Objective: To investigate whether JN403, a novel selective agonist of α-7-nicotine-acetylcholine-receptors (α7-nAChRs) can suppress inflammation and toxicity in human alpha-synuclein (αSyn) induced in vitro and in vivo Parkinson’s disease (PD) models.

Background: α7-nAChR agonists modulate the cholinergic anti-inflammatory pathway to attenuate proinflammatory signals and reduce dopaminergic neuronal cell loss in toxin-induced experimental murine models of PD, as well as in respective parkinsonian non-human primate models. However, no research has been performed to evaluate the effect of α7-nAChR agonists in αSyn mediated models.

Methods: We tested the effect of JN403 in primary mouse microglia cells exposed to human αSyn fragment 61-140, followed by inflammatory parameters measurement. In addition, we performed unilateral stereotactic operation targeting the Substantia nigra pars compacta (SNc), to deliver a recombinant adeno-associated viral vector (rAAV) containing wild-type-human αSyn (hαSyn) or luciferase (luc). JN403 30mg/kg or vehicle was administered daily for 10 weeks beginning on post-operative day 2. Further stereology and histology were performed accordingly. The viral-mediated vectors were provided by the Michael J. Fox Foundation.

Results: Human αSyn fragment 61-140 treatment increased the release of Nitric Oxide (NO), TNF-α and IL-6, and decreased cell viability. In contrast, 100 nM of JN403 pre- and co-incubation significantly reduced the level of NO and TNF-α release in the microglial cells. However, cell viability and IL-6 cytokine release were not affected. The rAAV-mediated hαSyn overexpression reduced 20% of the number of tyrosine hydroxylase (TH) immunoreactive (ir) nigral neurons after 10 weeks. Subcutaneous daily treatment JN403 over 10 weeks had no effect on the number of TH ir nigral neurons (nor Iba1 ir density) in hαSyn or luc overexpression mouse model. The density of TH-ir striatal terminals was unchanged in all groups.

Conclusions: In summary, JN403, an α7-nAChR specific agonist showed a beneficial effect on ameliorating proinflammatory signals in αSyn exposed microglia cells, however, no significant treatment effect was found in intranigral hαSyn overexpression in vivo mouse model. Therapeutic responses vary per experimental models employed, and long-lasting nAChRalpha7 activation may be required for clinical efficacy in future translational in vivo research of PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-jn403-an-%ce%b1-7-nicotine-acetylcholine-receptor-%ce%b17-nachr-agonist-on-human-alpha-synuclein-mediated-in-vitro-and-in-vivo-models-of-parkinsons-disease/