Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China, 710032.
Department of Acupuncture-moxibustion-massage, Shaanxi University of Chinese Medicine, Xi'an, Shaanxi Province, People's Republic of China, 712000.
Mol Neurobiol. 2021 Oct;58(10):5272-5288. doi: 10.1007/s12035-021-02446-2. Epub 2021 Jul 19.
Sleep deprivation (SD) leads to cognitive impairment due to neuroinflammation associated with impaired hippocampal neuronal plasticity and memory processes. Liver X receptors (LXRs), including LXRα and LXRβ isoforms, are crucial for synaptic plasticity and neuroinflammation. However, the potential roles of LXRs in the pathogenesis of cognitive impairment induced by SD remain unclear. We revealed that SD resulted in LXRβ reduction in the hippocampus, which was associated with upregulated expression of high mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4)/NF-κB p65, and knockdown of hippocampal LXRβ by shRNA (shLXRβ) led to cognitive impairment. GW3965, a dual agonist for both LXRα and LXRβ, ameliorated SD-induced cognitive impairment by inhibiting microglia activation, suppressing HMGB1/TLR4/NF-κB p65 pathway, and ultimately affecting the hippocampal expression of inflammatory cytokines in SD mice. LXRβ knockdown by shLXRβ abrogated the GW3965-mediated inhibition of the HMGB1/TLR4/NF-κB p65 pathway, therefore, abolishing the cognitive improvement. Moreover, inhibition of HMGB1 by glycyrrhizin (GLY) synergistic promoted GW3965-mediated anti-inflammation in activated microglia after lipopolysaccharide (LPS)/ATP stimulation and facilitated the cognitive improvement after GW administration by activating LXRβ. All the data suggested that GW3965 ameliorated impaired cognition in SD mice by suppressing the HMGB1/TLR4/NF-κB p65 pathway followed LXRβ activation. This study correlates a deficit of LXRβ in cognitive dysfunction in SD associated with HMGB1 inflammatory pathway in hippocampus, and LXRs may serve as a potential therapeutic target for cognitive impairment with anti-inflammation.
睡眠剥夺（SD）会导致认知障碍，这是由于与海马神经元可塑性和记忆过程受损相关的神经炎症引起的。肝 X 受体（LXRs），包括 LXRα 和 LXRβ 异构体，对突触可塑性和神经炎症至关重要。然而，LXRs 在 SD 引起的认知障碍发病机制中的潜在作用尚不清楚。我们发现 SD 导致海马体中 LXRβ 减少，这与高迁移率族蛋白 1（HMGB1）/Toll 样受体 4（TLR4）/NF-κB p65 的表达上调有关，并且通过 shRNA（shLXRβ）敲低海马体中的 LXRβ 会导致认知障碍。LXRα 和 LXRβ 的双重激动剂 GW3965 通过抑制小胶质细胞激活、抑制 HMGB1/TLR4/NF-κB p65 通路，最终影响 SD 小鼠海马体中炎症细胞因子的表达，改善 SD 诱导的认知障碍。shLXRβ 敲低 abrogated GW3965 介导的 HMGB1/TLR4/NF-κB p65 通路抑制，从而消除了认知改善。此外，甘氨酸（GLY）抑制 HMGB1 通过协同促进 LPS/ATP 刺激后激活的小胶质细胞中 GW3965 介导的抗炎作用，并通过激活 LXRβ 促进 GW 给药后的认知改善。所有数据表明，GW3965 通过抑制 HMGB1/TLR4/NF-κB p65 通路，随后激活 LXRβ，改善了 SD 小鼠受损的认知。本研究将 SD 相关的认知功能障碍与海马体中 HMGB1 炎症通路相关的 LXRβ 缺陷相关联，并且 LXRs 可能作为具有抗炎作用的认知障碍的潜在治疗靶点。
