Valproic acid prevents brain injury in a canine model of hypothermic circulatory arrest: a promising new approach to neuroprotection during cardiac surgery.
BACKGROUND
The anticonvulsant valproic acid (sodium valproate, Depacon) acts as a neuroprotectant in rodents, but has never been tested in larger animals. We used valproate in our canine model of hypothermic circulatory arrest to evaluate its neuroprotective benefit in complex cardiac surgical cases.


METHODS
Thirteen dogs pretreated with valproate before 2 hours of hypothermic circulatory arrest survived for 24 hours (n = 7) or 72 hours (n = 6). Thirteen control animals (placebo only) also survived for 24 hours (n = 7) or 72 hours (n = 6) after hypothermic circulatory arrest. Blinded clinical neurologic evaluation was performed daily until sacrifice using the Pittsburgh Canine Neurologic Scoring System. Brains were harvested for blinded histopathologic analysis by a neuropathologist to determine the extent of apoptosis and necrosis in 11 brain regions (Total Brain Cell Death Score: 0 = normal, 99 = extensive neuronal death in all regions). Quantification of N-acetyl-aspartate, an established marker for brain injury, was performed with mass spectrometry.


RESULTS
Valproate dogs scored significantly better than control animals on clinical neurologic evaluation. Histopathologic examination revealed that valproate animals demonstrated less neuronal damage (by Total Brain Cell Death Score) than control animals at both 24 hours (16.4 versus 11.4; p = 0.03) and 72 hours (21.7 versus 17.7; p = 0.07). At 72 hours, the entorhinal cortex, an area involved with learning and memory, was significantly protected in valproate dogs (p < 0.05). Furthermore, the cortex, hippocampus, and cerebellum demonstrated preservation of near-normal N-acetyl-aspartate levels after valproate pretreatment.


CONCLUSIONS
These data demonstrate clinical, histologic, and biochemical improvements in dogs pretreated with valproate before hypothermic circulatory arrest. This commonly used drug may offer a promising new approach to neuroprotection during cardiac surgery.
Williams
Jason A
JA
Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Kennedy-Krieger Institute, Baltimore, Maryland, USA.
Barreiro
Christopher J
CJ
Nwakanma
Lois U
LU
Lange
Mary S
MS
Kratz
Lisa E
LE
Blue
Mary E
ME
Berrong
Jennifer
J
Patel
Nishant D
ND
Gott
Vincent L
VL
Troncoso
Juan C
JC
Johnston
Michael V
MV
Baumgartner
William A
WA
D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000032:analysis; D001522:Behavior, Animal; D015415:Biomarkers; D001921:Brain / Q000201:enzymology / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D050792:Circulatory Arrest, Deep Hypothermia Induced / Q000009:adverse effects*; D003244:Consciousness Disorders / Q000209:etiology / Q000517:prevention & control; D003389:Cranial Nerve Diseases / Q000209:etiology / Q000517:prevention & control; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors; D020925:Hypoxia-Ischemia, Brain / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009069:Movement Disorders / Q000209:etiology / Q000517:prevention & control; D009336:Necrosis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D012678:Sensation Disorders / Q000209:etiology / Q000517:prevention & control; D016037:Single-Blind Method; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*
D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D018696:Neuroprotective Agents; D001224:Aspartic Acid; D014635:Valproic Acid; C000179:N-acetylaspartate