Neuroprotective activity of the α7-nAChR positive allosteric modulator PNU-120596 on short term outcomes after traumatic brain injury

Traumatic brain injury (TBI) often leads to long-lasting neurological, cognitive, and behavioral impairments. Despite its high global burden, no disease-modifying therapies currently exist to mitigate secondary injury processes that contribute to chronic neurological deficits. Activation of α7 nicotinic acetylcholine receptors (α7-nAChRs), which are expressed on neurons, glia, and immune cells, has been implicated in neuroprotection, modulation of neuronal excitability, and suppression of neuroinflammation. The present study investigated the efficacy of α7-nAChRs using the selective positive allosteric modulator PNU-120596 (PNU) on functional recovery and inflammatory responses. TBI was induced in adult mice using a cortical contusion injury model, which was followed by PNU (1 or 3 mg/kg, ip) treatment for six days. Neurological and behavioral outcomes were assessed using composite neuroscore, beam-walk, rotarod, burrowing, and health assessment tests. Serum inflammatory markers were measured using multiplex assays, hippocampal gene expression and glial activation markers by quantitative PCR. PNU treatment significantly improved neurological motor performance and motor coordination following TBI. In addition, PNU attenuated systemic inflammatory responses, reducing circulating levels of pro-inflammatory cytokines, including IFN-γ, GM-CSF, and IL-12. In the contralateral hippocampus, the lower dose of PNU normalized injury-induced increases in GFAP, IL-1β, and CXCL10 mRNA expression, indicating reduced astrogliosis and inflammatory signaling, whereas the higher dose was ineffective. Collectively, these findings demonstrate that potentiation of α7-nAChRs promotes dose-limited functional recovery and modulates inflammatory responses following TBI. Targeting α7-nAChR signaling may represent a promising therapeutic strategy to improve neurological outcomes after TBI.