Neuroinflammation is a major contributor to bilirubin-induced neurotoxicity, which results in severe neurological deficits. Microglia are the primary immune cells in the brain, with M1 microglia promoting inflammatory injury and M2 microglia inhibiting neuroinflammation. Controlling microglial inflammation could be a promising therapeutic strategy for reducing bilirubin-induced neurotoxicity. Primary microglial cultures were prepared from 1–3-day-old rats. In the early stages of bilirubin treatment, pro-/anti-inflammatory (M1/M2) microglia mixed polarization was observed. In the late stages, bilirubin persistence induced dominant proinflammatory microglia, forming an inflammatory microenvironment and inducing iNOS expression as well as the release of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Simultaneously, nuclear factor-kappa B (NF-κB) was activated and translocated into the nucleus, upregulating inflammatory target genes. As well known, neuroinflammation can have an effect on N-methyl-D-aspartate receptor (NMDAR) expression or function, which is linked to cognition. Treatment with bilirubin-treated microglia-conditioned medium did affect the expression of IL-1β, NMDA receptor subunit 2A (NR2A), and NMDA receptor subunit 2B (NR2B) in neurons. However, VX-765 effectively reduces the levels of proinflammatory cytokines TNF-α, IL-6, and IL-1β, as well as the expressions of CD86, and increases the expressions of anti-inflammatory related Arg-1. A timely reduction in proinflammatory microglia could protect against bilirubin-induced neurotoxicity.

神经炎症是胆红素引起的神经毒性的主要原因，可导致严重的神经功能缺损。小胶质细胞是大脑中的主要免疫细胞，M1 小胶质细胞促进炎症损伤，M2 小胶质细胞抑制神经炎症。控制小胶质细胞炎症可能是减少胆红素诱导的神经毒性的一种有前途的治疗策略。原代小胶质细胞培养物是从 1-3 日龄的大鼠中制备的。在胆红素治疗的早期阶段，观察到促炎/抗炎（M1/M2）小胶质细胞混合极化。在后期，胆红素持续存在诱导占优势的促炎性小胶质细胞，形成炎症微环境并诱导iNOS表达以及肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和IL-1β的释放。同时，核因子-κB (NF-κB) 被激活并易位到细胞核中，上调炎症靶基因。众所周知，神经炎症会影响 N-甲基-D-天冬氨酸受体 (NMDAR) 的表达或功能，而这与认知有关。用胆红素处理的小胶质细胞条件培养基处理确实影响神经元中 IL-1β、NMDA 受体亚基 2A (NR2A) 和 NMDA 受体亚基 2B (NR2B) 的表达。然而，VX-765 有效降低促炎细胞因子 TNF-α、IL-6 和 IL-1β 的水平以及 CD86 的表达，并增加抗炎相关 Arg-1 的表达。及时减少促炎性小胶质细胞可以防止胆红素引起的神经毒性。