Abstract
Homocysteine (Hcy) has been shown to have a neurotoxic effect on ischemic brain cells; however, the underlying mechanisms remain incompletely understood. Here, we examined whether Hcy treatment influences mitochondria injury, oxidative stress, and mitochondrial STAT3 (mitoStat3) expression in rat ischemic brain. Our results demonstrated that Hcy treatment aggravated the damage of mitochondrial ultrastructure in the brain cortex and the dentate gyrus region of the hippocampus after focal cerebral ischemia. An elevated Hcy level was also accompanied by the significant inhibition of mitochondrial complex I–III enzymatic activities in addition to an increase in cytochrome c release. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) content and mitoStat3 protein phosphorylation level were increased in Hcy-treated animals, whereas AG490, a Jak2 inhibitor, inhibited mitoStat3 phosphorylation as well as 8-OHdG levels induced by Hcy. In vitro studies revealed that Hcy also markedly increased reactive oxygen species (ROS) and mitoStat3 levels. In addition, the inhibition of pSTAT3 reduced Hcy-mediated increase in ROS levels, whereas quenching ROS using the ROS inhibitor glutathione ethyl ester inhibited Hcy-mediated pSTAT3 overactivation in Neuro2a cells. These findings suggest that the development of therapies that interfere with the ROS/pSTAT3 pathway may be helpful for treating cerebral infarction-related diseases associated with Hcy.
Highlights
Cerebral ischemic stroke represents a life threatening neurological disorder that leads to mortality and long-term disability in surviving patients
The signal transducers and activators of transcription family 3 (STAT3) protein, which has been historically studied as a signal transduction and transcriptive activation factor, has been shown by several groups to be activated by cerebral ischemic injury, implicating that it may play a vital role in the pathophysiological process of cerebral ischemia and reperfusion injury as well[16,17,18]
Factors remaining to be determined include the potential for STAT3 activation in mitochondria after cerebral ischemia injury, whether STAT3 is affected by Hcy, and the mechanisms associated with such potential effects in the ischemic brain
Summary
Cerebral ischemic stroke represents a life threatening neurological disorder that leads to mortality and long-term disability in surviving patients. Hcy aggravates neural cell injury in brain cortex region following rat cerebral ischemia-reperfusion (MCAO), and autophagy overactivation which occurs in cortical neurons may be an important mechanism for Hcy neurotoxicity[6]. Folbergrova et al reported that Hcy results in an accumulation of ROS at high concentrations and inhibits the mitochondrial respiration in rat epilepsy model[15] Whether both mitochondrial dysfunction and ROS generation occurred in Hcy-treated ischemic brains has not yet been determined. Factors remaining to be determined include the potential for STAT3 activation in mitochondria after cerebral ischemia injury, whether STAT3 is affected by Hcy, and the mechanisms associated with such potential effects in the ischemic brain. The present study was designed to elucidate the molecular mechanism of neurotoxicity by Hcy in relation to mitochondrial damage, ROS generation, and mitochondrial STAT3 activation in rat ischemic brains. The potential for crosstalk between ROS production and STAT3 activation in the relevant mechanisms during cerebral ischemia-reperfusion injury was investigated
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