三个月，子宫内接触乙醇会产生广泛的神经病理学后果。人类大脑发育的这一时期大致相当于啮齿动物出生后第一周，新生小鼠急性接触乙醇会在整个大脑中产生大量神经元凋亡。我们之前已经证明，乙醇诱导的神经元凋亡严重依赖于Bax的表达，Bax是Bcl-2家族的促凋亡成员。为了进一步确定调节乙醇诱导的神经元凋亡的分子途径，我们在体内和体外分析了急性乙醇暴露对小脑内颗粒细胞神经元的影响。乙醇在小脑内颗粒细胞层产生广泛的依赖于Bax的半胱天冬酶-3激活和神经元凋亡，在给药后约6小时达到最大值。这种效应在体外得到重现，并且需要新基因转录、蛋白质翻译、Bax表达和半胱天冬酶激活。乙醇诱导的神经元死亡与p53表达无关，并且不受促凋亡Bcl-2家族成员Bid或Bad缺乏的影响。这些研究表明，乙醇激活了神经元内的固有凋亡死亡程序，这可能导致人类胎儿酒精暴露的神经病理学效应。
