Document Type : Research Articles
Pharmaceutical Sciences Research Center, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran.
Department of Biology, Faculty of Sciences, Razi University, Kermanshah, Iran.
Substance Abuse Prevention Research Center, Health Institute, Kermanshah University of Medical Sciences, kermanshah, Iran.
Objective: Interaction of methamphetamine and sigma (σ) receptors lead to up-regulation and activation of these
receptors. The σ receptors induced apoptosis in some parts of the brain by increasing calcium, dopamine, ROS,
mitochondrial pores and caspase activity. Ibudilast is a phosphodiesterase inhibitor and anti-inflammatory drug,
which can decrease the inflammatory cytokines. Also, it has a neuroprotective effect. It seems that ibudilast can
reduce the methamphetamine-induced cell death due to inhibition of σ receptors. Materials and Methods: There
were seven treatments including; control: culture medium, Treatment 1: 1mM methamphetamine, Treatment 2: 1mM
methamphetamine and 1nM ibudilast, Treatment 3: 1mM methamphetamine and 10nM ibudilast, Treatment 4: 1mM
methamphetamine and 100nM ibudilast, Treatment 5: 1mM methamphetamine and 1uM ibudilast, Treatment 6: 1mM
methamphetamine and 10uM ibudilast, and Treatment 7: 1mM methamphetamine and 100uM ibudilast. Finally, for
inhibition of PKA, CREB, IP3 receptor, NMDA receptor, Sigma receptor antagonist, sigma receptor agonist, cells
were preincubated with adding H89 dihydrochloride, 666-15, Heparin, Ketamine, BMY 14802, and Pentazocine.
MTT and LDH tests were performed for cell viability and cytotoxicity measurement, respectively. In continuing, the
caspase activity colorimetric assay kit used for caspase 3 activity diagnosis. Rhodamine-123 performed to detection of
mitochondrial membrane potential. TUNEL test used to DNA fragmentation and apoptosis, Fura-2 used to Measurement
of (Ca2+) ic and (Ca2+) m, and fluorescence microscope used to Measurement of antioxidant enzyme activities. Results:
Ibudilast increased the cell viability and the rhodamine-123 absorbance in methamphetamin-treated PC12 cells. It
reduced cell cytotoxicity, caspase 3 activity, ic and m Ca2+ concentration, (OH) generation and DNA fragmentation in
all concentrations of 1 nM t0 100 μM (p<0.05) by the optimal concentration of 100 μM, between our tested treatments.
Conclusion: Ibudilast as a phosphodiesterase inhibitor can reduce the methamphetamine-induced cell death due to
inhibition of σ receptors through cAMP production.