Hepatoprotection and lethality rescue by histone deacetylase inhibitor valproic acid in fatal hemorrhagic shock.

BACKGROUND: Pharmacological histone deacetylase (HDAC) inhibitors, such as known anticonvulsant valproic acid (VPA), demonstrate cytoprotective effects and increase acetylation of nuclear histones, promoting transcriptional activation of deregulated genes. Therefore, we examined protective effects of VPA administration in lethal hemorrhage and analyzed the patterns of hepatic histone acetylation. METHODS: Male Wistar Kyoto rats were pretreated with VPA (n = 10) and 2-methyl-2-pentenoic acid (2M2P), structural VPA analog with limited HDAC inhibiting activity (2M2P; n = 8), at 300 mg/kg/dose, administered subcutaneously, 24 hour and immediately before lethal, if untreated, hemorrhage was induced by removing the 60% of total blood volume. Both drugs were dissolved in normal saline (NS) and rats pretreated with corresponding volume of NS served as control group (n = 8). Time to death, the degree of histone acetylation in liver, HDAC activity and markers of cytotoxicity (alpha-glutathione S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and lactate), and apoptosis were analyzed. RESULTS: VPA-pretreated animals demonstrated five-fold increase in survival duration. At 12 hours posthemorrhage, 70% (VPA) and 12% (2M2P) pretreated rats were alive versus 0% in NS group. Hyperacetylation of histones H2A, H3, and H4 indicated the presence of active genes and correlated with survival (VPA > 2M2P > NS). Hemorrhage-induced increases in lactate, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were alleviated by VPA. Moreover, alpha-glutathione S-transferase release, indicative of liver damage, was completely abolished. CONCLUSION: VPA offers considerable protection in severe hemorrhagic shock. The role of HDAC inhibition is suggested in mediating prosurvival actions of VPA.

Epilepsy in Irish Wolfhounds.

During the last 15 years, breeders have reported an increase in the proportion of Irish Wolfhounds with seizure disorders. Clinical data and pedigrees from closely related Irish Wolfhounds were collected retrospectively and analyzed. Idiopathic epilepsy was diagnosed, by exclusion of other causes for seizures, in 146 (18.3%) of 796 Irish Wolfhounds from 115 litters. The first seizure occurred by the age of 3 years in 73% of all dogs. Males were more commonly affected than females (61.6% versus 38.4%), with males having a later average age of seizure onset. The life expectancy of affected dogs was decreased by 2 years when compared with the average Irish Wolfhound population. The heritability index for the affected dogs, their littermates, and unaffected parents was 0.87. No simple mode of inheritance explains the pattern of affected dogs in pedigrees. Hallmarks of dominant and sex-linked inheritance were notably absent, and the segregation ratio was less than would be expected for simple autosomal recessive inheritance. Assuming all affected dogs have the same form of epilepsy, the simplest description of the complex pattern of inheritance observed is autosomal recessive, with incomplete penetrance and male dogs at increased risk.