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 + saline, (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 decreased 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.