title: Protein kinase Cδ mediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism.
abstract: We investigated whether protein kinase C (PKC) is involved in trimethyltin (TMT)-induced neurotoxicity. TMT treatment (2.8 mg/kg, i.p.) significantly increased PKCδ expression out of PKC isozymes (i.e., α, βI, βII, δ, and ς) in the hippocampus of wild-type (WT) mice. Consistently, treatment with TMT resulted in significant increases in cleaved PKCδ expression. Genetic or pharmacological inhibition (PKCδ knockout or rottlerin) was less susceptible to TMT-induced seizures than WT mice. TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species. These effects were more pronounced in the WT mice than in PKCδ knockout mice. In addition, the ability of TMT to induce nuclear translocation of Nrf2, Nrf2 DNA-binding activity, and upregulation of γ-glutamylcysteine ligase was significantly increased in the PKCδ knockout mice and rottlerin (10 or 20 mg/kg, p.o. × 6)-treated WT mice. Furthermore, neuronal degeneration (as shown by nuclear chromatin clumping and TUNEL staining) in WT mice was most pronounced 2 days after TMT. At the same time, TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling was evident, thereby decreasing phospho-Bad, expression of Bcl-xL and Bcl-2, and the interaction between phospho-Bad and 14-3-3 protein, and increasing Bax expression and caspase-3 cleavage were observed. Rottlerin or PKCδ knockout significantly protected these changes in anti- and pro-apoptotic factors. Importantly, treatment of the PI3K inhibitor LY294002 (0.8 or 1.6 µg, i.c.v.) 4 h before TMT counteracted protective effects (i.e., Nrf-2-dependent glutathione induction and pro-survival phenomenon) of rottlerin. Therefore, our results suggest that down-regulation of PKCδ and up-regulations of Nrf2-dependent glutathione defense mechanism and PI3K/Akt signaling are critical for attenuating TMT neurotoxicity.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Yunsung
authors.initials: Y
authors.lastname: Nam
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Thu-Hien Thi
authors.initials: TH
authors.lastname: Tu
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Yong Kwang
authors.initials: YK
authors.lastname: Lim
authors.affiliation: School of Veterinary Medicine, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Myung-Bok
authors.initials: MB
authors.lastname: Wie
authors.affiliation: Department of Anatomy and Cell Biology, Medical School, Kangwon National University, Chunchon, 200-701, Republic of Korea.
authors.forename: Dae-Joong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea. kimhc@kangwon.ac.kr.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D014298:Trimethyltin Compounds / Q000633:toxicity*
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D047428:Protein Kinase Inhibitors; D014298:Trimethyltin Compounds; C046488:trimethyltin; C085746:rottlerin; D019869:Phosphatidylinositol 3-Kinases; D051745:Protein Kinase C-delta; D005978:Glutathione
keywords: Glutathione; Nrf-2; Oxidative burdens; PI3K/Akt signaling; PKCδ gene; Trimethyltin