Chronic THC exposure modulates behavioral outcomes and endocannabinoid signaling in HIV-1 Tg26 mice in a sex-dependent manner.

Chronic CBD treatment differentially modulates neurobehavioral outcomes and endocannabinoid signaling in an aged HIV-1 Tat transgenic mouse model

It is demonstrated that chronic CBD intervention interacts with the eCB system of aged mice in a region-specific manner and underscores the critical importance of considering age, sex, and treatment duration when evaluating cannabinoid-based therapies for the management of neuroHIV.

Low-Dose Cannabidiol Treatment does not Alter Cognitive Performance in the HIV-1 Transgenic Rat Model of NeuroHIV

The prefrontal cortex as a target of HIV-1 neurotoxicity: molecular mechanisms of viral protein-mediated neurodegeneration and executive dysfunction

Despite the success of combined antiretroviral therapy (cART) in achieving peripheral viral suppression, HIV-associated neurocognitive disorder (HAND) remains a persistent challenge, affecting approximately 50% of people living with HIV. This review identifies the prefrontal cortex (PFC) as a primary target of HIV-1 neurotoxicity, as HIV-1 can directly infect the brain, and cART fails to eliminate the production of viral proteins from latent HIV-microglial reservoirs. The blood–brain barrier receives several hits from HIV-1 proteins, leading to a leaky and highly permeable barrier. Several proteins drive chronic neuroinflammation through inflammasome activation and pyroptosis, and ferroptosis in microglia. Glutamatergic dysregulation in the CNS results in increased neuron excitability and neurotoxicity. Also, overactive complement-mediated synaptic pruning and microglial senescence disrupt the intricate neural networks required for higher-order signaling. Neuroimaging and PFC dysfunction can be linked to specific HIV-1 proteins and their effects on the brain. Clinical symptoms of HAND directly reflect specialized PFC dysfunction. Deficits include impaired executive processes, which can present as lacking foresight for goal-directed actions, poor planning, and difficulty switching between tasks. Significant behavioral changes, including disinhibition, impaired moral reasoning, and increased risk-taking, can also be seen. Patients experience apathy, emotional blunting, and rapid mood shifts. Cognitive impairments include working memory loss, distractibility, and inappropriate memory linking. PFC disruptions can escalate into neuropsychiatric sequelae, driven by damaged dopamine and serotonin pathways. Defining these viral-mediated mechanisms will facilitate the development of pharmacological strategies that target several HIV-mediated neurotoxic pathways to prevent the debilitating characteristics of HAND.

Therapeutic potential of a novel PPARγ agonist in a mouse model of HIV-associated neurocognitive impairment.

HIV-associated neurocognitive impairment (NCI) affects up to 50% of individuals living with HIV, causing cognitive, motor, and behavioral deficits, largely driven by brain inflammation. Activation of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor primarily involved in regulating lipid and glucose metabolism, has demonstrated anti-inflammatory effects in neurodegenerative diseases. However, its efficacy in addressing HIV-associated NCI remains unclear. We investigated whether INT131, a novel selective PPARγ agonist, could mitigate HIV-induced brain inflammation and neurocognitive deficits in male and female mice using the EcoHIV mouse model. Mice were intraperitoneally (IP) injected with either saline or EcoHIV and evaluated six weeks post-infection across four groups: (i) saline control, (ii) saline + INT131 (20 mg/kg/day, administered IP via osmotic pumps for 28 days), (iii) EcoHIV + saline, and (iv) EcoHIV + INT131 (n = 10-12/group). We analyzed the expression of viral genes, inflammatory, and oxidative stress markers in spleen and brain tissues, along with neuroprotective/apoptotic markers, p-NF-κB p65, PPARγ and blood-brain barrier (BBB) tight junction proteins. Behavioral assessment evaluated locomotion, learning, memory and anxiety. In EcoHIV infected male and female spleen and brain tissues, INT131 significantly reduced the expression of viral genes, viral p24, inflammatory cytokines/chemokines, and oxidative stress markers. Furthermore, INT131 mitigated expression of BBB tight junction proteins, PPARγ, and neuroprotective markers. Behavioral deficits induced by EcoHIV were reversed following INT131 treatment in both sexes. These findings suggest that PPARγ could serve as a novel molecular target for the treatment of HIV-associated NCI, with INT131 identified as a promising therapeutic candidate.

Chronic Δ9-Tetrahydrocannabinol Vapor Self-Administration Modulates Gut Microbiota and the Immune and Endocannabinoid Systems in Female Sprague- Dawley Rats

CB1R-dependent mitochondrial biogenesis may contribute to the antidepressant effects of esketamine in a chronic variable stress male mouse model.

Major depressive disorder (MDD) is a leading cause of disability worldwide, and current antidepressants are limited by delayed onset and incomplete efficacy. Esketamine produces antidepressant effects more rapidly than conventional treatments, but its underlying mechanisms remain unclear. We examined whether cannabinoid type 1 receptor (CB1R) signaling is associated with hippocampal mitochondrial biogenesis-related changes following esketamine treatment in a chronic variable stress (CVS) mouse model. Mice underwent 21 days of CVS and received a single intraperitoneal injection of esketamine (15 mg/kg) 24 h before behavioral testing. Hippocampal CB1R, nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and total cytochrome c expression were assessed by Western blotting. Additional groups received the CB1R antagonists AM251 or SR141716A before esketamine administration. CVS induced depressive-like behavioral changes in the forced swim, tail suspension, and novelty-suppressed feeding tests. These effects were accompanied by reduced hippocampal CB1R, NRF1, and TFAM expression and altered total cytochrome c expression. Esketamine reversed the behavioral abnormalities and normalized these molecular changes. Pretreatment with either CB1R antagonist prevented both the behavioral and molecular effects of esketamine. These findings indicate that the antidepressant-like effects of esketamine observed 24 h after administration are associated with CB1R-dependent changes in hippocampal mitochondrial biogenesis-related protein expression. Further studies using direct mitochondrial functional assays and loss-of-function approaches are needed to establish causality.