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NEUROLOGY 1998;51:41-48
© 1998 American Academy of Neurology

Comparison of valproate and phenobarbital treatment after status epilepticus in rats

A. R. Bolanos, MD, M. Sarkisian, BS, Y. Yang, MD, A. Hori, MD, PhD, S. L. Helmers, MD, M. Mikati, MD, P. Tandon, PhD, C. E. Stafstrom, MD, PhD and G. L. Holmes, MD

From the Department of Neurology (Drs. Bolanos, Yang, Hori, Helmers, Mikati, Tandon, and Holmes, and M. Sarkisian), Harvard Medical School, Children's Hospital Boston; and the Division of Pediatric Neurology (Dr. Stafstrom), New England Medical Center, Tufts University School of Medicine, Boston, MA.

Address correspondence and reprint requests to Dr. Gregory L. Holmes, Division of Epilepsy and Clinical Neurophysiology, Hunnewell 2, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115.

Objective: To investigate the long-term effects of two widely used antiepileptic medications, valproate and phenobarbital, on learning and behavior in the kainic acid (KA) model of epilepsy.

Background: Prior clinical and animal studies have demonstrated that phenobarbital administered during development may result in subsequent cognitive impairment. It is unclear whether these adverse effects of phenobarbital extend to other antiepileptic drugs.

Methods: A convulsant dose of KA was administered to rats on postnatal day (P) 35. From P36-75 rats received daily injections of phenobarbital (PH), valproate(VPA), or saline and spontaneous seizure frequency was monitored with video recordings. After tapering of the drugs, the rats were tested in the water maze (a measure of visuospatial memory) and handling test (a measure of emotionality). Brains were then analyzed for histologic lesions.

Results: KA caused status epilepticus in all the rats. In the PH- and saline-treated groups, there was impaired learning in the water maze, increased emotionality, recurrent seizures, and histologic lesions in the hippocampal areas CA3, CA1, and dentate hilus. However, VPA-treated rats had no spontaneous seizures, abnormalities in handling, or deficits in visuospatial learning, and had fewer histologic lesions than animals receiving KA alone.

Conclusions: The long-term consequences of AED treatment during development are related to the drug used. VPA treatment after KA-induced status epilepticus prevents many of the neurologic sequelae typically seen after KA.

Supported by the Emily P. Rogers Research Fund, Abbott Laboratories, and grants to G.L.H. from the NINDS (NS27984) and Fogarty Foundation.

Received November 24, 1997. Accepted in final form March 8, 1998.




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