The anticonvulsant and neuroprotective effects of kir2.3 activation in PTZ-induced seizures and the kainic acid model of TLE

Abstract

PurposeTo elucidate the role of activating the inwardly rectifying K+ channel 2.3 (Kir2.3) in acute seizure and chronic epilepsy, we investigated the effect of a Kir2.3 agonist (tenidap) on epileptic and electrophysiological activities in mice. Neuronal excitability and damage were also evaluated. MethodsA Pentylenetetrazole (PTZ)-induced acute seizure model and a kainic acid (KA)-induced temporal epilepsy model were used in adult mice. The mice were given tenidap 30 min before PTZ injection or were given tenidap for 7 days after entering the chronic stage of the KA model. Video monitoring and EEG recordings were performed for comparisons. Immunofluorescence of c-fos was detected in the PTZ model, and Nissl staining was performed in the KA model. ResultsTenidap intervention significantly reduced the duration and severity of PTZ-induced acute seizures, which conformed with the power-spectrum analyses of the EEG and the quantification of spikes on EEG. C-fos expression representing neuronal excitability was also reduced with tenidap pretreatment. However, the latency time to seizure onset was unaltered. Seven days of tenidap treatment in the chronic KA model significantly attenuated seizure and spike frequencies compared to the same animal before administration. Nissl staining showed reduced hilar neuron loss in the tenidap-intervention group but showed no difference in the width of the granule cell layer. ConclusionTo our knowledge, few studies have reported the relevance of Kir2.3 to epilepsy. The present data suggested that activation of Kir2.3 exerts an anticonvulsant effect in acute seizures and the chronic stage of TLE, which makes this channel a potent therapeutic target.