title: Role of autophagy inhibitors and inducers in modulating the toxicity of trimethyltin in neuronal cell cultures.
abstract: Trimethyltin (TMT) is a triorganotin compound which determines neurodegeneration of specific brain areas particularly damaging the limbic system. Earlier ultrastructural studies indicated the formation of autophagic vacuoles in neurons after TMT intoxication. However, no evaluation has been attempted to determine the role of the autophagic pathway in TMT neurotoxicity. To assess the contribution of autophagy to TMT-induced neuronal cell death, we checked the vulnerability of neuronal cultures to TMT after activation or inhibition of autophagy. Our results show that autophagy inhibitors (3-methyladenine and L-asparagine) greatly enhanced TMT neurotoxicity. Conversely, known activators of autophagy, such as lithium and rapamycin, displayed neuroprotection against this toxic compound. Due to its diverse targets, the action of lithium was complex. When lithium was administered according to a chronic treatment protocol (6 days pretreatment) it was able to rescue both hippocampal and cortical neurons from TMT (or from glutamate toxicity used as reference). This effect was accompanied by an increased phosphorylation of glycogen synthase kinase 3 which is a known target for lithium neuroprotection. If the pre-incubation time was reduced to 2 h (acute treatment protocol), lithium was still able to counteract TMT toxicity in hippocampal but not in cortical neurons. The neuroprotective effect of lithium acutely administered against TMT in hippocampal neurons can be completely reverted by an excess of inositol and is possibly related to the inactivation of inositol monophosphatase, a key regulator of autophagy. These data indicate that TMT neurotoxicity can be dramatically modified, at least in vitro, by lithium addition which seems to act through different mechanisms if acutely or chronically administered.
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Fabrizi
authors.forename: F
authors.initials: F
authors.lastname: Somma
authors.forename: E
authors.initials: E
authors.lastname: Pompili
authors.forename: F
authors.initials: F
authors.lastname: Biagioni
authors.forename: P
authors.initials: P
authors.lastname: Lenzi
authors.forename: F
authors.initials: F
authors.lastname: Fornai
authors.forename: L
authors.initials: L
authors.lastname: Fumagalli
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001216:Asparagine / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D001921:Brain / Q000166:cytology; D002452:Cell Count; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014298:Trimethyltin Compounds / Q000633:toxicity*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000447:Aldehydes; D013778:Tetrazolium Salts; D013844:Thiazoles; D014298:Trimethyltin Compounds; C111472:mitotracker green FM; C046488:trimethyltin; D012694:Serine; C025946:3-methyladenine; D001216:Asparagine; D007770:L-Lactate Dehydrogenase; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; C022616:thiazolyl blue; D018021:Lithium Chloride; D000225:Adenine; D020123:Sirolimus