Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Neurobiol Dis. 2022 Jul;169:105734. doi: 10.1016/j.nbd.2022.105734. Epub 2022 Apr 21.
People living with HIV (PLH) have significantly higher rates of cognitive impairment (CI) and major depressive disorder (MDD) versus the general population. The enzyme neutral sphingomyelinase 2 (nSMase2) is involved in the biogenesis of ceramide and extracellular vesicles (EVs), both of which are dysregulated in PLH, CI, and MDD. Here we evaluated EcoHIV-infected mice for behavioral abnormalities relevant to depression and cognition deficits, and assessed the behavioral and biochemical effects of nSMase2 inhibition. Mice were infected with EcoHIV and daily treatment with either vehicle or the nSMase2 inhibitor (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC) began 3 weeks post-infection. After 2 weeks of treatment, mice were subjected to behavior tests. EcoHIV-infected mice exhibited behavioral abnormalities relevant to MDD and CI that were reversed by PDDC treatment. EcoHIV infection significantly increased cortical brain nSMase2 activity, resulting in trend changes in sphingomyelin and ceramide levels that were normalized by PDDC treatment. EcoHIV-infected mice also exhibited increased levels of brain-derived EVs and altered microRNA cargo, including miR-183-5p, miR-200c-3p, miR-200b-3p, and miR-429-3p, known to be associated with MDD and CI; all were normalized by PDDC. In conclusion, inhibition of nSMase2 represents a possible new therapeutic strategy for the treatment of HIV-associated CI and MDD.
与普通人群相比，人类免疫缺陷病毒（HIV）感染者（PLHIV）的认知障碍（CI）和重度抑郁症（MDD）发生率显著更高。中性鞘氨醇酶 2（nSMase2）参与神经酰胺和细胞外囊泡（EVs）的生物发生，这两者在 PLHIV、CI 和 MDD 中均失调。在这里，我们评估了 EcoHIV 感染小鼠是否存在与抑郁和认知缺陷相关的行为异常，并评估了 nSMase2 抑制的行为和生化效应。感染 EcoHIV 的小鼠每日接受 vehicle 或 nSMase2 抑制剂（R）-（1-（3-（3,4-二甲氧基苯基）-2,6-二甲基咪唑并[1,2-b]哒嗪-8-基）吡咯烷-3-基）-氨基甲酸酯（PDDC）治疗，感染后 3 周开始治疗。治疗 2 周后，对小鼠进行行为测试。EcoHIV 感染的小鼠表现出与 MDD 和 CI 相关的行为异常，而 PDDC 治疗可逆转这些异常。EcoHIV 感染显著增加了皮质脑 nSMase2 活性，导致鞘磷脂和神经酰胺水平的趋势变化，而 PDDC 治疗可使其恢复正常。EcoHIV 感染的小鼠还表现出脑源性 EVs 水平升高和 miRNA 载物改变，包括 miR-183-5p、miR-200c-3p、miR-200b-3p 和 miR-429-3p，这些 miRNA 与 MDD 和 CI 相关；所有这些都可以通过 PDDC 来调节。总之，抑制 nSMase2 可能是治疗 HIV 相关 CI 和 MDD 的一种新的治疗策略。
