Activation of alpha 7 nicotinic acetylcholine receptor ameliorates HIV-associated neurology and neuropathology

HIV-associated neurocognitive disorders (HAND) in the era of combination antiretroviral therapy are primarily manifested as impaired behaviours, glial activation/neuroinflammation and compromised neuronal integrity, for which there are no effective treatments currently available. In the current study, we used doxycycline-inducible astrocyte-specific HIV Tat transgenic mice (iTat), a surrogate HAND model, and determined effects of PNU-125096, a positive allosteric modulator of alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) on Tat-induced behavioural impairments and neuropathologies. We showed that PNU-125096 treatment significantly improved locomotor, learning and memory deficits of iTat mice while inhibited glial activation and increased PSD-95 expression in the cortex and hippocampus of iTat mice. Using alpha 7 nAChR knockout mice, we showed that alpha 7 nAChR knockout eliminated the protective effects of PNU-125096 on iTat mice. In addition, we showed that inhibition of p38 phosphorylation by SB239063, a p38 MAPK-specific inhibitor exacerbated Tat neurotoxicity in iTat mice. Last, we used primary mouse cortical individual cultures and neuron-astrocytes co-cultures and in vivo staining of iTat mouse brain tissues and showed that glial activation was directly involved in the interplay among Tat neurotoxicity, alpha 7 nAChR activation and the p38 MAPK signalling pathway. Taken together, these findings demonstrated for the first time that alpha 7 nAChR activation led to protection against HAND and suggested that alpha 7 nAChR modulator PNU-125096 holds significant promise for development of therapeutics for HAND.