Antiplatelet therapy as a novel approach in Parkinson's disease: Repositioning Ticagrelor to alleviate rotenone-induced parkinsonism via modulation of ER stress, apoptosis, and autophagy

Cardiovascular diseases, such as myocardial infarction, ischemic stroke, and coronary heart ailments have been closely associated with Parkinson's disease (PD). Despite this established link, the potential neuroprotective impact of the potent antiplatelet agent ticagrelor (Tica) remains unexplored against PD. Thus, we hypothesized that Tica could be repurposed as a therapeutic agent against PD. Rotenone experimental model was adopted in Wistar male rats by administering rotenone subcutaneously on alternate days during a 21-day experimental period and treating a subset of rats with Tica orally for the last 11 consecutive days. The administration of Tica improved motor function (open field test, hanging wire test) and restored striatal histological features. Additionally, Tica opposed the rotenone effect and markedly obliterated the striatal α-synuclein content but enhanced the protein expression of tyrosine hydroxylase and dopamine content. On the molecular level, Tica inhibited striatal endoplasmic reticulum stress (ERS) as evidenced by the downregulation of the ER-resident transmembrane sensor inositol-requiring enzyme 1 alpha and its downstream molecular targets, TNF receptor-associated factor 2 and c-Jun N-terminal kinase, along with a reduction in caspase-3 activity. On the other hand, Tica augmented the autophagy machinery by upregulating the autophagosome markers Beclin-1 and light chain 3-II, while inhibiting the content of cathepsin D. Therefore, the current study is the first to accentuate the neuroprotective potential of Tica in a rat model of PD via modulating the crosstalk between ERS, apoptosis, and autophagy to represent a potential novel therapeutic candidate for managing PD, particularly in patients with or prone to cardiovascular diseases.