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

Abstract

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.

Absence of Glia Maturation Factor Protects Dopaminergic Neurons and Improves Motor Behavior in Mouse Model of Parkinsonism

“…Post-mortem analysis and in vivo imaging of PD patient brains showed activation of microglia, astrogliosis and infiltration of peripheral immune cells in the SN and STR (Hirsch et al, 1998; Ouchi et al, 2009; Tansey and Goldberg, 2010). These features were also observed in experimental rodents brain after MPTP treatment (Khan et al, 2013; Lee et al, 2014; Noelker et al, 2013). The glia maturation factor (GMF), discovered and characterized in our laboratory, is a conserved protein in mammalian brain/central nervous system (Lim et al, 1989; Lim et al, 1990; Zaheer et al, 2011a).…”

Astrocytic Oxidative/Nitrosative Stress Contributes to Parkinson’s Disease Pathogenesis: The Dual Role of Reactive Astrocytes

“…The majority of PD cases are of unknown etiology, but numerous studies demonstrate that neuroinflammatory signaling significantly contributes to the initiation of reactive astrogliosis and consequent astrocytic oxidative/nitrosative stress [79,80,81]. Experimental evidence also indicates that neuroinflammation and astrocytic oxidative/nitrosative stress reciprocally modulate each other to promote neurotoxicity and PD pathogenesis [82].…”

Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

“…Ach released from the vagus nerve termination, agonizes α7 nAChR, which responds by opening a central channel allowing an influx of Ca 2+ into macrophages [11,30,31]. Increased levels of Ca 2+ activate the nuclear factor κ B (NF κB) resulting in suppression of inflammatory cytokine production including tumor necrosis factor α (TNFα), high mobility group box of proteins and interleukin 6 (IL-6) [32,33].…”