Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xinsi Road 1, Xi'an 710038, Shaanxi Province, PR China; Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi Province, PR China.
Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, Shaanxi Province, PR China.
Exp Neurol. 2018 Jun;304:21-29. doi: 10.1016/j.expneurol.2018.02.006. Epub 2018 Feb 12.
Chronic cerebral hypoperfusion (CCH), a leading cause of various cerebrovascular diseases, leads to cognitive dysfunction due to neuron loss and impaired neurogenesis. Liver X receptors (LXRs), including LXRα and LXRβ isoforms, are crucial for cholesterol metabolism, synaptic plasticity as well as neurogenesis. However, it is not clear the potential roles of LXRs in the pathogenesis of cognitive impairment induced by CCH. In this study, we demonstrated that LXRβ expression decreased in hippocampus of CCH mice. GW3965, a synthetic dual agonist for both LXRα and LXRβ, ameliorated impairment of learning and memory in CCH mice by promoting neuronal survival and neural stem cells (NSCs) proliferation in dentate gyrus (DG) of CCH mice. The proliferative effects of GW3965 were further confirmed in cultured neural progenitor cells (NPCs) and showed in a concentration-dependent manner. Moreover, GW3965 phosphorylated protein kinase B (Akt) at Ser473 in a time- and concentration-dependent manner in NPCs. Furthermore, both LY294002, an inhibitor for phosphoinositide-3-kinase (PI3K), and short hairpin RNAs for LXRβ knockdown, abrogated GW3965-induced Akt phosphorylation, and therefore abolished GW3965-mediated proliferation-promoting of NPCs. All the data suggested that GW3965 ameliorated impaired cognitive functions in CCH by promoting NSC proliferation through PI3K/Akt pathway followed LXRβ activation. This study correlates a deficit of LXRβ in cognitive dysfunction in CCH with impaired neurogenesis in hippocampus, and LXRs may serve as a potential therapeutic target for chronic cerebral ischemia.
慢性脑灌注不足（CCH）是各种脑血管疾病的主要原因，由于神经元丧失和神经发生受损，导致认知功能障碍。肝 X 受体（LXRs），包括 LXRα和 LXRβ异构体，对于胆固醇代谢、突触可塑性以及神经发生至关重要。然而，LXRs 在 CCH 引起的认知障碍发病机制中的潜在作用尚不清楚。在这项研究中，我们表明 LXRβ在 CCH 小鼠海马中的表达减少。GW3965 是 LXRα和 LXRβ的合成双重激动剂，通过促进 CCH 小鼠齿状回（DG）中的神经元存活和神经干细胞（NSCs）增殖，改善 CCH 小鼠的学习和记忆障碍。GW3965 在培养的神经祖细胞（NPCs）中的增殖作用进一步得到证实，并呈浓度依赖性。此外，GW3965 在 NPCs 中以时间和浓度依赖的方式使蛋白激酶 B（Akt）在 Ser473 位点磷酸化。此外，LY294002（PI3K 的抑制剂）和 LXRβ短发夹 RNA 的敲低均消除了 GW3965 诱导的 Akt 磷酸化，从而消除了 GW3965 介导的 NPCs 增殖促进作用。所有数据表明，GW3965 通过激活 LXRβ 后激活 PI3K/Akt 通路促进 NSC 增殖，从而改善 CCH 中受损的认知功能。这项研究将 CCH 中认知功能障碍的 LXRβ缺乏与海马中神经发生受损相关联，并且 LXRs 可能成为慢性脑缺血的潜在治疗靶点。
