Prolonged attenuation of amygdala-kindled seizures in rats by convection-enhanced delivery of omega-conotoxins

Abstract

Convection-enhanced delivery (CED) may be an approach to the treatment of epilepsy through direct delivery of homogenous concentrations of antiepileptic drugs into the central nervous system (CNS). ro-conotoxins GVIA (Conus geographus) and MVIIA (Conus magus) are N-type calcium channel blockers and thus have potential antiepileptic properties. I proposed that CED of GVIA and MVIIA into amygdala-kindled rats would attenuate afterdischarge and the resulting behavioral seizures. Electrode-cannula guides were implanted into the right basolateral amygdala of 20 male Sprague-Dawley rats. The kindling parameters evaluated were the following: afterdischarge threshold, afterdischarge duration, behavioral seizure stage, behavioral seizure duration, and post-ictal duration. Rats were divided into two groups, each group containing ten rats. Each rat from Group 1 received four infusions in random order: GVIA (0.005, 0.05, 0.5 nmol) and bovine serum albumin. Each rat from Group 2 received four infusions in random order: MVIIA (0.05, 0.15, 0.5 nmol) and bovine serum albumin. Both groups of rats randomly received infusions of proteolyzed (inactive) MVIIA and CBZ. The total volume of drug delivered through convection-enhanced delivery was 5 μL at a rate of 0.25 μL/min. Kindling parameters were evaluated at 20 min, 24h, 48h, 72h, 96h, and 1 week after infusions. Behavioral studies were completed with daily monitoring of locomotor activity after drug infusions. One week after infusions, rats were electrically stimulated to determine kindling parameters. The following changes in kindling parameters demonstrated anticonvulsant properties of GVIA and MVIIA: increased afterdischarge threshold, decreased afterdischarge duration, decreased seizure stage, decreased behavioral seizure duration, and decreased post-ictal duration. The duration of the toxins' effects lasted one week, unlike carbamazepine, whose effects were no longer present at 24h. Proteolyzed MVIIA had no effects on kindling parameters. Behavioral studies showed no change in locomotor activity levels after infusions. Convection-enhanced delivery can be used to repeatedly administer antiepileptic drugs to targeted regions of the brain. Both GVIA and MVIIA responded in a time and dose dependent manner. Comparisons in responses to carbamazepine and proteolyzed MVIIA indicated that the observed effects are properties of GVIA and MVIIA acting on the N-type calcium channels. In conclusion, compounds infused by convection-enhanced delivery into amygdala-kindled rats can be comprehensively evaluated for their anticonvulsant and behavioral effects.