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.