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

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

Results demonstrate that HIV-1 viral protein expression was associated with impaired acquisition of cerebellum-dependent motor learning in a sex-dependent manner and identify sex-specific eCB signaling as a critical factor associated with the neurobiological response to HIV-1 proteins and provide a biological framework for understanding sex-dependent variability in cannabinoid efficacy.

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

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.

677. Effects of cannabidiol on social behaviour of Shank3 and Fmr1 mutant mice

Abstract Background Despite the growing prevalence of autism, no pharmacological interventions have been approved for core symptoms. The endocannabinoid system (ECS) has recently gained interest as a potential target for treating autism. Cannabidiol (CBD), a compound found in Cannabis sativa, is a potential treatment due to its tolerability and promising early results in fragile X syndrome patients. Aims & Objectives Here, we aimed to evaluate the efficacy of CBD in treating social deficits and restrictive/repetitive behaviours in Shank3 and Fmr1 knockout (KO) mice. Method Male and female mice were tested in the 3-chamber social apparatus or for self-grooming and in the open field (baseline), followed by five daily treatments with vehicle or CBD (s.c., 5 mg/kg for males, 50 mg/kg for females), and retested post-treatment. Results At baseline and following vehicle treatment, male and female Shank3 and Fmr1 KO mice exhibited deficits in social novelty, which were restored to control levels following CBD administration. Meanwhile, self-grooming (increased in Shank3 KO mice) and open-field exploration (decreased locomotion in Shank3 KO mice) were not affected by CBD. Females had hippocampal CBD levels ~11.6 times higher than males (consistent with dosing) and exhibited elevated anandamide (AEA) levels in CBD-treated groups. Transcriptomic analysis of the hippocampus revealed few sex- and strain-specific differentially expressed genes (DEGs) and only three mRNAs regulated by CBD (Vwf and Lcn2 in females and Grm2 in Shank3 KO mice). Discussion & Conclusions These findings highlight the potential for CBD as a treatment for social deficits in syndromic autism and indicate that the therapeutic effect may be driven by dose-, sex-, or strain-specific mechanisms.

Δ9-Tetrahydrocannabinol Modulates Hippocampal Neurogenesis in Female Wistar Rats: Interaction with Estradiol

PT320, a GLP-1 receptor agonist, mitigates nucleus accumbens–associated depression- and anxiety-like behaviors in MitoPark mice of Parkinson's disease

By restoring neurotrophic signaling and dopaminergic function, PT320 represents a promising therapeutic strategy for PD-related anxiety and depression by restoring neurotrophic signaling and dopaminergic function in the nucleus accumbens.