EFFECT OF PENTOXIFYLLINE INHIBITE THE SIGMA RECEPTOR, OXIDATIVE STRESS, CALCIUM INFLUX AND MITOCHONDRIAL DYSFUNCTION AND SUPPRESS CELL DEATH INDUCE BY METHAMPHETAMINE

Background and Aim : The neuroprotective role of pentoxiffylline against methamphetamine-induced cell death has been not demonstrated. Methamphetamine increases the expression of sigma receptors. However, the exact mechanisms underlying such neuroprotection, especially the role of sigma receptors, has not yet been fully clarified.Methods : We investigated the effects of different concentration of pentoxifylline on methamphetamine-induced cell death in PC12 cell line as an in vitro model of Parkinson’s disease. Cell damage was induced by 1mM methamphetamine. First we certaine the optimum vital concentration of pentoxifylline, next in continuing, H89 dihydrochloride, 666-15, Heparin, Ketamine, BMY 14802, Pentazocine, were added to the cells for inhibition of PKA, CREB, IP3 receptor, NMDA receptor, Sigma receptor antagonist, sigma receptor agonistFor the signal transduction were study, respectively. MTT test for cell viability detection, LDH test for cytotoxicity measurement, the caspase activity colorimetric assay kit for caspase 3 activity diagnosis, rhodamine 123 for detection of mitochondrial membrane potential, TUNEL test for DNA fragmentation, fura-2 for measurement of (Ca2+)ic and (Ca2+)m and fluorescence microscope for measurement of antioxidant enzyme activities. Results : The data showed that methamphetamine caused significant cell death. Pentoxyphilline increased cell viability and rhodamine-123 absorbance and reduced cell cytotoxicity, caspase-3 activity, mitochondrial and intracellular Ca2+ concentration, (.OH) generation and DNA fragmentation in all concentrations of 10 nM to 1mM (p<0.05). Incubation of PC12 cells with different inhibitor of signal mediators show that pentoxifylline has protective effect and reduced biochemical markers of cell damage and death by inhibiting the sigma receptor signal transduction.Conclusion : The results suggest that production of cAMP and sigma receptor signaling participates in the Pentoxyphilline neuroprotective effects against methamphetamine-induced neurotoxicity.

کلیدواژه ها:

Methamphetamine ، Cell death ، Pentoxyphilline ، sigma receptor