PNU-120596, an α7 nicotinic acetylcholine receptor positive allosteric modulator, attenuates microglial activation and protects dopaminergic neurons from inflammatory injury independently of canonical α7 nicotinic acetylcholine receptor signaling.

Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease, with microglial overactivation contributing to dopaminergic neuronal loss. Recent studies indicate that α7 nicotinic acetylcholine (nACh) receptors modulate the inflammatory responses of immune cells. Although α7 nACh receptors are expressed in microglia, their precise role in microglial activation is unclear. In this study, we determined whether α7 nACh receptor stimulation could protect dopaminergic neurons from inflammation-induced injury. Nicotine and PNU-120596, an α7 nACh receptor positive allosteric modulator, significantly attenuated dopaminergic neurotoxicity in primary mesencephalic cultures treated with inflammatory stimuli. However, only PNU-120596 inhibited microglial activation, and this effect was not reversed following treatment with an α7 nACh receptor antagonist, suggesting a mechanism distinct from the classical α7 nACh receptor-mediated signaling. PNU-120596 suppressed inducible nitric oxide synthase (iNOS) expression and signal transducer and activator of transcription 1 (STAT1) phosphorylation, but did not alter the nuclear translocation of nuclear factor-κB. Moreover, in BV2 cells, which lack detectable full-length α7 nACh receptor mRNA, PNU-120596 also suppressed iNOS expression and STAT1 phosphorylation. These results suggest that PNU-120596 exerts anti-inflammatory and neuroprotective effects independently of canonical pathways that are not dependent on classical α7 nACh receptor-mediated signaling.