JN403, an alpha-7-nicotine-acetylcholine-receptor agonist, reduces alpha-synuclein induced inflammatory parameters ofin vitromicroglia but fails to attenuate the reduction of TH positive nigral neurons in a focal alpha-synuclein overexpression mouse model of Parkinson’s disease

• DOI: 10.1101/2020.04.04.996892
• Publication Date: 2020-04-06T03:59:29Z
• Authors: Bolam Lee; Carmen Noelker; Dominik Feuerbach; Lars Timmermann; W.-H Chiu; Wolfgang H. Oertel
• Keywords: Proinflammatory cytokine

Abstract Alpha-7-nicotine-acetylcholine-receptor (α7-nAChRs) agonists modulate the cholinergic antiinflammatory pathway to attenuate proinflammatory signals and reduce dopaminergic neuronal cell loss in toxin-induced experimental murine models of Parkinson’s disease (PD). The protein α-synuclein (αSyn) is considered represent major pathogenic component etiology progression sporadic PD. However, no research has been performed evaluate effect α7-nAChR human αSyn mediated We, therefore, investigated compound JN403, an specific agonist, treated vitro microglia culture a overexpression vivo mouse model. In primary cells, fragment 61-140 treatment increased release nitric oxide (NO), tumor necrosis factor (TNF)-α interleukin (IL)-6, decreased viability. contrast, 100 nM or 1 μM JN403 co-incubation significantly reduced level NO TNF-α microglial cells. For in-vivo testing recombinant adeno-associated viral vector (rAAV)-mediated unilateral intranigral wild-type-αSyn (WT-αSyn) control luciferase (luc) was induced via stereotactic delivery C57/BL6N mice. Targeted WT-αSyn 20% number tyrosine hydroxylase (TH) positive (+) nigral neurons after 10 weeks. Subcutaneous daily 30 mg/kg over 9 weeks starting at postoperative week did not alter decrease TH+ numbers, density striatal terminals groups also recovered by treatment. summary, agonist shows beneficial on ameliorating exposed significant found model