On the other hand, reduction of TNF- considered as an important factor in cellular survival (Mizuno et al., 1994; Kambayashi et al., 1995). antagonist, sigma receptor agonist, cells were preincubated with adding H89 dihydrochloride, 666-15, Heparin, Ketamine, BMY 14802, and Pentazocine. MTT and LDH assessments 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+) Fedovapagon 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 1 nM t0 100 M (p<0.05) by the optimal concentration of 100 M, between our tested treatments. Conclusion: Fedovapagon Ibudilast as a phosphodiesterase inhibitor can reduce the methamphetamine-induced cell death due to inhibition of receptors through cAMP production. Key Words: Methamphetamine, Ibudilast, cell death, PC12 Introduction N-methyl-1-phenylpropane-2-amine so-called methamphetamine created in Japan, 1893 (Anglin et al., 2000; Sato, 2009) and at first was used to treatment of Attention-deficit hyperactivity disorder, idiopathic insomnia, and Narcolepsy. During World War II it was also used to relieve fatigue at low dosage (5-60 mg/day). Also, in western countries methamphetamine was subjected to abuse and it increased dosage (500-3, 500 mg/day) show psychotic and addictive features (Gillberg et al., 1997; Sato, 2008; Monti, 2015; Kotagal, 2017; Castells et al., 2018; Chigome et al., 2018). Methamphetamine abuses have increased in a few past decades on all of the word, notably in the USA. Methamphetamine have other common names such as Glass, crystal, ice, meth, and velocity (Rasmussen, 2015; Ben-Yehuda and Siecke, 2018; Champion et al., 2018). Methamphetamine reduces dopamine reabsorption and acts as a chemical mediator in the brain neurons in long-term abuse (Abuse, 2006; Volkow et al., 2015; Graves et al., 2017). Long-time consumption of this drug leads to massive disruption in the midfrontal gray matter, right frontal white matter and right basal ganglia regions of the brain. Methamphetamine toxic effect on dopaminergic and serotonergic neurons is usually clear in rodent but not in humans. Methamphetamine abusers differences in the chemistry of the brain, low concentration of N-acetylaspartate Fedovapagon and high concentration of choline-containing compounds and myo-inositol compared normal individuals (Ali, 2006). Abusers of methamphetamines show a lower degree of dopamine D2 receptors, that leads to decreased metabolism within the orbitofrontal cortex and could cause a system for compulsive medication intake and addicting procedure (Volkow et al., 2001). Earlier studies show reduced viability and improved apoptotic guidelines in Personal computer12 cell range as rat adrenal medulla pheochromocytoma powered cells, after methamphetamine publicity (Pitaksalee et al., 2015; Govitrapong and Wongprayoon, 2017; Xiong et al., 2018). Shreds of proof show that reduced dopaminergic neuron cells may bring about signaling systems of oxidative stress-mediated cell loss of life (Kanthasamy et al., 2011). Earlier studies recommended the system of methamphetamine by activation of receptors. These receptors get excited about many ramifications of methamphetamine such as for example increased dopamine launch, ROS, and apoptotic cell loss of life (Ostenfeld et al., 2005; Schetz et al., 2007). cAMP takes on a critical part in regulating the manifestation of receptors. Consequently, these receptors are believed suitable therapeutic focuses on (Nguyen et al., 2005). Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is really a phosphodiesterase inhibitor which involves in lymphocytes, endothelial cells, and glial cells make use of to treatment of asthma also, FAM124A inflammatory and neurological illnesses,.