Department of Anesthesiology, Xiang'an Hospital, Xiamen University, Xiamen 361101, China; Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
Department of Anesthesiology, Xiang'an Hospital, Xiamen University, Xiamen 361101, China.
Neuropharmacology. 2018 Jun;135:514-528. doi: 10.1016/j.neuropharm.2018.04.014. Epub 2018 Apr 11.
Liver X receptors (LXRs), including LXRα and LXRβ isoforms, have been implicated in multiple physiological functions including promoting neurogenesis, improving synaptic plasticity, preventing neurodegeneration, inhibiting inflammation as well as regulating cholesterol metabolism. However, a potential role of LXRs in the treatment of major depressive disorder (MDD) has never been investigated previously. Our present results demonstrated that levels of hippocampal LXRβ but not LXRα were down-regulated in rats exposed to chronic unpredictable stress (CUS) and were negatively correlated with the severity of CUS-induced depressive-like behaviors. Furthermore, rats with LXRβ knockdown by short hairpin RNA (shRNA) in hippocampus displayed depressive-like behaviors and impaired hippocampal neurogenesis similar to those observed after CUS exposure. Conversely, LXRs activation by GW3965 (GW), a synthetic dual agonist for both LXRα and LXRβ isoforms, could improve depression-like behaviors and reverse the impaired hippocampal neurogenesis in rats exposed to CUS. LXRβ knockdown by shRNA completely abrogated the antidepressant and hippocampal neurogenesis-promoting effects of GW, suggesting that LXRβ isoform mediated the antidepressant and hippocampal neurogenesis-promoting effects of the LXRα/β dual agonist. However, ablation of hippocampal neurogenesis with x-irradiation only partly but not completely abolished the antidepressant effects of GW in the behavioral tests, implying that the antidepressant effects mediated by LXRβ isoform are likely through both neurogenesis-dependent and -independent pathways. Thus, our findings suggest that LXRβ activation may represent a potential novel target for the treatment of MDD and also provide a novel insight into the underlying mechanisms of MDD.
肝 X 受体（LXRs），包括 LXRα 和 LXRβ 异构体，与多种生理功能有关，包括促进神经发生、改善突触可塑性、预防神经退行性变、抑制炎症以及调节胆固醇代谢。然而，LXRs 在治疗重度抑郁症（MDD）中的潜在作用以前从未被研究过。我们目前的结果表明，慢性不可预测应激（CUS）暴露的大鼠海马 LXRβ 水平而非 LXRα 水平下调，与 CUS 诱导的抑郁样行为的严重程度呈负相关。此外，海马 LXRβ 通过短发夹 RNA（shRNA）敲低的大鼠表现出抑郁样行为和海马神经发生受损，类似于 CUS 暴露后观察到的情况。相反，LXRα 和 LXRβ 同工型的合成双重激动剂 GW3965（GW）激活 LXRs 可改善抑郁样行为并逆转 CUS 暴露大鼠的海马神经发生受损。海马 LXRβ 通过 shRNA 敲低完全消除了 GW 的抗抑郁和促进海马神经发生作用，表明 LXRβ 同工型介导了 LXRα/β 双重激动剂的抗抑郁和促进海马神经发生作用。然而，用 X 射线照射破坏海马神经发生仅部分但不能完全消除 GW 在行为测试中的抗抑郁作用，这表明 LXRβ 同工型介导的抗抑郁作用可能通过神经发生依赖和非依赖途径。因此，我们的研究结果表明，LXRβ 的激活可能是治疗 MDD 的一个潜在新靶点，并为 MDD 的潜在机制提供了新的见解。
