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

Xiaolei Zhu; Kristen R. Hollinger; Yiyao Huang; Alejandra Borjabad; Boe-Hyun Kim; Tanina Arab; Ajit G. Thomas; Mohammed Moniruzzaman; Lyndah Lovell; Andrey Turchinovich; Kenneth W. Witwer; David J. Volsky; Norman J. Haughey; Barbara S. Slusher

Neurobiology of Disease (Jul 2022)

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

Xiaolei Zhu,
Kristen R. Hollinger,
Yiyao Huang,
Alejandra Borjabad,
Boe-Hyun Kim,
Tanina Arab,
Ajit G. Thomas,
Mohammed Moniruzzaman,
Lyndah Lovell,
Andrey Turchinovich,
Kenneth W. Witwer,
David J. Volsky,
Norman J. Haughey,
Barbara S. Slusher

Affiliations

Xiaolei Zhu: 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
Kristen R. Hollinger: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Yiyao Huang: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Alejandra Borjabad: Department of Medicine, Infectious Diseases Division, Icahn School of Medicine at Mount Sinai, NY, New York, USA
Boe-Hyun Kim: Department of Medicine, Infectious Diseases Division, Icahn School of Medicine at Mount Sinai, NY, New York, USA
Tanina Arab: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Ajit G. Thomas: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Mohammed Moniruzzaman: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Lyndah Lovell: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Andrey Turchinovich: Heidelberg Biolabs GmbH, Heidelberg, Germany; Division of Cancer Genome Research, German Cancer Research Center, Heidelberg, Germany
Kenneth W. Witwer: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
David J. Volsky: Department of Medicine, Infectious Diseases Division, Icahn School of Medicine at Mount Sinai, NY, New York, USA
Norman J. Haughey: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Barbara S. Slusher: 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; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Corresponding author at: 855 N. Wolfe Street, Rangos 278, Baltimore, MD 21205, USA.

Journal volume & issue: Vol. 169
p. 105734

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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