As the population of older individuals living with HIV continues to expand, identifying non-euphoric therapeutic interventions for HIV-associated complications is essential. While cannabidiol (CBD) has demonstrated neuroprotective potential, its effects following prolonged exposure in the context of an aging biological environment remain poorly understood. This study utilized aged (15–18 months) male and female HIV-1 Tat transgenic mice to evaluate the impact of chronic CBD (3 mg/kg, s.c., for 12 weeks). A behavioral battery was employed to assess object recognition memory, anxiety-like behavior, spontaneous nociception, and locomotor activity. Subsequently, liquid chromatography-tandem mass spectrometry and Western blotting were used to map endocannabinoid ligands (AEA, 2-AG, AA), metabolic enzymes (FAAH, MAGL), and receptors (CB1R, CB2R, GPR55) across the prefrontal cortex, amygdala, brainstem, and spinal cord. Results indicated that chronic CBD improved recognition memory specifically in female Tat(+) mice. While CBD treatment did not affect spinal cord-related tail flick sensitivity it universally increased supraspinal hot plate sensitivity. Chronic CBD treatment also elevated baseline body temperature and modulated body mass without impairing general locomotion. Furthermore, chronic CBD restructured the eCB signaling landscape across all examined CNS regions in a highly sex- and genotype-dependent manner. Notably, cannabinoid receptor and GPR55 expression exhibited distinct regulatory shifts governed by significant three-way interactions. These findings demonstrate that chronic CBD intervention interacts with the eCB system of aged mice in a region-specific manner. These results underscore the critical importance of considering age, sex, and treatment duration when evaluating cannabinoid-based therapies for the management of neuroHIV.
Barkha J. Yadav-Samudrala, Morgan L Johnson, Ashima Ale et al.· PLoS ONE· 0 citations
While combined antiretroviral therapy (cART) has transitioned HIV-1 into a manageable chronic condition, it fails to eradicate latent viral reservoirs in the central nervous system (CNS) that drive persistent neuroinflammation and synaptodendritic injury. Consequently, people living with human immunodeficiency virus type-1 (HIV-1) often utilize cannabis to manage neurological symptoms, yet the long-term impact of exogenous cannabinoids on the HIV-1-burdened brain remains poorly understood. In this study, we utilized the HIV-1 Tg26 mouse model to evaluate how chronic Δ9-tetrahydrocannabinol (THC, 3mg/kg) exposure influences motor coordination, thermal nociception, and endocannabinoid (eCB) signaling in the context of constitutive viral protein expression. Our results demonstrate that HIV-1 viral protein expression was associated with impaired acquisition of cerebellum-dependent motor learning in a sex-dependent manner. This deficit was primarily driven by females and coincided with altered markers of eCB plasticity, characterized by elevated monoacylglycerol lipase (MAGL) expression and a depletion of 2-arachidonoylglycerol (2-AG). Conversely, males exhibit increased cerebellar CB1R and CB2R expression, which paralleled preserved rotarod performance. In the spinal cord, viral protein expression was associated with thermal hyposensitivity and a reduction in 2-AG and cannabinoid receptor levels, a pattern consistent with HIV-1-associated alterations in sensory processing circuits. While chronic THC failed to produce detectable antinociceptive effects, consistent with spinal CB1R downregulation, it successfully attenuated the temporal decline of motor coordination with upregulating cerebellar CB1R. Data from a separate acute THC cohort demonstrated detectable THC and metabolite concentrations in plasma and cortex, while also revealing sex- and genotype-dependent differences in these measures. Together, these findings 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.
Barkha J. Yadav-Samudrala, Laith E. Sawaqed, Caitlin J. Huguely Wilkinson et al.· Brain Research Bulletin· 0 citations