L-4- Chlorokynurenine Attenuates Kainate-Induced Seizures and Lesions in the Rat

Abstract

Blockade of the strychnine-insensitive glycine site of the NMDA receptor is considered an attractive strategy for the development of novel neuroprotective and anticonvulsive agents. 7-Cl-kynurenic acid (7-Cl-KYNA) is a potent, selective antagonist of the NMDA/glycine receptor but penetrates poorly through the blood-brain barrier. Its prodrug, l-4-Cl-kynurenine (4-Cl-KYN), readily enters the brain from the circulation and provides antiexcitotoxic neuroprotection after systemic application. We now examined the effect of 4-Cl-KYN on seizures and neuronal loss caused by the systemic administration of the chemoconvulsant kainate (KA). 4-Cl-KYN (50 mg/kg, ip) was given 10 min before and 30, 120, and 360 min after KA (10 mg/kg, sc). Microdialysis and tissue level measurements in 4-Cl-KYN-treated rats showed increases in the concentration of 7-Cl-KYNA in several limbic brain regions of KA-injected animals. Continuous EEG recording for 24 h revealed that 4-Cl-KYN significantly delayed seizure onset and reduced the total time spent in seizures. Repeated 4-Cl-KYN administration also prevented KA-induced lesions in the piriform cortex and provided protection of hippocampal pyramidal cells in area CA1. In contrast, neurons in the hilus and in layer III of the entorhinal cortex were not protected. Consistent with the in vivo results, in vitro application of 7-Cl-KYNA to brain slices containing hippocampus and entorhinal cortex preferentially blocked low Mg 2+-induced seizure activity in hippocampal pyramidal cells. Taken together, these data suggest that a prodrug approach using 4-Cl-KYN might offer advantages in the treatment of temporal lobe epilepsy.