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


RESULTS
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.


CONCLUSIONS
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.
Dash
Pramod K
PK
Department of Neurobiology and Anatomy, University of Texas Health Science Center at Houston, Houston, Texas, United States of America. P.Dash@uth.tmc.edu
Orsi
Sara A
SA
Zhang
Min
M
Grill
Raymond J
RJ
Pati
Shibani
S
Zhao
Jing
J
Moore
Anthony N
AN
D000107:Acetylation; D000818:Animals; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D006657:Histones; D018696:Neuroprotective Agents; D014635:Valproic Acid