Valproate administered after traumatic brain injury provides neuroprotection and improves cognitive function in rats

• Published in: PloS one 2010-06, Vol.5 (6), p.e11383
• Main Authors: Dash, Pramod K, Orsi, Sara A, Zhang, Min, Grill, Raymond J, Pati, Shibani, Zhao, Jing, Moore, Anthony N
• Format: Article
• Language: English
• Subjects: 4-Aminobutyrate transaminase; Acetylation; Animal cognition; Animals; Antiepileptic agents; Apoptosis; Behavior; Blood transfusions; Blood-Brain Barrier; Blotting, Western; Brain; Brain injuries; Brain Injuries - drug therapy; Cognition - drug effects; Cognitive ability; Combination drug therapy; Critical Care and Emergency Medicine/Trauma; Damage; Disease Models, Animal; Dose-Response Relationship, Drug; Drug dosages; Edema; Extravasation; GABA; Gene expression; Glutamate; Glycogen; Glycogen synthase kinase 3; Glycogen synthesis; Head injuries; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Histone deacetylase; Histone H3; Histones - metabolism; Hydroxamic acid; Hyperactivity; Immunoglobulins; Immunohistochemistry; Injury prevention; Ischemia; Laboratory animals; Male; Membrane permeability; Memory; Memory tasks; Neurobiology; Neurological Disorders/Neurorehabilitation and Trauma; Neurons; Neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Neurosurgery; Permeability; Rats; Rats, Sprague-Dawley; Rodents; Science; Signaling; Sodium; Sodium channels (voltage-gated); Spatial analysis; Spatial memory; Surgery/Neurosurgery; Transaminase; Trauma; Traumatic brain injury; Valproic acid; Valproic Acid - administration & dosage; Valproic Acid - pharmacology; Valproic Acid - therapeutic use; γ-Aminobutyric acid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0011383

Traumatic 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. Using 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. Our 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.