Abstracts

Convection-enhanced delivery (CED) permits safe and precise delivery of high-weight therapeutic agents (e.g., peptides, proteins, gene vectors) in therapeutically relevant concentrations into the brain (Bobo et al., 1994). Site-specific delivery of such agents may be an approach to the treatment of some forms of epilepsy. The present study tested if CED could be used to deliver highly selective N-type calcium channel antagonists of natural origin, [omega]-conotoxins GVIA ([italic]Conus geographus[/italic]) and MVIIA ([italic]Conus magus[/italic]), to attenuate seizures in rats that had been previously subjected to amygdala kindling. Each rat was implanted with a combination of guide cannula and stimulation electrode into the right basolateral amygdala. Daily kindling stimulations continued until the kindling criterion was met (stage 5 seizures for at least five consecutive days). Then, the rats received four infusions of GVIA (vehicle, 0.005, 0.05, 0.5 nmol) or MVIIA (vehicle, 0.05, 0.15, 0.5 nmol) into the stimulation site. Each infusion (5 microL volume, 0.25 microL/min rate) was separated by at least two weeks. Electrophysiological (afterdischarge threshold and duration) and behavioral (seizure stage and duration) measures of amygdala-kindled seizures were recorded at 20 min, 24 hrs, 48 hrs, 72 hrs, 96 hrs and 1 week after the infusion. CED of vehicle failed to alter stimulation-induced afterdischarge threshold and duration. The vehicle also had no effect on the stage and duration of behavioral seizures. In contrast, infusions of GVIA resulted in a dose- and time-dependent attenuation of kindled seizures as reflected by significant increases in the afterdischarge threshold with accompanying decreases in the other measures of amygdala-kindled seizures. The protective effects of GVIA reached a maximum at 48 h post infusion and then gradually dissipated within the next five days. MVIIA also had protective properties. Compared to GVIA, the protective effects of MVIIA appeared to have more rapid onset. These studies support the use of CED delivery of anticonvulsant peptides in the treatment of focal epilepsy. (Supported by ERS\NINDS\NIH)