Valproate Administered after Traumatic Brain Injury Provides Neuroprotection and Improves Cognitive Function in Rats

Abstract

BackgroundTraumatic brain injury (TBI) initiates a complex series of neurochemical and signaling changes that lead to pathological events including neuronal hyperactivity, excessive glutamate release, inflammation, increased blood-brain barrier (BBB) permeability and cerebral edema, altered gene expression, and neuronal dysfunction. It is believed that a drug combination, or a single drug acting on multiple targets, may be an effective strategy to treat TBI. Valproate, a widely used antiepileptic drug, has a number of targets including GABA transaminase, voltage-gated sodium channels, glycogen synthase kinase (GSK)-3, and histone deacetylases (HDACs), and therefore may attenuate a number of TBI-associated pathologies.Methodology/Principal FindingsUsing a rodent model of TBI, we tested if post-injury administration of valproate can decrease BBB permeability, reduce neural damage and improve cognitive outcome. Dose-response studies revealed that systemic administration of 400 mg/kg (i.p.), but not 15, 30, 60 or 100 mg/kg, increases histone H3 and H4 acetylation, and reduces GSK-3 activity, in the hippocampus. Thirty min post-injury administration of 400 mg/kg valproate improved BBB integrity as indicated by a reduction in Evans Blue dye extravasation. Consistent with its dose response to inhibit GSK-3 and HDACs, valproate at 400 mg/kg, but not 100 mg/kg, reduced TBI-associated hippocampal dendritic damage, lessened cortical contusion volume, and improved motor function and spatial memory. These behavioral improvements were not observed when SAHA (suberoylanilide hydroxamic acid), a selective HDAC inhibitor, was administered.Conclusion/SignificanceOur findings indicate that valproate given soon after TBI can be neuroprotective. As clinically proven interventions that can be used to minimize the damage following TBI are not currently available, the findings from this report support the further testing of valproate as an acute therapeutic strategy.

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

“…We recently reported that Scriptaid, a novel inhibitor of class I/II HDACs, protects gray matter against experimental TBI (10). These findings are consistent with reports indicating that other HDAC inhibitors can attenuate gray matter injury in TBI models (11)(12)(13)(14). Whether Scriptaid can protect white matter is unclear, however.…”

“…At present, there are no therapies that can cure the cognitive and motor deficits in TBI patients (5,15); however, an increasing number of studies show that HDAC inhibition can ameliorate injury in experimental models of TBI and other diseases, perhaps by modulating gene expression in a cell type-dependent manner (11)(12)(13)(14)24). Taken together with previously reported findings, our present study supports the view that Scriptaid is a suitable therapeutic candidate for trauma-induced mechanical injury and secondary inflammation-induced cell death in both gray and white matter.…”

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

“…A vestibulomotor (beam balance) and a motor skill task (paw placement) were used to determine animals' motor performance on days 1-3 post-treatment, as described previously. 39,[46][47][48] For beam balance, rats were preassessed by placing them on a narrow wooden beam (1.5 cm wide) and measuring the duration they remained on the beam for up to 60 sec. Animals were given repeated training until capable of balancing on the beam for the entire 60-sec period for three consecutive trials.…”

Omega-3 Polyunsaturated Fatty Acid Supplementation Improves Neurologic Recovery and Attenuates White Matter Injury after Experimental Traumatic Brain Injury

“…10,35,36 However, long-term dietary supplementation with o-3 PUFAs did not significantly prevent o-3 PUFAs protects against TBI H Pu et al tissue loss at the impact region. Nonetheless, o-3 PUFAs completely abolished neuronal loss in the CA3 region of the hippocampus.…”