Protein kinase Cδ mediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism

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 ?) 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.     

Transient left bundle branch block after posture change to the prone position during general anesthesia: A case report

Rationale:The prone position is commonly used in spinal surgery. There have been many studies on hemodynamic changes in the prone position during general anesthesia. We report a rare case of transient left bundle branch block (LBBB) in a prone position.Patient concern:Electrocardiogram (ECG) of a 64-year-old man scheduled for spinal surgery showed normal sinus rhythm change to LBBB after posture change to the prone position.Diagnosis:Twelve lead ECG revealed LBBB. His coronary angio-computed tomography results showed right coronary artery with 30% to 40% stenosis and left circumflex artery with 40% to 50% stenosis. The patient was diagnosed with stable angina and second-degree atrioventricular block of Mobitz type II.Intervention:Nitroglycerin was administered intravenously during surgery. Adequate oxygen was supplied to the patient. After surgery, the patient was prescribed clopidogrel, statins, angiotensin II receptor blocker, and a permanent pacemaker was inserted.Outcome:Surgery was completed without complications. After surgery, the transient LBBB changed to a normal sinus rhythm. The patient did not complain of chest pain or dyspnea.Lesson:The prone position causes significant hemodynamic changes. A high risk of cardiovascular disease may cause ischemic heart disease and ECG changes. Therefore, careful management is necessary.