4-METHYLPYRAZOLE, AN ALCOHOL-DEHYDROGENASE INHIBITOR, EXACERBATES ALCOHOL-INDUCED MICRENCEPHALY DURING THE BRAIN GROWTH SPURT

Whether alcohol-induced microencephaly occurs as a result of the effect of alcohol or acetaldehyde remains an unanswered, yet important, question. The present study addressed this issue by using an alcohol dehydrogenase (ADH) inhibitor, 4-methylpyrazole (4-MP), that works by blocking the metabolism of alcohol to its primary metabolite acetaldehyde, thereby prolonging the actions of alcohol while minimizing the generation of acetaldehyde. Four groups of artificially reared Sprague-Dawley rat pups were treated with alcohol treatment (3.3 g/kg EtOH or isocalorically matched control formula from postnatal days 4 through 9) and 4-MP administration (IP, 50 mg/kg or saline). A suckle control group was introduced to control the effects of the artificial rearing procedure. On postnatal day 10, all pups were perfused. Alcohol in combination with 4-MP treatment produced a marked microencephaly, as assessed by brain weights or brain to body weight ratios, compared with other artificially reared groups. The peak BACs in the pups that received both alcohol and 4-MP were increased at least twofold compared with those that received alcohol alone. These findings indicate that 4-MP is an effective nontoxic ADH inhibitor and that microencephaly is associated with BAC levels. Most importantly, these results support the hypothesis that alcohol is a causative agent for alcohol-induced microencephaly and implicates the importance of functional ADH activity in attenuating alcohol-induced neuroteratogenicity.