Lin Suizhen, Wei Xing, Bales Kelly R, Paul Aaron B C, Ma Zhizhong, Yan Guangmei, Paul Steven M, Du Yansheng
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Eur J Neurosci. 2005 Jul;22(1):21-7. doi: 10.1111/j.1460-9568.2005.04182.x.
Encephalopathy induced by hyperbilirubinemia in infants has been described in the medical literature for over a century but neither the cellular nor molecular mechanisms underlying bilirubin neurotoxicity are well understood. In this study, we have demonstrated that minocycline potently protects primary cultured rat cerebellar granule neurons against bilirubin neurotoxicity (IC50 approximately 2 microm) and almost completely blocks cerebellar hypoplasia and the profound loss of Purkinje and granule neurons observed in homozygous Gunn rats, a genetic model of hyperbilirubinemia-induced neurotoxicity. Minocycline-treated newborn Gunn rats had nearly equivalent numbers of viable Purkinje and granule neurons in the cerebellum as did control animals. Moreover, minocycline inhibits the bilirubin-induced phosphorylation of p38 mitogen-activated protein kinase both in vivo as well as in vitro. Taken together our data demonstrate that minocycline is able to greatly reduce bilirubin-induced neurotoxicity and suggest that minocycline's neuroprotective effects may be due in part to an inhibition of p38 mitogen-activated protein kinase activity. Our findings may lead to novel approaches for treating bilirubin-induced encephalopathy.
婴儿高胆红素血症所致的脑病在医学文献中已有一个多世纪的描述，但胆红素神经毒性的细胞和分子机制仍未完全明了。在本研究中，我们已证明米诺环素能有效保护原代培养的大鼠小脑颗粒神经元免受胆红素神经毒性（IC50约为2微摩尔），并几乎完全阻止纯合子冈恩大鼠（高胆红素血症诱导神经毒性的遗传模型）中观察到的小脑发育不全以及浦肯野神经元和颗粒神经元的大量丧失。用米诺环素处理的新生冈恩大鼠小脑内存活的浦肯野神经元和颗粒神经元数量与对照动物几乎相当。此外，米诺环素在体内和体外均能抑制胆红素诱导的p38丝裂原活化蛋白激酶的磷酸化。综合我们的数据表明，米诺环素能够大大降低胆红素诱导的神经毒性，并提示米诺环素的神经保护作用可能部分归因于对p38丝裂原活化蛋白激酶活性的抑制。我们的发现可能会带来治疗胆红素诱导脑病的新方法。
