Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV

Neurobiology of Disease

Kristen R. Hollinger¹  David J. Volsky²  Tanina Arab³  Boe-Hyun Kim³  Barbara S. Slusher³  Norman J. Haughey⁴  Alejandra Borjabad⁴  Ajit G. Thomas⁴  Lyndah Lovell⁵  Kenneth W. Witwer⁶  Mohammed Moniruzzaman⁷  Xiaolei Zhu⁷  Yiyao Huang⁷  Andrey Turchinovich⁷ 

[1] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Division of Cancer Genome Research, German Cancer Research Center, Heidelberg, Germany;Department of Medicine, Infectious Diseases Division, Icahn School of Medicine at Mount Sinai, NY, New York, USA;Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Heidelberg Biolabs GmbH, Heidelberg, Germany;Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA;

关键词: Neutral sphingomyelinase 2;    Depression;    Sleep;    HIV;    Extracellular vesicle;    EcoHIV;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown