Inhibition of miR-134-5p protects against kainic acid-induced excitotoxicity through Sirt3-mediated preservation of mitochondrial function.

Epilepsy is a neurological disorder which is characterized by brain hyper-excitability and manifests as seizure. Due to its complicated pathogenesis, treatment for epilepsy still remains a huge challenge for neurology in the whole world. MciroRNA-134 (miR-134) is one kind of miRNAs which was firstly found abundant in synapses. In this study, we tried to unveil the role of inhibiting MciroRNA-134-5p (miR-134-5p) in excitotoxicity induced by kainic acid (KA) in the hippocampal neurons (HT22) cells. The results showed that treatment of KA increased the expression of miR-134-5p significantly and caused marked neuron excitotoxicity, evidenced by risen cell death rate, higher LDH release and aggravated cell viability. After suppressing miR-134-5p expression via transfecting HT22 cells with miR-134-5p antisense (Anti-134), cell viability was promoted obviously, along with decreased LDH release and cell death rate. In addition, KA-induced lipid peroxidation, cytochrome c release and mitochondrial ROS generation were also attenuated by Anti-134. The level of Sirtuin 3 (Sirt3) and its downstream antioxidant enzymes, such as mitochondrial superoxide dismutase 2 (SOD2), isocitrate dehydrogenase 2 (IDH2) and glutathione peroxidase (GSH-Px), were significantly higher in Anti-134 group compared with the control and scramble group. After inhibiting Sirt3 expression with SiRNA targeting Sirt3 (Si-Sirt3) and 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), the positive role of Anti-134 was apparently reversed. In conclusion, this research highly suggests that inhibition of miR-134-5p could protect neurons from KA-induced excitotoxicity through Sirt3-mediated preservation of mitochondrial function.