Over-expression of survivin could prevent the oxidative stress and toxicity of rotenone in SH-SY5Y cells.

Objectives: It is important to find novel therapeutic molecular targets for curing Parkinson's disease (PD). Accordingly, this study aimed to evaluate the effect of over-expression of the survivin gene, a gene frequently reported as neuroprotective, on the in vitro model of PD. Materials and Methods: Survivin was over-expressed in SH-SY5Y cells. Next, the cells were treated with rotenone (500 nM) for 24 hr. Then, viability and the total antioxidant capacity were assessed. The expression levels of 15 important genes of key cellular processes (oxidative stress, apoptosis, cell cycle, and autophagy) were assessed. The studied genes included survivin, superoxide dismutase, catalase, BAX, bcl2, caspase 3, caspase 8, caspase 9, p53, SMAC, ß-catenin, mTOR, AMPK, ATG7, RPS18. The apoptosis level and the frequency of cell cycle stages were assessed by flow cytometry. For analyzing the data, the ANOVA test followed by Tukey's test was used to evaluate the significant differences between the experimental groups. P<0.05 was considered significant. Results: Survivin could significantly decrease the rotenone-induced apoptosis in SH-SY5Y cells. The rotenone treatment led to down-regulation of catalase and up-regulation of bax, bcl2, caspase 3, caspase 8, P53, ß-catenin, and ATG7. Survivin could significantly neutralize the effect of rotenone in most the genes. It could also increase the total antioxidant capacity of SH-SY5Y cells. Conclusion: Survivin could prevent the toxic effect of rotenone on SH-SY5Y cells during the development of in vitro PD model via regulating the genes of key cellular processes, including anti-oxidation, apoptosis, cell cycle, and autophagy.

The neuroprotective roles of Dietary Micronutrients on Parkinson's disease: a review.

Parkinson's disease (PD) is a prevalent elderly neurodegenerative disease. The nature of PD is strongly bounded with certain cellular processes, including oxidative stress, neuro-inflammation, apoptosis, and mitochondrial dysfunction. Therefore, many clinical and pre-clinical studies have reported protective effects of certain dietary micronutrients for PD. Hence, this review tried to introduce a series of important dietary micronutrients, which to our best of knowledge, were among those compounds known as beneficial for PD with a high consensus. The compounds possess neuroprotective properties (e.g. anti-oxidation, anti-inflammation, anti-apoptosis, boosting mitochondrial performance, regulating autophagy process). Thus, the compounds probably may act on several cellular targets to prevent the development of PD or to attenuate the progress of the disease. Investigating these compounds probably can lead to the development of novel supplementary therapeutic approaches, as well as refinement of dietary regimen of PD patients.

Effect of lobeglitazone on motor function in rat model of Parkinson's disease with diabetes co-morbidity.

Parkinson's disease (PD) and diabetes mellitus share similar pathophysiological characteristics, genetic and environmental factors. It has been reported that people with diabetes mellitus appear to have a remarkable higher incidence of PD than age matched non diabetic individuals. Evidences suggest that use of antidiabetic glitazone is associated with a diminished risk of PD incidence in patients with diabetes. This study examined the effect of lobeglitazone, a member of thiazolidinedione class, in rat model of Parkinson's disease with diabetes co-morbidity. Rats received either rotenone and/or a combination of streptozocin and a high calorie diet for disease induction and they were treated with different doses of lobeglitazone or its vehicle. Behavioral tests comprising rotarod, bar test and rearing test were conducted to evaluate the motor function. Changes in the level tyrosine hydroxylase, TNF-α and NF-κB were analyzed using ELISA. In the same brain regions the possible changes in PPAR-γ receptor level were evaluated. Findings showed that although lobeglitazone tends to reverse the effect of rotenone in animals with diabetes, it was just able to prevent partly the motor defect in rearing test. Furthermore, lobeglitazone (1 mg/kg) reversed, in substantia nigra and striatum, the changes in tyrosine hydroxylase, TNF-α, NF-κB and PPAR-γ receptor content induced by rotenone in rats with diabetic condition. Although other preclinical studies are needed, these findings suggest that lobeglitazone is a promising neuroprotective candidate for clinical trials for PD patients with diabetes co-morbidity.

miR-185 and SEPT5 Genes May Contribute to Parkinson's Disease Pathophysiology.

