Abstract
The etiology of Parkinson’s disease is poorly understood and is most commonly associated with advancing age, genetic predisposition, or environmental toxins. Epidemiological findings suggest that patients have a higher risk of developing Parkinson’s disease after ischemic stroke, but this potential causality lacks mechanistic evidence. We investigated the long-term effects of ischemic stroke on pathogenesis in hemizygous TgM83 mice, which express human α-synuclein with the familial A53T mutation without developing any neuropathology or signs of neurologic disease for more than 600 days. We induced transient focal ischemia by middle cerebral artery occlusion in 2-month-old TgM83+/− mice and monitored their behavior and health status for up to 360 days post surgery. Groups of mice were sacrificed at 14, 30, 90, 180, and 360 days after surgery for neuropathological analysis of their brains. Motor deficits first appeared 6 months after focal ischemia and worsened until 12 months afterward. Immunohistochemical analysis revealed ischemia-induced neuronal loss in the infarct region and astrogliosis and microgliosis indicative of an inflammatory response, which was most pronounced at 14 days post surgery. Infarct volume and inflammation gradually decreased in size and severity until 180 days post surgery. Surprisingly, neuronal loss and inflammation were increased again by 360 days post surgery. These changes were accompanied by a continuous increase in α-synuclein aggregation, its neuronal deposition, and a late loss of dopaminergic neurons in the substantia nigra, which we detected at 360 days post surgery. Control animals that underwent sham surgery without middle cerebral artery occlusion showed no signs of disease or neuropathology. Our results establish a mechanistic link between ischemic stroke and Parkinson’s disease and provide an animal model for studying possible interventions.
Highlights
Stroke is the third most common cause of death after ischemic heart disease and neonatal disorders, causing 9% of all fatalities worldwide, and even silent strokes without any immediate clinical manifestation are observed in up to 28% of the population [14, 54]
TgM83+/− mice subjected to MCAO continuously gain body weight but develop motor deficits within 180 days after surgery that further worsen over time We induced a mild, 30-min-long focal ischemia in the right brain hemisphere of 6–8-week-old male and female TgM83+/− mice by middle cerebral artery occlusion (MCAO)
Because we were only interested in the longterm effects of stroke, motor deficits were not tested until 90 days after stroke
Summary
Stroke is the third most common cause of death after ischemic heart disease and neonatal disorders, causing 9% of all fatalities worldwide, and even silent strokes without any immediate clinical manifestation are observed in up to 28% of the population [14, 54]. Reoxygenation of ischemic tissue during reperfusion further enhances the detrimental primary effects of ischemia by an increase of neurotoxic reactive oxygen and nitrogen species [13, 21]. This secondary neuronal injury upon reperfusion triggers inflammatory and pathological changes in brain regions connected to the ischemic core [8, 59]. To these short-term effects, ischemic stroke has many long-term consequences [56]. Epidemiological studies have revealed an increased risk of Parkinson’s disease (PD) after ischemic stroke, but there is currently no mechanistic model that adequately explains this association [6, 28]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
