Abstract
While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus 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 for supplemental strategies to combat virus-associated pathology presenting frequently as HIV-associated neurocognitive disorders (HAND), the present study aimed to characterize the potential utility of inhibiting monoacylglycerol lipase (MAGL) activity to increase inhibitory activity at cannabinoid receptor-type 1 receptors through upregulation of 2-arachidonoylglycerol (2-AG) and downregulation of its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium and increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic MJN110 administration in vivo increased 2-AG levels in the prefrontal cortex (PFC) and striatum across Tat(+) and Tat(–) groups and restored PFC N-arachidonoylethanolamine (AEA) levels in Tat(+) subjects. While Tat expression significantly increased rate of reward-related behavioral task acquisition in a novel discriminative stimulus learning and cognitive flexibility assay, MJN110 altered reversal acquisition specifically in Tat(+) mice to rates indistinguishable from Tat(–) controls. Collectively, our results suggest a neuroprotective role of MAGL inhibition in reducing neuronal hyperexcitability, restoring dendritic arborization complexity, and mitigating neurocognitive alterations driven by viral proteins associated with latent HIV-1 infection.
Highlights
With the advent of combination antiretroviral therapy, mortality rates among human immunodeficiency virus type-1 (HIV-1)-infected individuals have decreased by more than 50% [1]
Glutamate-Induced Intracellular [Ca2+]i Increase Was Dysregulated by Tat Pretreatment and Downregulated by MJN110 in a Concentration-Dependent Manner To understand the role of monoacylglycerol lipase (MAGL) inhibition and Tat in mediating neurotoxicity after a glutamate challenge, [Ca2+]i responses of frontal cortex neuron cultures pretreated with Tat (50 nM) and MJN110 (0–1 μM) and challenged with glutamate (10 μM) during imaging (Figure 1) were investigated
A three-way mixed analysis of variance (ANOVA) was conducted with Tat application [2 levels: control, Tat 50 nM], MJN110 treatment (3 levels: vehicle, 0.5 μM, 1 μM) as betweensubjects factors and time as a within-subjects factor
Summary
With the advent of combination antiretroviral therapy (cART), mortality rates among human immunodeficiency virus type-1 (HIV-1)-infected individuals have decreased by more than 50% [1]. CART is largely unable to deplete expression of residual HIV-1 proteins in the tissues of the central nervous system [CNS; [6,7,8,9]]. One such viral protein, transactivator of transcription (Tat) enters the host genome early after infection [10], and has been shown to induce synaptodendritic injury and cognitive deficits in murine models of HIV-1 [11,12,13,14] by altering the cellular environment through proinflammatory processes which contribute significantly to the pathogenesis of HAND [7, 15, 16]. Therapeutic enhancement of cannabinoid signaling by enzyme inhibitors appears to be localized to sites of injury in contrast to direct agonists, which more widely affect cannabinoid signaling across the brain and are more likely to drive off-target effects [24,25,26,27]
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