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.

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…Here, we sought to study the beneficial effects of melatonin on TMT‐induced neurotoxicity. Trimethyltin chloride induces seizure symptoms and the impairment of learning and memory according to the passive avoidance test, as previously reported . The results of our present study also demonstrated that TMT neurotoxicity is characterized by the deterioration of recognition memory, as shown by the NOR test in mice.…”

“…Mental confusion, memory defects, and seizures have been demonstrated to be typical clinical symptoms of acute exposure to TMT . Similarly, acute TMT toxicity induces seizures and deficiencies in learning and memory in rodent models . TMT selectively induces neuronal loss, particularly in the hippocampus .…”

Genetic overexpressing of GPx‐1 attenuates cocaine‐induced renal toxicity via induction of anti‐apoptotic factors

“…Genetic overexpression of GPx‐1 clearly enhanced the expression of Bcl‐2 and Bcl‐xl. These increases in expression might facilitate Bad phosphorylation and formation of the 14‐3‐3‐/phosphor‐Bad complex and also inhibit Bax expression and caspase‐3 cleavage . Therefore, it is proposed here that the pro‐apoptotic profile may be a pathogenic factor of cocaine‐induced tubular degeneration in the kidneys of mice.…”

“…These increases in expression might facilitate Bad phosphorylation and formation of the 14-3-3-/phosphor-Bad complex and also inhibit Bax expression and caspase-3 cleavage. [27][28][29] Therefore, it is proposed here that the pro-apoptotic profile may be a pathogenic factor of cocaine-induced tubular degeneration in the kidneys of mice. The initial oxidative damage might lead to loss of compensative induction of GPx activity, which might facilitate pro-apoptotic alterations, followed by renal degeneration, as primarily manifested by renal tubular degeneration.…”

Glutathione peroxidase‐1 overexpressing transgenic mice are protected from neurotoxicity induced by microcystin‐leucine‐arginine

“…The synaptosomal fraction was prepared as described previously . Hippocampal tissue was homogenized in 10 volumes of ice‐cold 0.32 mol/L sucrose and centrifuged at 800 g for 12 min at 4°C.…”