Neuroprotective effect of crocin against rotenone-induced Parkinson's disease in rats: Interplay between PI3K/Akt/mTOR signaling pathway and enhanced expression of miRNA-7 and miRNA-221

The complexity of Parkinson's disease (PD) pathogenesis is attributed to multiple pathways involved in the neurodegeneration process. Among these pathways arise the phosphoinositide 3–kinase (PI3K)/protein kinase B (Akt), and mammalian target of rapamycin (mTOR) axis, where inhibition of this cascade has been implicated in the pathogenesis of PD. Crocin, a carotenoid found in saffron, has shown beneficial effects against neurodegenerative diseases via anti-apoptotic, anti-inflammatory, and antioxidant activities. However, the exact molecular pathways involved in crocin's neuroprotective effects have not been fully elucidated. This drove our attention to unravel the possible involvement of PI3k/Akt/mTOR pathway in the neuroprotective effect of crocin against rotenone (ROT)-induced PD in rats. Sixty adult male Wistar rats were divided into four groups: control, crocin (30 mg/kg/day; i.p.), ROT (1.5 mg/kg/day, i.p.) and ROT pre-treated with crocin for 30 days. Crocin administration showed a substantial behavioral improvement. At the cellular level, crocin significantly stimulated the PI3K/Akt pathway, augmented phospho-proline-rich Akt substrate 40 kDa (p-PRAS40), mTOR and p-p70S6K levels. Consequently, glycogen synthase kinase-3β (GSK-3β), forkhead box transcription factor of the O class (FoxO3a), and the downstream caspase-9 were decreased; thus, attenuating neurodegeneration, which was witnessed through increased tyrosine hydroxylase (TH) and dopamine (DA), and hampered α-synuclein levels. Moreover, crocin showed enhanced expression of microRNA-7 (miRNA-7) and miRNA-221, which contributed to Akt/mTOR activation. These results were verified by improved histopathological portrait and increased number of intact neurons. In conclusion, crocin showed promising neuroprotective effects in ROT-induced PD via activation of PI3K/Akt/mTOR axis and enhanced miRNA-7 and miRNA-221. Graphical representation of the mechanistic neuroprotective effect of crocin on ROT-induced PD in rats via modulation of PI3K/Akt/mTOR signaling pathway and enhanced expression of miRNA-7 and miRNA-221. Akt, protein kinase B; Bcl-2, B-cell lymphoma 2; FoxO, forkhead box transcription factor of the O class; GSK-3β, glycogen synthase kinase-3β; miRNA, microRNA; mTOR, mammalian target of rapamycin; PD, Parkinson's disease; PI3K, phosphoinositide 3–kinase; PRAS40, Proline-rich Akt substrate 40 kDa; ROT, rotenone. [Display omitted] •PI3K/Akt/mTOR pathway is altered in rotenone-induced Parkinson's