Neuroprotection of low dose carbon monoxide in Parkinson’s disease models commensurate with the reduced risk of Parkinson’s among smokers | npj Parkinson's Disease
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Paradoxically, cigarette smoking is associated with a reduced risk of Parkinson’s Disease (PD). This led us to hypothesize that carbon monoxide (CO) levels, which are constitutively but modestly elevated in smokers, might contribute to neuroprotection. Using rodent models of PD based on α-synuclein (αSyn) accumulation and oxidative stress, we show that low-dose CO mitigates neurodegeneration and reduces αSyn pathology. Oral CO administration activated signaling cascades mediated by heme oxygenase-1 (HO-1), which have been implicated in limiting oxidative stress, and in promoting αSyn degradation, thereby conferring neuroprotection. Consistent with the neuroprotective effect of smoking, HO-1 levels in cerebrospinal fluid were higher in human smokers compared to nonsmokers. Moreover, in PD brain samples, HO-1 levels were higher in neurons without αSyn pathology. Thus, CO in rodent PD models reduces pathology and increases oxidative stress responses, phenocopying possible protective effects of smoking evident in PD patients. These data highlight the potential for low-dose CO-modulated pathways to slow symptom onset and limit pathology in PD patients.

Paradoxically, cigarette smoking is associated with a reduced risk of Parkinson’s Disease (PD). This led us to hypothesize that carbon monoxide (CO) levels, which are constitutively but modestly elevated in smokers, might contribute to neuroprotection.

In this study, we tested the hypothesis that low doses of carbon monoxide (CO), which are constitutively and intermittently elevated in individuals who smoke, might contribute to neuroprotection.

We demonstrate in genetic and toxin models of PD that treatment with low-dose CO preserves SNpc dopamine neurons and associated striatal dopamine.

Further, we show that CO treatment reduces the accumulation of αSyn within neuron somas and reduces the phosphorylation of αSyn that is associated with toxicity. These results suggest that the administration of low-dose CO in rodent PD models may afford neuroprotection and contribute to the reduced risk of PD among smokers.

Until low-dose CO is proven safe in PD, low-dose CO will nonetheless have value as a modulator of PD-relevant pathways with utility for its dissection and treatment.

In the context of the epidemiologic foundation that has identified smoking tobacco as a large inverse risk factor for PD, these results support the potential of pathways modified by low-dose CO to slow disease progression in PD. The present results demonstrating neuroprotection in PD models support further investigation of these pathways in PD.