Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice
Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice
复制标题
胆红素增强 ASIC 通道活性加剧小鼠新生儿高胆红素血症神经毒性
DOI：
10.1126/scitranslmed.aax1337
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发表时间：
2020-02-12
影响因子：
17.1
通讯作者：
Yin, Shan-Kai
中科院分区：
文献类型：
--
作者：
Lai, Ke;Song, Xing-Lei;Yin, Shan-Kai
新生儿高胆红素血症是一种常见的临床病症，可导致脑性脑病，尤其是在与因感染、缺血和缺氧引发的酸中毒并存时。目前普遍观点认为，酸中毒会增加血脑屏障对胆红素的通透性，并加剧其神经毒性。在本研究中，我们发现，同时患有高胆红素血症和酸中毒的婴儿，其脑脊液（CSF）中细胞死亡标志物乳酸脱氢酶（LDH）的浓度升高，且与酸中毒的严重程度相关性更强，而非与胆红素浓度升高的相关性更强。在新生小鼠神经元中，胆红素本身毒性有限，但能显著增强酸敏感离子通道（ASICs）的活性，导致细胞内钙离子浓度升高、动作电位发放增加以及细胞死亡。此外，新生小鼠同时经历高胆红素血症和缺氧诱导的酸中毒，会在体内引发学习记忆和复杂感觉运动功能的长期损伤，而在ASIC1a基因敲除小鼠中，这些损伤在很大程度上有所减轻。这些研究结果表明，针对酸中毒和ASICs进行干预，或许能够减轻新生儿高胆红素血症的并发症。
Neonatal hyperbilirubinemia aggravates acidosis-dependent long-term brain injury. Targeting acidity in jaundice Neonatal hyperbilirubinemia, also called jaundice, is a pediatric condition caused by high bilirubin levels. When associated with acidosis, jaundice can trigger neurotoxicity and lead to neurological impairments. Now, Lai et al. investigated the link between acidosis and jaundice in human samples and animal models. In samples from children with concomitant acidosis and jaundice, neuronal injury was increased compared with children with jaundice and no acidosis. In mice, bilirubin potentiated the activity of acid-sensing ion channels (ASICs) in neurons, increased firing, and caused cell death. Hyperbilirubinemia and acidosis promoted cognitive impairments in mice that were prevented by ASIC deletion. Targeting ASICs might reduce neurological impairments associated with jaundice. Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration. In mouse neonatal neurons, bilirubin exhibits limited toxicity but robustly potentiates the activity of acid-sensing ion channels (ASICs), resulting in increases in intracellular Ca2+ concentration, spike firings, and cell death. Furthermore, neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory and complex sensorimotor functions in vivo, which are largely attenuated in ASIC1a null mice. These findings suggest that targeting acidosis and ASICs may attenuate neonatal hyperbilirubinemia complications.