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CNI-1493 Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in the Acute MPTP Mouse Model of Parkinson's Disease

Background: Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons in the substantia nigra. Neuroinflammatory processes have been shown to be a key component of this neurodegeneration and, as such, small molecule compounds which inhibit these inflammatory events are a critical research focus. Objective: CNI-1493 is an anti-inflammatory compound that strongly inhibits macrophages and also stimulates the cholinergic anti-inflammatory pathway. We have examined whether CNI-1493 has a neuroprotective effect in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Methods: CNI-1493 (8 mg/kg i.p.) or placebo administration was started 1 day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57/Bl6 mice - either treated with CNI-1493 or with placebo - were injected intraperitoneally 4 times at 2-hour intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or 7 days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis. Results: Administration of CNI-1493 markedly protected tyrosine hydroxylase-positive substantia nigra neurons against MPTP neurotoxicity. CNI-1493 treatment in the MPTP model was also accompanied by a profound reduction of activated microglia within the substantia nigra, as measured by ionized calcium-binding adapter molecule-1 staining. Conclusions: These findings support that CNI-1493 could reduce the MPTP-induced toxicity likely by inhibition of neuroinflammatory responses. The neuroprotective effect of CNI-1493 suggests that CNI-1493 might be a valuable neuroprotective candidate in the future treatment of PD.