Unconjugated bilirubin, the end product of heme catabolism and antioxidant, induced brain damage in human neonates is a well-recognized clinical syndrome. However, the cellular and molecular mechanisms underlying bilirubin neurotoxicity remain unclear. To characterize the sequence of events leading to bilirubin-induced neurotoxicity, we investigated whether bilirubin-induced glial activation was involved in bilirubin neurotoxicity by exposing co-cultured rat glial cells and cerebellar granule neurons (CGN) to bilirubin. We found that bilirubin could markedly induce the expression of TNF-α and iNOS in glial cells, and even at low concentrations, the co-culture of glial cells with neurons significantly enhances neurotoxicity of bilirubin. Pretreatment of the co-cultured cells with minocycline protected CGN from glia-mediated bilirubin neurotoxicity and inhibited overexpression of TNF-α and iNOS in glia. Furthermore, we found that high doses of bilirubin were able to induce glial injury, and minocycline attenuated bilirubin-induced glial cell death. Our data suggest that glial cells play an important role in brain damage caused by bilirubin, and minocycline blocks bilirubin-induced encephalopathy possibly by directly and indirectly inhibiting neuronal death pathways.

中文翻译：

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Minocycline保护神经元免受神经胶质细胞介导的胆红素神经毒性。

非结合胆红素是血红素分解代谢和抗氧化剂的终产物，可引起人类新生儿脑部损伤，是公认的临床综合征。但是，尚不清楚胆红素神经毒性的细胞和分子机制。为了表征导致胆红素诱导的神经毒性的事件序列，我们通过将共培养的大鼠神经胶质细胞和小脑颗粒神经元（CGN）暴露于胆红素来研究胆红素诱导的神经胶质激活是否与胆红素神经毒性有关。我们发现胆红素可以明显诱导神经胶质细胞中TNF-α和iNOS的表达，即使在低浓度时，神经胶质细胞与神经元的共培养也会显着增强胆红素的神经毒性。用米诺环素预处理共培养细胞可保护CGN免受胶质细胞介导的胆红素神经毒性，并抑制胶质细胞中TNF-α和iNOS的过度表达。此外，我们发现高剂量的胆红素能够诱导神经胶质损伤，而美满霉素可减轻胆红素诱导的神经胶质细胞死亡。我们的数据表明，神经胶质细胞在胆红素引起的脑损伤中起重要作用，而美诺环素可能通过直接和间接抑制神经元死亡途径来阻断胆红素诱发的脑病。