Neuroprotection of low dose carbon monoxide in Parkinson’s disease models commensurate with the reduced risk of Parkinson’s among smokers

Abstract

ABSTRACTParadoxically, cigarette smoking is associated with a reduced risk of PD. This led us to hypothesize that carbon monoxide (CO) levels, which are constitutively 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. Accordingly, 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 protective effects of smoking evident in PD patients. These data suggest that low-dose CO may slow the onset of symptoms and limit pathology in PD patients.TeaserNeuroprotective effects of carbon monoxide in rodent PD models are consistent with the protective effect of smoking on PD risk