Department of Biochemistry, University of Cambridge, Cambridge, UK.
J Neuroinflammation. 2021 Oct 11;18(1):225. doi: 10.1186/s12974-021-02280-2.
Inflammation may contribute to multiple brain pathologies. One cause of inflammation is lipopolysaccharide/endotoxin (LPS), the levels of which are elevated in blood and/or brain during bacterial infections, gut dysfunction and neurodegenerative diseases, such as Parkinson's disease. How inflammation causes neuronal loss is unclear, but one potential mechanism is microglial phagocytosis of neurons, which is dependent on the microglial P2Y receptor. We investigated here whether the P2Y receptor was required for inflammatory neuronal loss. Intraperitoneal injection of LPS on 4 successive days resulted in specific loss of dopaminergic neurons (measured as cells staining with tyrosine hydroxylase or NeuN) in the substantia nigra of wild-type mice, but no neuronal loss in cortex or hippocampus. This supports the hypothesis that neuronal loss in Parkinson's disease may be driven by peripheral LPS. By contrast, there was no LPS-induced neuronal loss in P2Y receptor knockout mice. In vitro, LPS-induced microglial phagocytosis of cells was prevented by inhibition of the P2Y receptor, and LPS-induced neuronal loss was reduced in mixed glial-neuronal cultures from P2Y receptor knockout mice. This supports the hypothesis that microglial phagocytosis contributes to inflammatory neuronal loss, and can be prevented by blocking the P2Y receptor, suggesting that P2Y receptor antagonists might be used to prevent inflammatory neuronal loss in Parkinson's disease and other brain pathologies involving inflammatory neuronal loss.
炎症可能导致多种脑部病变。炎症的一个原因是脂多糖/内毒素 (LPS)，在细菌感染、肠道功能障碍和神经退行性疾病（如帕金森病）期间，其在血液和/或大脑中的水平会升高。炎症如何导致神经元丢失尚不清楚，但一种潜在的机制是小胶质细胞吞噬神经元，这依赖于小胶质细胞 P2Y 受体。我们在这里研究了 P2Y 受体是否是炎症性神经元丢失所必需的。连续 4 天腹腔注射 LPS 会导致野生型小鼠黑质中多巴胺能神经元（通过酪氨酸羟化酶或 NeuN 染色测量）的特异性丢失，但皮质或海马中没有神经元丢失。这支持了帕金森病中神经元丢失可能是由外周 LPS 驱动的假说。相比之下，P2Y 受体敲除小鼠中没有 LPS 诱导的神经元丢失。在体外，P2Y 受体的抑制可防止 LPS 诱导的小胶质细胞吞噬细胞，并且从 P2Y 受体敲除小鼠的混合神经胶质-神经元培养物中降低了 LPS 诱导的神经元丢失。这支持了小胶质细胞吞噬作用导致炎症性神经元丢失的假说，并且可以通过阻断 P2Y 受体来预防，这表明 P2Y 受体拮抗剂可能用于预防帕金森病和其他涉及炎症性神经元丢失的脑部病变中的炎症性神经元丢失。
