Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV.
Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV.
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中性鞘磷脂酶2抑制作用减轻细胞外囊泡的释放，并改善鼠HIV中的神经行为缺陷。
DOI：
10.1016/j.nbd.2022.105734
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发表时间：
2022-07
影响因子：
6.1
通讯作者：
Slusher, Barbara S.
中科院分区：
文献类型：
--
作者：
Zhu, Xiaolei;Hollinger, Kristen R.;Borjabad, Alejandra;Kim, Boe-Hyun;Arab, Tanina;Thomas, Ajit G.;Moniruzzaman, Mohammed;Lovell, Lyndah;Turchinovich, Andrey;Witwer, Kenneth W.;Volsky, David J.;Haughey, Norman J.;Slusher, Barbara S.
与普通人群相比，艾滋病毒感染者 (PLH) 的认知障碍 (CI) 和重度抑郁症 (MDD) 发生率明显更高。中性鞘磷脂酶 2 (nSMase2) 参与神经酰胺和细胞外囊泡 (EV) 的生物合成，这两者在 PLH、CI 和 MDD 中均失调。在这里，我们评估了感染 EcoHIV 的小鼠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。小鼠感染了 EcoHIV，并在感染后 3 周开始每日使用载体或 nSMase2 抑制剂 (R)-(1-(3-(3,4-二甲氧基苯基)-2,6-二甲基咪唑[1,2-b]哒嗪-8-基)吡咯烷-3-基)-氨基甲酸酯 (PDDC) 进行治疗。治疗两周后，对小鼠进行行为测试。感染 EcoHIV 的小鼠表现出与 MDD 和 CI 相关的行为异常，但 PDDC 治疗可逆转这些行为异常。 EcoHIV 感染显着增加了大脑皮质 nSMase2 活性，导致鞘磷脂和神经酰胺水平发生趋势变化，而 PDDC 治疗使这些水平恢复正常。感染 EcoHIV 的小鼠还表现出脑源性 EV 水平增加和 microRNA 含量改变，包括 miR-183-5p、miR-200c-3p、miR-200b-3p 和 miR-429-3p，已知这些与 MDD 和 CI 相关；所有均通过 PDDC 标准化。总之，抑制 nSMase2 代表了治疗 HIV 相关 CI 和 MDD 的一种可能的新治疗策略。
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.
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DOI：
10.1080/13803395.2014.943696
发表时间：
2014
影响因子：
2.2
作者：
Fellows RP;Byrd DA;Morgello S
通讯作者：
Morgello S
影响因子：
5.1
作者：
Du, Yumin;Chi, Xiaowen;An, Wen
通讯作者：
An, Wen
影响因子：
16
作者：
Arab, T.;Raffo-Romero, A.;Sautiere, P-E
通讯作者：
Sautiere, P-E
影响因子：
3.7
作者：
Fitzgerald, Paul J.;Yen, Jessica Y.;Watson, Brendon O.
通讯作者：
Watson, Brendon O.
影响因子：
5.3
作者：
Fan, Yan;Gao, Xiang;He, Johnny J.
通讯作者：
He, Johnny J.