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NEUROPHARMACOLOGY

Prolonged Attenuation of Amygdala-Kindled Seizure Measures in Rats by Convection-Enhanced Delivery of the N-Type Calcium Channel Antagonists -Conotoxin GVIA and -Conotoxin MVIIA

Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.G., N.A.W., M.A.R.); and Department of Neurology, University of California, Davis, Sacramento, California (M.A.R.)

Convection-enhanced delivery (CED) permits the homogeneous distribution of therapeutic agents throughout localized regions of the brain parenchyma without causing tissue damage as occurs with bolus injection. Here, we examined whether CED infusion of the N-type calcium channel antagonists -conotoxin GVIA (-CTX-G) and -conotoxin MVIIA (-CTX-M) can attenuate kindling measures in fully amygdala-kindled rats. Rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received infusions of vehicle, -CTX-G (0.005, 0.05, and 0.5 nmol), -CTX-M (0.05, 0.15, and 0.5 nmol), proteolytically inactivated -CTX-M (0.5 nmol), or carbamazepine (500 nmol) into the stimulation site. CED of -CTX-G and -CTX-M over a 20-min period resulted in a dose-dependent increase in the afterdischarge threshold and a decrease in the afterdischarge duration and behavioral seizure score and duration during a period of 20 min to 1 week after the infusion, indicating an inhibitory effect on the triggering and expression of kindled seizures. The protective effects of -conotoxins reached a maximum at 48 h postinfusion, and then they gradually resolved over the next 5 days. In contrast, carbamazepine was active at 20 min but not at 24 h after the infusion, whereas CED of vehicle or inactivated -CTX-M had no effect. Except for transient tremor in some rats receiving the highest toxin doses, no adverse effects were observed. These results indicate that local CED of high-molecular-weight presynaptic N-type calcium channel blockers can produce long-lasting inhibition of brain excitability and that they may provide prolonged seizure protection in focal seizure disorders.

Address correspondence to: Dr. Michael A. Rogawski, Department of Neurology, 4860 Y St., Suite 3700, University of California, Davis, Sacramento, CA 95817. E-mail: rogawski{at}ucdavis.edu