The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies

Current HIV/AIDS Reports, Journal Year: 2024, Volume and Issue: 21(3), P. 87 - 115

Published: April 11, 2024

Language: Английский

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Effects of acute cannabidiol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: March 5, 2024

Background Some evidence suggests that cannabidiol (CBD) has potential to help alleviate HIV symptoms due its antioxidant and anti-inflammatory properties. Here we examined acute CBD effects on various behaviors the endocannabinoid system in Tat transgenic mice. Methods mice (female/male) were injected with (3, 10, 30 mg/kg) assessed for antinociception, activity, coordination, anxiety-like behavior, recognition memory. Brains taken quantify endocannabinoids, cannabinoid receptors, catabolic enzymes. Additionally, metabolite 7-hydroxy-CBD quantified plasma cortex. Results decreased supraspinal-related nociception locomotion. sex had little no any of behavioral measures. For male was associated elevated concentration proinflammatory arachidonic acid CNS regions, including cerebellum also showed higher FAAH expression levels Tat(+) males. GPR55 striatum females compared metabolism altered by expression. Conclusion Findings indicate are not Tat, minimal behavior system.

Language: Английский

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HIV-1 Tat protein alters medial prefrontal cortex neuronal activity and recognition memory

iScience, Journal Year: 2025, Volume and Issue: 28(3), P. 112075 - 112075

Published: Feb. 22, 2025

Despite advancements in combined antiretroviral therapy, human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) continue to affect 40%-50% of people living with HIV. While neuroimaging studies have revealed HIV-1-induced alterations cortical networks and brain macrostructures, it still remains unclear how individual neurons the medial prefrontal cortex (mPFC) are affected during recognition memory. Using vivo calcium imaging an HIV-1 transactivator transcription (Tat) transgenic mouse model, we examined mPFC neuronal activity a novel object memory task. Our findings show that HIV Tat expression reduces overall Tat(+) mice without altering number activated cells. Moreover, distinct subpopulations up- downmodulated both Tat(-) depending on exploration. Importantly, familiarity-driven increases were disrupted by expression. These enhance our understanding HAND may inform future pharmacological strategies aimed at restoring cognitive function.

Language: Английский

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Acute Effects of Monoacylglycerol Lipase Inhibitor ABX1431 on Neuronal Hyperexcitability, Nociception, Locomotion, and the Endocannabinoid System in HIV-1 Tat Male Mice

Cannabis and Cannabinoid Research, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 23, 2024

Background: Evidence suggests that monoacylglycerol lipase (MAGL) inhibitors can potentially treat HIV symptoms by increasing the concentration of 2-arachidonoylglycerol (2-AG).We examined a selective MAGL inhibitor ABX1431 in context neuroHIV.Methods: To assess effects ABX1431, we conducted vitro and vivo studies.In calcium imaging on frontal cortex neuronal cultures was performed to evaluate role (10, 30, 100 nM) transactivator transcription (Tat)-induced hyperexcitability.Following experiments, experiments were using Tat transgenic male mice.Mice treated with 4 mg/kg assessed for antinociception tail-flick hot plate assays followed locomotor activity.After behavioral their brains harvested quantify endocannabinoids (eCB) related lipids through mass spectrometry, cannabinoid type-1 -2 receptors (CB 1 R CB 2 R) quantified western blot.Results: In studies revealed adding directly significantly increased intracellular concentration, which completely reversed at all concentrations.Preincubating antagonists showed exhibited its partially R.In demonstrated acute overall total distance traveled speed mice regardless genotype.Mass spectrometry blot analyses differential eCB system based expression.The 2-AG levels upregulated following treatment striatum spinal cord.Arachidonic acid (AA) also vehicle-treated Tat( + ) mice.No changes noted expression levels; however, ABX1431-treated Tat(À) only. Conclusion:Findings indicate has potential neuroprotective mediated R. Acute shows antinociceptive effects, seems alter activity, upregulating cord.

Language: Английский

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Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of endogenous signaling ligand 2-arachidonoylglycerol, neuroprotective endocannabinoid intimately linked to central nervous system (CNS) disorders associated with neuroinflammation. In quest for novel MAGL inhibitors, focused screening approach on Roche library subset provided reversible benzoxazinone hit exhibiting high efficiency. The subsequent design three-dimensional

Language: Английский

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Inhibitory Neurotransmission Is Sex-Dependently Affected by Tat Expression in Transgenic Mice and Suppressed by the Fatty Acid Amide Hydrolase Enzyme Inhibitor PF3845 via Cannabinoid Type-1 Receptor Mechanisms

