crocin and Parkinson-Disease--Secondary

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.

Topics: Animals; Behavior, Animal; Carotenoids; Male; MicroRNAs; Neuroprotective Agents; Oncogene Protein v-akt; Parkinson Disease, Secondary; Phosphatidylinositol 3-Kinases; Rats; Rats, Wistar; Rotenone; Signal Transduction; TOR Serine-Threonine Kinases; Uncoupling Agents; Weight Loss

Previously we have demonstrated the potential neuroprotective propensity of saffron and Crocin (CR) employing a Drosophila model of Parkinsonism. Rotenone (ROT) has been extensively used as a model neurotoxin to induce Parkinson's disease (PD) like symptoms in mice. In the present study, as a proof of concept we evaluated the efficacy of CR prophylaxis (25 mg/ kg bw/d, 7d) to attenuate ROT(0.5 mg/Kg bw/d,7d) -induced neurotoxic effects in male mice focussing on neurobehavioural assessments and biochemical determinants in the striatum. CR prophylaxis significantly alleviated ROT-induced behavioural alterations such as increased anxiety, diminished exploratory behaviour, decreased motor co-ordination, and grip strength. Concomitantly, we evidenced diminution of oxidative stress markers, enhanced levels of antioxidant enzyme and mitochondrial enzyme function in the striatal region. Further, varying degree of restoration of cholinergic function, dopamine and α-synuclein levels were discernible suggesting the possible mechanism/s of action of CR in this model. Based on our earlier data in flies and in worm model, we propose its use as an adjuvant therapeutic agent in oxidative stress-mediated neurodegenerative conditions such as PD.

Topics: Animals; Behavior, Animal; Carotenoids; Corpus Striatum; Exploratory Behavior; Hand Strength; Male; Mice; Mitochondria; Neuroprotective Agents; Oxidative Stress; Parkinson Disease, Secondary; Rotenone