The α7 nAChR allosteric modulator PNU-120596 amends neuroinflammatory and motor consequences of parkinsonism in rats: Role of JAK2/NF-κB/GSk3β/ TNF-α pathway

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and a leading cause of disability. The current gold standard for PD treatment, L-Dopa, has limited clinical efficacy and multiple side effects. Evidence suggests that activation of α7 nicotinic acetylcholine receptors (α7nAChRs) abrogates neuronal and inflammatory insults. Here we tested whether PNU-120596 (PNU), a type II positive allosteric modulator of α7 nAChR, has a critical role in regulating motor dysfunction and neuroinflammation correlated with the associated PD dysfunction. Neuroprotective mechanisms were investigated through neurobehavioral, molecular, histopathological, and immunohistochemical studies. PNU reversed motor incoordination and hypokinesia induced via the intrastriatal injection of 6-hydroxydopamine and manifested by lower falling latency in the rotarod test, short ambulation time and low rearing incidence in open field test. Tyrosine hydroxylase immunostaining showed a significant restoration of dopaminergic neurons following PNU treatment, in addition to histopathological restoration in nigrostriatal tissues. PNU halted striatal neuroinflammation manifested as a suppressed expression of JAK2/NF-κB/GSk3β accompanied by a parallel decline in the protein expression of TNF-α in nigrostriatal tissue denoting the modulator anti-inflammatory capacity. Moreover, the protective effects of PNU were partially reversed by the α7 nAChR antagonist, methyllycaconitine, indicating the role of α7 nAChR modulation in the mechanism of action of PNU. This is the first study to reveal the positive effects of PNU-120596 on motor derangements of PD via JAK2/NF-κB/GSk3β/ TNF-α neuroinflammatory pathways, which could offer a potential therapeutic strategy for PD.