Valproic acid affects neuronal fate and microglial function via enhancing autophagic flux in mice after traumatic brain injury

• Published in: Journal of neurochemistry Vol. 154; no. 3; pp. 284 - 300
• Main Authors: Zheng, Zhilong, Wu, Yanqing, Li, Zhengmao, Ye, Luxia, Lu, Qi, Zhou, Yajiao, Yuan, Yuan, Jiang, Ting, Xie, Ling, Liu, Yanlong, Chen, Daqing, Ye, Junming, Nimlamool, Wutigri, Zhang, Hongyu, Xiao, Jian
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.08.2020
• Subjects: Animal models; Animals; Apoptosis; autophagic flux; Autophagy; Autophagy - drug effects; Brain; Brain Injuries, Traumatic - pathology; Central nervous system; Epilepsy; Fluctuations; Flux; Head injuries; Immunofluorescence; Inflammation; Inflammatory response; Lysosomes; Male; Maze Learning - drug effects; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Neurons - drug effects; Neuroprotection; Neuroprotective Agents - pharmacology; Organelles; Phagocytosis; Phenotypic variations; Recovery of function; Recovery of Function - drug effects; Staining; Traumatic brain injury; traumatic brain injury (TBI); Valproic acid; valproic acid (VPA); Valproic Acid - pharmacology; Water treatment; Western blotting; autophagic flux; traumatic brain injury (TBI); valproic acid (VPA); inflammation; microglia
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14892

In recent years, many studies have focused on autophagy, an evolutionarily conserved mechanism that relies on lysosomes to achieve cellular metabolic requirements and organelle turnover, and revealed its important role in animal models of traumatic injury. Autophagy is a double‐edged sword. Appropriate levels of autophagy can promote the removal of abnormal proteins or damaged organelles, while hyperactivated autophagy can induce autophagic apoptosis. However, recent studies suggest that autophagic flux seems to be blocked after traumatic brain injury (TBI), which contributes to the apoptosis of brain cells. In this study, valproic acid (VPA), which was clinically used for epilepsy treatment, was used to treat TBI. The Morris water maze test, hematoxylin & eosin staining and Nissl staining were first conducted to confirm that VPA treatment had a therapeutic effect on mice after TBI. Western blotting, enzyme‐linked immunosorbent assay and immunofluorescence staining were then performed to reveal that VPA treatment reversed TBI‐induced blockade of autophagic flux, which was accompanied by a reduced inflammatory response. In addition, the variations in activation and phenotypic polarization of microglia were observed after VPA treatment. Nevertheless, the use of the autophagy inhibitor 3‐methyladenine partially abolished VPA‐induced neuroprotection and the regulation of microglial function after TBI, resulting in the deterioration of the central nervous system microenvironment and neurological function. Collectively, VPA treatment reversed the TBI‐induced blockade of autophagic flux in the mouse brain cortex, subsequently inhibiting brain cell apoptosis and affecting microglial function to achieve the promotion of functional recovery in mice after TBI. Cover Image for this issue: doi: 10.1111/jnc.14755. We proposed that daily intraperitoneal injection of valproic acid (VPA) in mice for three days after traumatic brain injury (TBI) can reverse TBI‐induced lysosomal functional damage and inhibit mammalian target of rapamycin (mTOR) phosphorylation to enhance autophagic flux in mice brain. In addition, increased autophagic flux inhibits excessive activation of microglia and promotes the polarization of activated microglia to M2 phenotype. It is revealed that VPA treatment may stabilize the central nervous system (CNS) microenvironment by enhancing autophagic flux in the brain and thereby affecting microglial activation and polarization to support the recovery of neurological function after TBI. Cover Image for this issue: doi: 10.1111/jnc.14755.