Oxidative stress plays an important role in the secondary neuronal damage after traumatic brain injury (TBI). Inhibition of histone deacetylases (HDACs) has been shown to reduce reactive oxygen species (ROS) production and NADPH oxidases (Nox) transcription. Vorinostat is an HDAC inhibitor. This study investigated the influence of vorinostat on neurological impairments in a rat model of TBI induced by lateral fluid percussion injury (LFPI). Different concentrations of vorinostat (5, 25, and 50 mg/kg) were administered via intraperitoneal injection. Neurological deficits were evaluated by modified neurological severity scoring (mNSS). Evans blue extravasation was performed to assess blood-brain barrier (BBB) permeability. Morris water maze assay was performed to evaluate cognitive impairments. Protein levels were evaluated through ELISA and Western blot. Vorinostat was found to attenuate TBI induced brain edema and BBB permeability in rats. Vorinostat also alleviated TBI-induced neurological impairments and anxiety-like behavior in rats. Vorinostat attenuated TBI induced apoptosis and oxidative stresses in ipsilateral injury cortical tissue. Vorinostat inhibited HDAC1, HDAC3, and Nox4 while activated AMPK signaling in ipsilateral injury cortical tissue. In conclusion, administration of vorinostat alleviates the secondary damage of TBI in rat model. The oxidative stress in the ipsilateral injury cortical tissues is decreased by the inhibition of Nox4 expression and the activation of AMPK.
Keywords: AMPK; HDAC; Nox; Traumatic brain injury; vorinostat.
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