Cobrotoxin suppresses TLR4-NF-κB/STAT1 signaling to mitigate glia-mediated neuroinflammation and motor deficits in Parkinson's disease.
Cobrotoxin suppresses TLR4-NF-κB/STAT1 signaling to mitigate glia-mediated neuroinflammation and motor deficits in Parkinson's disease.
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Original abstract
Chronic neuroinflammation is implicated in the pathogenesis of Parkinson's disease (PD), contributing to progressive dopaminergic neuron loss. Cobrotoxin (CoTX), a short-chain α-neurotoxin isolated from Naja atra venom, exerts anti-inflammatory and analgesic effects in several inflammation-related disease models. However, whether CoTX modulates glia-mediated neuroinflammation or confers neuroprotection in PD remains unknown. In this study, we conducted a randomized, placebo-controlled clinical trial and preclinical animal studies to explore the therapeutic efficacy and mechanisms of CoTX in PD. A 12-day subcutaneous regimen of Cobratide (an injectable form of CoTX), consisting of 70 μg daily for 5 days, a 2-day interval, and another 5-day course, significantly improved motor symptoms in PD patients, as reflected by the UPDRS Part II + III scores, with a well-tolerated safety profile. These beneficial effects were further validated in both MPTP- and lipopolysaccharide-induced PD mouse models. Specifically, intranasal administration of CoTX ameliorated motor coordination defects, attenuated dopaminergic neuronal loss, and suppressed glia-mediated neuroinflammation in the substantia nigra of MPTP-challenged mice. Mechanistically, CoTX did not directly protect neurons; instead, it conferred indirect neuroprotection by inhibiting neuroinflammation via blockade of the NF-κB/STAT1 signaling cascades. Furthermore, CoTX functionally interacted with TLR4, which may act as a putative molecular target of CoTX. Collectively, these findings demonstrate the anti-neuroinflammatory and neuroprotective effects of CoTX in PD, highlighting its potential as a promising therapeutic candidate.