There are still unknown mechanisms involved in the development of Parkinson's disease (PD), which elucidating them can assist in developing efficient therapies. Recently, studies showed that genes located on the human chromosomal location 22q11.2 might be involved in the development of PD. Therefore, the present study was designed to evaluate the role of two genes located on the chromosomal location (miR-185 and SEPT5), which were the most probable candidates based on our bibliography. In vivo and in vitro models of PD were developed using male Wistar rats and SHSY-5Y cell line, respectively. The expression levels of miR-185, SEPT5, LRRK2, and PARK2 genes were measured at a mRNA level in dopaminergic areas of rats' brains and SHSY-5Y cells using the SYBR Green Real-Time PCR Method. Additionally, the effect of inhibition on the genes or their products on cell viability and gene expression pattern in SHSY-5Y cells was investigated. The level of miR-185 gene expression was significantly decreased in the substantia nigra (SN) and striatum (ST) of the rotenone-treated group (control group) compared to the healthy normal group (P < 0.05). In addition, there was a significant difference in the expression of SEPT5 gene (P < 0.05) in the substantia nigra between two studied groups. The results of an in vitro study showed no significant change in the expression of the genes; however, the inhibition on miR-185 gene expression led to the increase in LRRK2 gene expression in SHSY-5Y cells. The inhibition on LRRK2 protein also decreased the cellular toxicity effect of rotenone on SHSY-5Y cells. The results suggested the protective role of miR-185 gene in preventing the development of PD.

Oxidative stress and neuroinflammation in the story of Parkinson's disease: Could targeting these pathways write a good ending?

Although, current medications for Parkinson's disease can control and relief symptoms of the disease efficiently, they are unable to either prevent progression of the disease or maintain their controlling ability as a long-term medication. To find suitable adjuvant and/or alternative treatments, researchers have investigated antioxidative and anti-inflammatory approaches, since emerging evidence consider oxidative stress and neuroinflammation as leading causes of the development of Parkinson's disease. Here, how oxidative stress and neuroinflammation take part in Parkinson's disease pathogenesis was discussed based on featured studies in this context. Then, preclinical and clinical trial studies, which evaluated antioxidative and anti-inflammatory compounds' ability to treat Parkinson's disease, were reviewed.

Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms in rats.

BACKGROUND/PURPOSE: Long-term exposure to opiates induces tolerance to the analgesic effect and dependence. In recent years, several studies have been conducted to find agents that can prevent the development of these two phenomena. The aim of the present study is to evaluate the effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on morphine-induced tolerance and withdrawal symptoms. METHODS: Groups of male rats received daily morphine [for induction of tolerance (10 mg/kg) and for induction of dependence (additive doses: 5 mg/kg/12 h, 10 mg/kg/12 h, 15 mg/kg/12 h, 20 mg/kg/12 h, and 25 mg/kg/12 h)] in combination with propylene glycol or simvastatin [5 mg/kg, per os (p.o.), 10 mg/kg, p.o., and 20 mg/kg, p.o.]. Next, the nociception was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. The animals received additional doses of morphine for 9 days in order to induce dependency. One hour after the last dose of the morphine injection, naloxone was administered and withdrawal symptoms were recorded for 1 hour. RESULTS: The results of the present study showed that chronic morphine administration induced tolerance to the analgesic effect for 19 days, whereas simvastatin (20 mg/kg, p.o.) delayed the day of the established tolerance by 5 days. The administration of simvastatin also prevented the morphine-induced shift to the right of the 50% effective dose (ED50) in the dose-response curve. Furthermore, the results showed that simvastatin decreased the total withdrawal score significantly. CONCLUSION: We found that simvastatin attenuated morphine-induced tolerance and withdrawal symptoms.

N-acetylcysteine prevents rotenone-induced Parkinson's disease in rat: An investigation into the interaction of parkin and Drp1 proteins.

There are convincing evidences that oxidative stress has an important role in both the initiation and progression of Parkinson's disease. N-acetylcysteine (NAC) is shown to have antioxidant properties via fortifying glutathione which is one of the main endogenous antioxidant systems. Therefore our study was aimed to evaluate the effect of NAC in management of Parkinson's disease. To this aim, male Wistar rats (10-12 months) received rotenone 2.5mg/kg/48 h intraperitoneally (ip) to induce a Parkinson's disease model. Pretreatment with NAC (25 and 50mg/kg/48 h ip) was administered 1h before the rotenone injection. Three behavioral tests (rotarod, rearing and bar tests) were performed for motor function assessment. Dopamine levels of dopaminergic areas in rat brain including substantia nigra (SN) and striatum (ST) were assessed using high performance liquid chromatography analysis to measure the loss of dopamine. Western blot analysis was also done for parkin and Drp1 (dynamin related protein-1) proteins quantification in SN and ST. Our results indicated that NAC significantly ameliorated the rotenone-induced motor dysfunction and dopamine loss. Furthermore, NAC was able to prevent the rotenone-induced changes in parkin and Drp1 levels in the both studied areas. In conclusion we found that NAC delayed the Parkinson's disease induction by rotenone and this effect might be related to its proved antioxidant effect.