Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN, USA.
Neuropharmacology. 2018 Jan;128:269-281. doi: 10.1016/j.neuropharm.2017.10.023. Epub 2017 Oct 20.
Monoacylglycerol lipase (MGL) hydrolyzes 2-arachidonoylglycerol to arachidonic acid and glycerol. Inhibition of MGL may attenuate neuroinflammation by enhancing endocannabinoid signaling and decreasing prostaglandin (PG) production. Almost half of HIV infected individuals are afflicted with HIV-associated neurocognitive disorder (HAND), a neuroinflammatory disease in which cognitive decline correlates with synapse loss. HIV infected cells shed the envelope protein gp120 which is a potent neurotoxin that induces synapse loss. Here, we tested whether inhibition of MGL, using the selective inhibitor JZL184, would prevent synapse loss induced by gp120. The number of synapses between rat hippocampal neurons in culture was quantified by imaging clusters of a GFP-tagged antibody-like protein that selectively binds to the postsynaptic scaffolding protein, PSD95. JZL184 completely blocked gp120-induced synapse loss. Inhibition of MGL decreased gp120-induced interleukin-1β (IL-1β) production and subsequent potentiation of NMDA receptor-mediated calcium influx. JZL184-mediated protection of synapses was reversed by a selective cannabinoid type 2 receptor (CBR) inverse agonist/antagonist. JZL184 also reduced gp120-induced prostaglandin E2 (PGE) production; PG signaling was required for gp120-induced IL-1β expression and synapse loss. Inhibition of MGL prevented gp120-induced synapse loss by activating CBR resulting in decreased production of the inflammatory cytokine IL-1β. Because PG signaling was required for gp120-induced synapse loss, JZL184-induced decreases in PGE levels may also protect synapses. MGL presents a promising target for preventing synapse loss in neuroinflammatory conditions such as HAND.
单酰甘油脂肪酶（MGL）水解 2-花生四烯酰甘油产生花生四烯酸和甘油。MGL 的抑制可能通过增强内源性大麻素信号和减少前列腺素（PG）的产生来减轻神经炎症。几乎一半的 HIV 感染者患有与 HIV 相关的神经认知障碍（HAND），这是一种神经炎症性疾病，认知能力下降与突触丢失相关。HIV 感染的细胞会脱落包膜蛋白 gp120，它是一种有效的神经毒素，会导致突触丢失。在这里，我们测试了使用选择性抑制剂 JZL184 抑制 MGL 是否会防止 gp120 诱导的突触丢失。通过成像 GFP 标记的类似抗体蛋白的簇来量化大鼠海马神经元培养物中突触的数量，该蛋白特异性结合突触后支架蛋白 PSD95。JZL184 完全阻断了 gp120 诱导的突触丢失。MGL 的抑制减少了 gp120 诱导的白细胞介素-1β（IL-1β）的产生以及随后增强的 NMDA 受体介导的钙内流。选择性大麻素类型 2 受体（CBR）反向激动剂/拮抗剂逆转了 JZL184 介导的突触保护。JZL184 还减少了 gp120 诱导的前列腺素 E2（PGE）的产生；PG 信号对于 gp120 诱导的 IL-1β表达和突触丢失是必需的。MGL 的抑制通过激活 CBR 防止了 gp120 诱导的突触丢失，从而减少了炎症细胞因子 IL-1β的产生。由于 PG 信号对于 gp120 诱导的突触丢失是必需的，因此 JZL184 诱导的 PGE 水平降低也可能保护突触。MGL 为预防 HAND 等神经炎症性疾病中的突触丢失提供了一个有前途的靶点。
