4-Phenylbutyrate ameliorates anxiety disorder by inhibiting endoplasmic reticulum stress following diffuse axonal injury.

Diffuse axonal injury (DAI) is accompanied frequently by adverse sequelae and psychiatric disorders, such as anxiety, leading to a decreased quality of life, social isolation, and poor outcomes in patients. The mechanisms regulating psychiatric disorders post-DAI are not well elucidated, however. Previous studies showed that endoplasmic reticulum (ER) stress functions as a pivotal factor in neurodegeneration disease. In this study, we showed that DAI can trigger ER stress and unfolded protein response (UPR) activation in both the acute and chronic periods, leading to cell death and anxiety disorder. Treatment with 4-phenylbutyrate (4-PBA) is able to inhibit the UPR and cell apoptosis and relieve the anxiety disorder in our DAI model. Later (14 days post-DAI) 4-PBA treatment, however, can restore only the related gene expression of ER stress and UPR but not the psychiatric disorder. Therefore, the early (5 min after DAI) administration of 4-PBA might be a therapeutic approach for blocking the ER stress/UPR-induced cell death and anxiety disorder after DAI.