No abstract

Methamphetamine (METH) is an illicit dopaminergic neurotoxin and is an extremely addictive psychostimulant drug that influences monoamine neurotransmitter system of the brain and is responsible for enhancing energy and satisfaction and feelings of alertness. Long-lasting exposure to METH causes psychosis and increases the risk of Parkinson’s disease. Studies have revealed that obestatin (OB) is a novel endogenous ligand, which may have neuroprotective effects. Hence, we hypothesized that OB might appropriately limit METH-induced neurotoxicity via the control of apoptotis and autophagy. In the current study, PC12 cells were exposed to both METH (0.5, 1, 2, 3, 4, and 6 mmol/L) and pretreatment OB (1, 10, 100, and 200 nmol/L) in vitro for 24 h to determine appropriate dose, and then downstream pathways were measured to investigate apoptosis and autophagy. The results have shown that OB reduced the apoptotic response post-METH exposure in PC12 cells by developing cell viability and diminishing apoptotic rates. Furthermore, the study has exhibited OB decreased gene expression of Beclin-1 by real-time polymerase chain reaction and LC3-II by Western blotting in METH-induced PC12 cells, which demonstrated that autophagy is reduced. The study is proposed that OB is useful in reducing oxidative stress, which may also play an essential role in the regulation of METH-triggered apoptotic response. So these data indicate that OB could potentially alleviate METH-induced neurotoxicity via the reduction of apoptotic and autophagy responses.

Diabetic neuropathy is a well-known complication of diabetes. It has been recently confirmed that hyperglycemia-induced toxicity participates in multiple cellular pathways that are typical for neural deterioration. Nampt/PBEF/visfatin is a novel endogenous ligand, which some studies have shown its neuroprotective effects on neurodegenerative disease. Therefore, we hypothesized that visfatin might prevent high glucose (HG)-induced neurotoxicity via the inhibition of apoptosis, autophagy, and reactive oxygen species (ROS) responses properly. In this study, Pheochromocytoma Cell Line 12 (PC12) cells were exposed to both HG concentrations (50, 75, 100,125, 150 mM) and visfatin (50, 100, 150 ng/ml) in different time-points to determine the optimum time and dose of glucose and visfatin. To investigate the effects of visfatin on HG-induced damage in PC12 diabetic neuropathy model, we examined ROS response, apoptosis, and autophagy by using ROS detection kit, flow cytometry, and Real-time PCR/western blot, respectively. We determined that HG concentration significantly increased ROS level and apoptosis of diabetic PC12 cells. However, visfatin treatment significantly decreased ROS production (P < 0.05) and apoptosis of diabetic PC12 cells (P < 0.0001). Beclin-1 mRNA level (P < 0.05) and Lc3-II protein level (P < 0.05) showed that autophagy pathway is impaired by HG concentrations. We concluded that visfatin could sufficiently decrease neural damage caused by ROS production and apoptosis under HG-induced toxicity.