Activation of microglia is a hallmark of neuroinflammation and has been implicated in the development of many psychiatric disorders. Hydrogen sulfide (H₂S); a gasotransmitter has recently emerged as a potent antioxidant and anti-inflammatory molecule. However, the protective potential of H₂S and its underpin molecular mechanisms in neuroinflammation associated behavioral deficits are still unknown. The present study has been designed to investigate the effect of sodium hydrogen sulfide (NaHS; a source of H₂S) on microglial activation and associated behavior phenotype in response to lipopolysaccharide (LPS)-induced neuroinflammation. LPS treatment decreased H₂S levels with a concomitant increase in reactive oxygen species (ROS) in the cortex and hippocampus. However, NaHS administration restored the endogenous H₂S levels to the normal and decreased ROS levels. NaHS supplementation reduced the number of active microglia in the cortex and hippocampus of LPS treated animals. Morphological analysis of microglia showed significant increase in microglial density, span ratio and soma area in the cortex and hippocampus of LPS treated animals which was decreased by NaHS supplementation. Moreover, NaHS administration reduced the expression of microglial M1 phenotype markers (IL-1β, TNF-α and nitrite) and concomitantly increased the expression of M2 phenotype markers (IL-4 and TGF-β) in the brain regions of LPS treated animals. Furthermore, LPS-induced anxiety-like behavior assessed by open field test and elevated plus maze was reversed by NaHS supplementation. Taken together, these findings suggest that H₂S supplementation ameliorates LPS-induced behavioral deficits by suppressing pro-inflammatory and promoting anti-inflammatory microglial response. Therefore, H₂S releasing drugs may be potential therapeutics to treat neuroinflammation associated psychiatric disorders.

Graphical abstract

小胶质细胞的激活是神经炎症的标志，并且与许多精神疾病的发展有关。硫化氢（H ₂ S）；最近出现了一种气体传送体，它是一种有效的抗氧化剂和抗炎分子。然而，H ₂ S的保护潜力及其在神经炎症相关行为缺陷中的基础分子机制仍然未知。本研究旨在研究硫化氢钠 (NaHS；H ₂ S的来源) 对小胶质细胞激活和相关行为表型的影响，以响应脂多糖 (LPS) 诱导的神经炎症。LPS 处理降低 H ₂S 水平伴随着皮层和海马中活性氧 (ROS) 的增加。然而，NaHS 管理恢复了内源性 H ₂S 水平恢复正常并降低 ROS 水平。NaHS 补充剂减少了 LPS 治疗动物皮层和海马体中活性小胶质细胞的数量。小胶质细胞的形态学分析显示，LPS 处理的动物的皮层和海马中的小胶质细胞密度、跨度比和躯体面积显着增加，而 NaHS 补充剂则降低了这一点。此外，NaHS 给药降低了小胶质细胞 M1 表型标志物（IL-1β、TNF-α 和亚硝酸盐）的表​​达，同时增加了 LPS 治疗动物大脑区域中 M2 表型标志物（IL-4 和 TGF-β）的表达。此外，通过野外试验和高架十字迷宫评估的 LPS 诱导的焦虑样行为被 NaHS 补充逆转。综上所述，这些发现表明 H ₂S 补充剂通过抑制促炎和促进抗炎小胶质细胞反应来改善 LPS 诱导的行为缺陷。因此，H ₂ S 释放药物可能是治疗神经炎症相关精神障碍的潜在疗法。

图形概要