Cells, Journal Year: 2022, Volume and Issue: 11(5), P. 857 - 857

Published: March 2, 2022

(1) Background. The endocannabinoid (eCB) system, which regulates physiological and cognitive processes, presents a promising therapeutic target for treating HIV-associated neurocognitive disorders (HAND). Here we examine whether upregulating eCB tone has potential protective effects against HIV-1 Tat (a key HIV transactivator of transcription) protein-induced alterations in synaptic activity. (2) Methods. Whole-cell patch-clamp recordings were performed to assess inhibitory GABAergic neurotransmission prefrontal cortex slices transgenic male female mice, the presence absence fatty acid amide hydrolase (FAAH) enzyme inhibitor PF3845. Western blot mass spectrometry analyses assessed cannabinoid receptor protein expression as well endogenous ligands, respectively, determine impact exposure on system. (3) Results. activity was significantly altered upon based sex, whereas effectiveness PF3845 suppress mice not by or sex involved CB1R-related mechanisms that depended calcium signaling. Additionally, our data indicated sex-dependent changes AEA related non-eCB lipids induction. (4) Conclusion. Results highlight sex- and/or Tat-dependent signaling further increase understanding about role FAAH inhibition neuroHIV.

Language: Английский

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Effects of acute Δ9-tetrahydrocannabinol on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

Brain Research, Journal Year: 2023, Volume and Issue: 1822, P. 148638 - 148638

Published: Oct. 17, 2023

Cannabis use is highly prevalent especially among people living with HIV (PLWH). Activation of the anti-inflammatory and neuroprotective endocannabinoid system by phytocannabinoids, i.e. Δ

Language: Английский

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Cannabinoid receptor 1 positive allosteric modulator ZCZ011 shows differential effects on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(6), P. e0305868 - e0305868

Published: June 24, 2024

The cannabinoid receptor type 1 (CB R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the potential of CB R by direct activation limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating utilizing positive allosteric modulators (PAMs). Studies have shown that PAMs (ZCZ011 and GAT211) are effective in mouse models Huntington’s disease neuropathic pain, hence, we assess ZCZ011 well-established model neuroHIV. current study investigates effect chronic treatment (14 days) behavioral paradigms endocannabinoid system HIV-1 Tat transgenic female male mice. Chronic (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless sex genotype. differential effects were noted hot plate latency, motor coordination, recognition memory mice only, with increasing latency improving coordination memory. Only minor no alterations seen related lipids except cerebellum, where was more pronounced Moreover, AEA PEA levels cerebellum positively correlated improved In summary, these findings indicate antinociception, memory, based expression, making options HAND without

Language: Английский

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A potent and selective inhibitor for the modulation of MAGL activity in the neurovasculature

PLoS ONE, Journal Year: 2022, Volume and Issue: 17(9), P. e0268590 - e0268590

Published: Sept. 9, 2022

Chronic inflammation and blood–brain barrier dysfunction are key pathological hallmarks of neurological disorders such as multiple sclerosis, Alzheimer’s disease Parkinson’s disease. Major drivers these pathologies include pro-inflammatory stimuli prostaglandins, which produced in the central nervous system by oxidation arachidonic acid a reaction catalyzed cyclooxygenases COX1 COX2. Monoacylglycerol lipase hydrolyzes endocannabinoid signaling lipid 2-arachidonyl glycerol, enhancing local pools brain leading to cyclooxygenase-mediated prostaglandin production neuroinflammation. inhibitors were recently shown act effective anti-inflammatory modulators, increasing glycerol levels while reducing including PGE 2 PGD . In this study, we characterized novel, highly selective, potent reversible monoacylglycerol inhibitor (MAGLi 432) mouse model lipopolysaccharide-induced permeability both human cells neurovascular unit: microvascular endothelial cells, pericytes astrocytes. We confirmed expression specific unit vitro , with showing highest level activity. However, MAGLi 432 did not ameliorate vivo or reduce cytokines brain. Our data confirm provide basis for further cell-specific analysis context caused inflammatory insults.

Language: Английский

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Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure

Viruses, Journal Year: 2023, Volume and Issue: 15(3), P. 590 - 590

Published: Feb. 21, 2023

Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. the viral protein Tat directly induce neuronal injury within reward emotionality brain circuitry, including prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms more indirect pathways through neuroinflammation, of which be worsened by opioid co-exposure. To assess whether excitotoxicity and/or neuroinflammation might drive depressive behaviors in persons infected with (PWH) those who opioids, male mice were exposed to HIV-1 for eight weeks, given escalating doses morphine during last two assessed depressive-like behavior. expression decreased sucrose consumption adaptability, whereas administration increased chow exacerbated Tat-induced decreases nesting burrowing-activities associated well-being. Across all treatment groups, behavior correlated proinflammatory cytokines PFC. Nevertheless, supporting theory innate immune responses adapt chronic exposure, most unaffected or morphine. Further, PFC levels anti-inflammatory cytokine IL-10, administration. Tat, but not morphine, dendritic spine density on layer V pyramidal neurons anterior cingulate. Together, our findings suggest differentially synaptic losses, fatigue

Language: Английский

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