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

Abstract

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), 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 Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alphasynuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment timedependent 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-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how

Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease

“…In an attempt to mimic the most likely route of rotenone exposure to humans, recent studies have begun to investigate the effects of intra‐gastric administration of rotenone to C57Bl/6J mice (Pan‐Montojo et al ., 2010). Although in early days, it appears that intragastric administration (5 mg·kg −1 5 days a week for 1.5 or 3 months) causes by 3 months a modest degeneration of SNpc cells, accompanied by α‐synuclein inclusions and reduced rotarod performance.…”

The hallmarks of Parkinson's disease

“…Finally, Pan Montojo et al . modeled environmental causes for the ascending spread of α‐synuclein accumulation through intragastric administration of the pesticide rotenone in mice . Resection of the autonomic nerves in these mice stops the spread of the PD‐specific pathology .…”

Lewy pathology and neurodegeneration in premotor Parkinson's disease

“…The lesions have been reported in cross‐sectionally and longitudinally studied cases in which LP was not found at any other predilection sites in the brain,19, 105, 106 and such findings continue to fuel speculation on whether PD begins there 102, 107. The existence of “bulb only” cases does not preclude the possibility that a pathogen from the nose could reach the intestinal lumen and induce α‐synuclein misfolding and aggregation in the intramural plexus neurons before entering the central nervous system (CNS) through retrograde axonal transport and transsynaptic transmission along parasympathetic as well as sympathetic nervous system pathways 107–115…”

“…The staging system developed by our group differs from other protocols in that it accords the same weight to axonal and/or neuronal dysfunction (attributed to the existence of LP) as it does to loss of nigral and coeruleus projection neurons. Currently, it is also known that unmyelinated axons45, 46 and physical contacts between nerve cells108, 115, 182, 183 very likely play an important pathogenic role.…”