Neutral sphingomyelinase 2 inhibition attenuates extracellular vesiclerelease and improves neurobehavioral deficits in murine HIV.

Zhu X. et al.

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.

D-Plex small RNA-seq

Share this article

July, 2022


Products used in this publication

  • Small RNA library preparation with UMI for Illumina
    D-Plex Small RNA-seq Kit x24 for Illumina
  • Illumina index primers for D-Plex small RNA library preparation with UMI
    D-Plex 24 Single Indexes for Illumina - Set #A


  • Symposium: "Signaling through Chromatin"
    Grenoble, France
    Oct 2-Oct 4, 2023
  • EMBL Symposium: The non-coding genome
    Heidelberg, Germany
    Oct 11-Oct 14, 2023
    Crete, Greece
    Oct 15-Oct 20, 2023



The European Regional Development Fund and Wallonia are investing in your future.

Extension of industrial buildings and new laboratories.

       Site map   |   Contact us   |   Conditions of sales   |   Conditions of purchase   |   Privacy policy   |   Diagenode Diagnostics