crocin and Parkinsonian-Disorders

Depression is a common non-motor symptom in patients with Parkinson's disease (PD) and difficult to treat. Crocin is a natural multipotential neuroprotective compound that has been shown to elicit antidepressant activity and is promising for the therapy of neuropsychological diseases. Here, we investigated the therapeutic effect of crocin in a mouse model of Parkinson's disease depression (PDD) and clarified the underlying mechanism. We prepared 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced subacute mouse model of PD, and found that around 60% of the model mice showed depression-like behavior, using the forced swimming test (FST). A regime of 10-day treatment of crocin alleviated the PDD symptoms. The crocin reduced the structural damage in soma volume and axon length of neurons and inhibited their spontaneous discharge in dopaminergic (DA) neurons in the ventral tegmental area (VTA). Notably, the MPTP-treated mice showed the decrease in the critical signaling for synaptic plasticity, including the proteins of PSD-95, synapsin-1, and GluR-1, in the medial prefrontal cortex (mPFC) where it receives efferent from VTA and regulates depression-like behavior. However, crocin treatment rescued the defect of the mammalian target of rapamycin (mTOR) signaling in PDD mice. Furthermore, the antidepressant action of crocin was blunted after blockade of mTOR signaling with the antagonist rapamycin. In conclusion, our study demonstrated that crocin protected the DA projection neurons in the VTA through activating mTOR, which subsequently improved the neural synaptic plasticity of mPFC, and ameliorated depression-like behavior in PD mice.

Topics: Animals; Behavior, Animal; Carotenoids; Depression; Male; Mice; Neural Pathways; Neuronal Plasticity; Parkinsonian Disorders; Prefrontal Cortex; Receptors, AMPA; Signal Transduction; Synapsins; Ventral Tegmental Area

In several epidemiological studies, an association between pesticide exposure and the incidence of Parkinson's disease (PD) has been reported. Increasing evidence showed that oxidative stress plays an important role in the pathogenesis of PD. The present study investigated the preventive effect of crocin, saffron active components, on malathion (an organophosphate pesticide (OP))-induced Parkinson-like behaviors in rat. Rats were divided into eight groups: control (normal saline), malathion (100 mg/kg/day, i.p), crocin (10, 20, or 40 mg/kg/day, i.p) plus malathion, levodopa (10 mg/kg/day, i.p) plus malathion, crocin (40 mg/kg/day, i.p), and PEG (vehicle of levodopa) groups. Treatments were continued for 28 days. The neurobehavioral tests which include open field, rotarod and catalepsy were performed on day 28. The activity of acetylcholinesterase (AChE) in serum, the levels of malondialdehyde (MDA), reduced glutathione (GSH), TNF-α, and IL-6 in striatum at the end of treatments were evaluated. Results showed that malathion induced neurobehavioral impairments together with elevation of MDA, TNF-α and IL-6 levels, reduction of GSH, and AChE activity. Crocin (10, 20, and 40 mg/kg) improved neurobehavioral impairments induced by malathion but not AChE activity. Crocin (10, 20, and 40 mg/kg) or levodopa plus malathion decreased MDA and increased GSH. Also crocin (10 mg/kg) decreased TNF-α and IL-6 levels in striatum. In summary, subchronic malathion exposure induced Parkinson-like behavior in rat. Crocin exhibited protective effects against malathion-induced Parkinson-like behavior through reducing lipid peroxidation, improvement of motor deficit and anti-inflammatory effects.

Topics: Acetylcholinesterase; Animals; Carotenoids; Crocus; Glutathione; Insecticides; Lipid Peroxidation; Malathion; Male; Malondialdehyde; Motor Disorders; Neuroprotection; Oxidative Stress; Parkinsonian Disorders; Rats; Rats, Wistar

Evidence suggests that saffron and its major bioactives exhibit significant neuromodulatory effects in various animal models. However, specific data related to their efficacy to attenuate oxidative stress and neurotoxicity in animal models of Parkinson's disease (PD) are limited. Hence, we investigated the neuroprotective efficacy of saffron methanolic extract (SME) and its active constituent, crocin (CR) employing a Drosophila model of parkinsonism. We focussed on attenuation of Rotenone (ROT)-induced locomotor phenotype, oxidative stress, mitochondrial dysfunction and neurotoxicity in this model. SME and CR-enrichment significantly reduced ROT (500μM) induced mortality, rescued the locomotor phenotype and diminished the enhanced levels of oxidative stress markers in head/body regions of flies. The reduced levels of reduced glutathione (GSH) and total thiols (TSH) resulting from ROT exposure were significantly restored with concomitant enhancement of the antioxidant enzymes activities. Further, ROT-induced mitochondrial dysfunctions (MTT reduction, activities of SDH and NADH-Cyt C reductase (complexes I-III) enzymes) were markedly attenuated by SME/CR enrichment. While ROT elevated the activity of acetylcholinesterase (AChE) in head/body regions, both the treatments caused marked diminution of AChE activity and restored the dopamine levels suggesting their effectiveness to mitigate cholinergic function. Interestingly, SME/CR enrichment significantly delayed the onset of locomotor deficits and extended life span of flies among ROT (50μM)-stressed flies. In a satellite study, flies provided with SME/CR prophylaxis exhibited marked resistance to an acute Paraquat (PQ) challenge as evidenced by the lower incidence of lethality and improved locomotor phenotype. Taken together, the neuroprotective effects of saffron and crocin in the fly model may be largely attributable to its antioxidant action. Based on our findings, we propose that saffron may be exploited as a supplementary therapeutic agent in PD and other oxidative stress mediated neurodegenerative conditions.

Topics: Acetylcholinesterase; Animals; Antioxidants; Biomarkers; Carotenoids; Crocus; Disease Models, Animal; Dopamine; Drosophila melanogaster; Glutathione; Hydrogen Peroxide; Locomotion; Longevity; Mitochondria; Neuroprotective Agents; Nitric Oxide; Oxidative Stress; Paraquat; Parkinsonian Disorders; Phytotherapy; Plant Extracts; Protein Carbonylation; Reactive Oxygen Species; Rotenone; Sulfhydryl Compounds