Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat DOI Creative Commons

Alexis F. League,

Benjamin L. Gorman,

Douglas J. Hermes

et al.

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 12

Published: Aug. 16, 2021

While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows supplemental combat virus-associated pathology presenting frequently HIV-associated neurocognitive disorders (HAND), present study aimed characterize potential utility inhibiting monoacylglycerol lipase (MAGL) activity increase inhibitory at cannabinoid receptor-type receptors through upregulation 2-arachidonoylglycerol (2-AG) downregulation its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic administration vivo 2-AG levels prefrontal (PFC) striatum across Tat(+) Tat(-) groups restored PFC N-arachidonoylethanolamine (AEA) subjects. Tat expression rate reward-related behavioral task acquisition a novel discriminative stimulus learning cognitive flexibility assay, altered reversal specifically mice rates indistinguishable from controls. Collectively, our results suggest neuroprotective role inhibition reducing neuronal hyperexcitability, restoring arborization complexity, mitigating alterations driven by associated latent HIV-1 infection.

Language: Английский

Dopaminergic impact of cART and anti-depressants on HIV neuropathogenesis in older adults DOI
Stephanie Matt, Peter J. Gaskill

Brain Research, Journal Year: 2019, Volume and Issue: 1723, P. 146398 - 146398

Published: Aug. 21, 2019

Language: Английский

Citations

27
Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection DOI
Lauren Killingsworth, Serena Spudich

Seminars in Immunopathology, Journal Year: 2022, Volume and Issue: 44(5), P. 709 - 724

Published: July 26, 2022

Language: Английский

Citations

15
Role of macrophages in HIV pathogenesis and cure: NIH perspectives DOI

Jeymohan Joseph,

William Daley,

Diane M. Lawrence

et al.

Journal of Leukocyte Biology, Journal Year: 2022, Volume and Issue: 112(5), P. 1233 - 1243

Published: Sept. 8, 2022

Abstract Macrophages play a significant role in HIV infection and contribute to pathogenesis of comorbidities as well establishment the viral reservoir people living with HIV. While CD4+ T cells are considered main targets infection, infected macrophages resist cytopathic effects contributing persistent reservoir. Furthermore, activated drive inflammation development comorbidities, including HIV-associated CNS dysfunction. Better understanding persistence, can lead innovative therapeutic strategies address HIV-related outcomes In October 2021, National Institute Mental Health Ragon MGH, MIT, Harvard conducted virtual meeting on pathogenesis, cure. This review article captures key highlights from this provides an overview interests activities various NIH institutes involved supporting research

Language: Английский

Citations

13
Extracellular vesicles released from macrophages modulates interleukin-1β in astrocytic and neuronal cells DOI Creative Commons

Sunitha Kodidela,

Namita Sinha, Asit Kumar

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Feb. 21, 2023

Abstract We have recently demonstrated that long-term exposure of cigarette smoke condensate (CSC) to HIV-uninfected (U937) and -infected (U1) macrophages induce packaging pro-inflammatory molecules, particularly IL-1β, in extracellular vesicles (EVs). Therefore, we hypothesize EVs derived from CSC-treated CNS cells can increase their IL-1β levels contributing neuroinflammation. To test this hypothesis, treated the U937 U1 differentiated once daily with CSC (10 µg/ml) for 7 days. Then, isolated these human astrocytic (SVGA) neuronal (SH-SY5Y) absence presence CSC. then examined protein expression oxidative stress related proteins, cytochrome P450 2A6 (CYP2A6), superoxide dismutase-1 (SOD1), catalase (CAT). observed lower compared respective EVs, confirming most produced are packaged into EVs. Further, HIV-infected uninfected cells, both CSC, were SVGA SH-SY5Y cells. These treatments showed a significant However, under same conditions, CYP2A6, SOD1, only markedly altered. findings suggest communicate astrocytes via EVs-containing HIV non-HIV setting could contribute

Language: Английский

Citations

8
Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat DOI Creative Commons

Alexis F. League,

Benjamin L. Gorman,

Douglas J. Hermes

et al.

Frontiers in Neurology, Journal Year: 2021, Volume and Issue: 12

Published: Aug. 16, 2021

While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows supplemental combat virus-associated pathology presenting frequently HIV-associated neurocognitive disorders (HAND), present study aimed characterize potential utility inhibiting monoacylglycerol lipase (MAGL) activity increase inhibitory at cannabinoid receptor-type receptors through upregulation 2-arachidonoylglycerol (2-AG) downregulation its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic administration vivo 2-AG levels prefrontal (PFC) striatum across Tat(+) Tat(-) groups restored PFC N-arachidonoylethanolamine (AEA) subjects. Tat expression rate reward-related behavioral task acquisition a novel discriminative stimulus learning cognitive flexibility assay, altered reversal specifically mice rates indistinguishable from controls. Collectively, our results suggest neuroprotective role inhibition reducing neuronal hyperexcitability, restoring arborization complexity, mitigating alterations driven by associated latent HIV-1 infection.

Language: Английский

Citations

16