Carloni Silvia, Mazzoni Erika, Balduini Walter
Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino, Urbino, Italy.
J Neurochem. 2004 Apr;89(1):197-203. doi: 10.1111/j.1471-4159.2004.02341.x.
Ethanol administration during the rat brain growth spurt triggers apoptotic neurodegeneration that appears to be mediated by caspase-3 activation. In order to gain more insight on the role of this caspase in ethanol-induced developmental neurotoxicity, we studied its expression and activity under different conditions of ethanol exposure during development. Furthermore, because of the cross-talk between caspase-3 and calpain we extended our study also at this protease. Ethanol was administered by gavage to rat pups as a single-day exposure on postnatal day (PN) 7 or from PN4 to PN10. Cleaved caspase-3 expression peaked in the cerebral cortex 12 h after ethanol treatment and returned to control values at 24 h. An identical pattern was found for caspase-3-like activity, that was increased only with the highest dose of ethanol tested (5 g/kg) and mostly in PN4. Repeated ethanol exposure, at a dose that was previously found to induce microencephaly, did not increase caspase-3 expression and activity although it decreased procaspase-3 expression and released mitochondrial cytochrome c. Repeated ethanol administration also increased calpain activity. These data show that acute and repeated ethanol administration differentially affect caspase-3 and calpain activity, suggesting that calpain activation may play a role in developmental neurotoxicity of ethanol.
在大鼠脑发育激增期给予乙醇会引发凋亡性神经退行性变，这似乎是由半胱天冬酶-3激活介导的。为了更深入了解这种半胱天冬酶在乙醇诱导的发育性神经毒性中的作用，我们研究了其在发育过程中不同乙醇暴露条件下的表达和活性。此外，由于半胱天冬酶-3和钙蛋白酶之间存在相互作用，我们也对这种蛋白酶进行了扩展研究。通过灌胃给幼鼠乙醇，在出生后第7天进行单日暴露，或从出生后第4天至第10天给药。乙醇处理后12小时，大脑皮层中裂解的半胱天冬酶-3表达达到峰值，并在24小时恢复到对照值。半胱天冬酶-3样活性也呈现相同模式，仅在测试的最高乙醇剂量（5 g/kg）下增加，且主要在出生后第4天。重复给予先前发现可诱导小头畸形剂量的乙醇，虽然会降低原半胱天冬酶-3表达并释放线粒体细胞色素c，但并未增加半胱天冬酶-3的表达和活性。重复给予乙醇也会增加钙蛋白酶活性。这些数据表明，急性和重复给予乙醇对半胱天冬酶-3和钙蛋白酶活性有不同影响，提示钙蛋白酶激活可能在乙醇的发育性神经毒性中起作用。
