title: Autophagy inhibition by caffeine increases toxicity of methamphetamine in SH-SY5Y neuroblastoma cell line.
abstract: Methamphetamine (METH) is a highly addictive CNS stimulant that its long-term use is associated with the loss of neurons in substantia nigra and development of Parkinson's disease later in life. Common form of METH is Ya-Ba tablet, in which, large portion of caffeine is added to the mass to enhance the stimulatory effect. Previous study demonstrated that caffeine potentiates the toxic effect of METH in association with the production of reactive oxygen species and the induction of apoptosis. Since METH causes induction of autophagy, the question was raised whether this pathway participates in the potentiating effect of caffeine on METH neurotoxicity. We used SH-SY5Y, a neuroblastoma cell line, as an in vitro model to study the effect of METH and caffeine. Co-treatment of non-toxic concentrations of METH, at 0.5 mM, and caffeine, at 1 mM, caused reduction of the cell viability. Reduction of the cell viability was associated with attenuation of autophagy, demonstrated by reduction of LC3-II levels and the number of autophagosome puncta, together with increase of caspase-3 activation. Similar effect was produced by treatment with autophagy inhibitors, 3-MA and wortmanin. Our results suggested that caffeine potentiates METH toxicity through inhibition of autophagy and that autophagy serves as a protective mechanism. In conclusion, we proposed the augmented hazard associated with caffeine and METH combination in Ya-Ba abusers.
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Rujiraporn
authors.initials: R
authors.lastname: Pitaksalee
authors.forename: Yupin
authors.initials: Y
authors.lastname: Sanvarinda
authors.forename: Theerin
authors.initials: T
authors.lastname: Sinchai
authors.forename: Pantip
authors.initials: P
authors.lastname: Sanvarinda
authors.forename: Anusorn
authors.initials: A
authors.lastname: Thampithak
authors.forename: Nattinee
authors.initials: N
authors.lastname: Jantaratnotai
authors.forename: Surawat
authors.initials: S
authors.lastname: Jariyawat
authors.forename: Patoomratana
authors.initials: P
authors.lastname: Tuchinda
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
authors.forename: Pimtip
authors.initials: P
authors.lastname: Sanvarinda
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D002110:Caffeine / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D006801:Humans; D008694:Methamphetamine / Q000633:toxicity*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D002110:Caffeine; D008694:Methamphetamine