The effects of phenobarbital and diazepam on cell proliferation and neurogenesis were studied in newborn rats followed for 6 months, in a study at University of Dresden, Germany; Medical University, Lublin, Poland; University Medicine Berlin, Germany; and Solvay Research Laboratories, Weesp, The Netherlands. The N-methyl-D-aspartate antagonist MK801, and the GABA subtype A agonists phenobarbital and diazepam administered to infant rats on postnatal days 6-10 caused reduced numbers of neurons in the hippocampal dentate gyrus at postnatal day 15. No apoptosis was demonstrated. At age 6 months, phenobarbital-treated rats had fewer neurons in the dentate gyrus and performed worse than saline-treated littermates in water maze learning and memory task. Blockade of N-methyl-D-aspartate receptor-mediated excitation and enhancement of GABA subtype A receptor activation impair cell proliferation and inhibit neurogenesis in the immature rat brain. These findings raise concerns about the frequent use of phenobarbital in the treatment of neonatal seizures. [1]

COMMENT. Neurogenesis in the hippocampal dentate gyrus is at its peak during the first week of postnatal life and declines progressively after day 9 in newborn rats. Phenobarbital administered in the first week to 10 days results in reduced neurogenesis at 2 weeks postnatally and impairment of learning and memory at 6 months, equivalent to adult life. These effects result in decreased hippocampal volume, reduced neuronal densities in the dentate gyrus, the CA1-hippocampus, and the cingulate cortex. These observations call for caution regarding the use of NMDA receptor antagonists and GABA-a agonists in neonatal, pediatric, and obstetric medicine.