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Both oxidative stress and endoplasmic reticulum (ER) stress are known to contribute to secondary injury, ultimately leading to cell death after spinal cord injury (SCI). Here, we showed that valproic acid (VPA) reduced cell death of motor neurons by inhibiting cytochrome c release mediated by oxidative stress and ER stress after SCI. After SCI, rats were immediately injected with VPA (300 mg/kg) subcutaneously and further injected every 12 h for an indicated time period. Motor neuron cell death at an early time after SCI was significantly attenuated by VPA treatment. Superoxide anion (O2-) production and inducible NO synthase (iNOS) expression linked to oxidative stress was increased after injury, which was inhibited by VPA. In addition, VPA inhibited c-Jun N-terminal kinase (JNK) activation, which was activated and peaked at an early time after SCI. Furthermore, JNK activation and c-Jun phosphorylation were inhibited by a broad-spectrum reactive oxygen species (ROS) scavenger, Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), indicating that ROS including O2- increased after SCI probably contribute to JNK activation. VPA also inhibited cytochrome c release and caspase-9 activation, which was significantly inhibited by SP600125, a JNK inhibitor. The levels of phosphorylated Bim and Mcl-1, which are known as downstream targets of JNK, were significantly reduced by SP600125. On the other hand, VPA treatment inhibited ER stress-induced caspase-12 activation, which is activated in motor neurons after SCI. In addition, VPA increased the Bcl-2/Bax ratio and inhibited CHOP expression. Taken together, our results suggest that cell death of motor neurons after SCI is mediated through oxidative stress and ER stress-mediated cytochrome c release and VPA-inhibited cytochrome c release by attenuating ROS-induced JNK activation followed by Mcl-1 and Bim phosphorylation and ER stress-coupled CHOP expression.

journal of neurotrauma

Valproic Acid Protects Motor Neuron Death by Inhibiting Oxidative Stress and Endoplasmic Reticulum Stress-Mediated Cytochrome C Release after Spinal Cord Injury