Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice

Abstract

In Parkinson’s disease patients pathology follows a characteristic pattern involving inter alia the enteric nervous system, the dorsal motor nucleus of the vagus, the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits mitochondrial Complex I, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce PD pathology in all the above-mentioned nervous system structures in wild-type mice. Interestingly, HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (CNS) (detection limit [rotenone]<20nM), indicating that rotenone is detoxified by the liver. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD progression and to reproduce the neuroanatomical and neurochemical features of PD staging. Thus, providing new insight into how environmental factors could trigger PD and pointing out a transsynaptic mechanism by which PD might propagate to and through the CNS.