In Situ–Produced 7‐Chlorokynurenate Has Different Effects on Evoked Responses in Rats with Limbic Epilepsy in Comparison to Naive Controls

Abstract

Summary:Purpose: Uncontrolled epilepsy remains a significant health concern and requires new approaches to therapy. N-methyl-D-aspartate (NMDA) receptor blockade has been considered, but the adverse cognitive and behavioral effects of conventional NMDA-receptor antagonists have prevented the development of clinically useful compounds. An alternative approach may be the blockade of the glycine coagonist ("glycine B ") site of the NMDA receptor.Methods: As a first step in the exploration of this approach, we examined the effect of 4-chloro-kynurenine (4-Cl-KYN), which is converted by astrocytes to the potent NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), on the in vivo epileptiform evoked potentials in the CA1 region of rats with chronic limbic epilepsy (CLE). 4-Cl-KYN (100 mg/kg) was administered intraperitoneally to naive and epileptic rats. Evoked potentials were induced in area CA1 of the hippocampus by electrical stimulation of the midline region of the thalamus. Simultaneous microdialysis was performed in the contralateral hippocampus to determine the extracellular levels of 7-Cl-KYNA over the course of the experiment.Results: Administration of 4-Cl-KYN caused a significant reduction in the amplitude of the population spike and in the number of population spikes in epileptic animals (p < 0.01) but had no effect on the evoked response in naive rats. In contrast, 4-Cl-KYN significantly altered the paired response in naive animals (p < 0.01), but had no significant effect on this parameter in epileptic animals. The levels of 7-Cl-KYNA measured achieved known pharmacologically effective concentrations and paralleled the observed physiological effects.Conclusions: The use of glial cells for the neosynthesis and local delivery of neuroactive compounds may be a viable strategy for the treatment of limbic epilepsy. These results also underscore the unique pharmacology of neurons in epilepsy. Key Words: Glycine-Chronic limbic epilepsy-4-Chloro-kynurenine.In searching for new treatments for epilepsy, a key component is the identification of cellular mechanisms that will reduce neuronal hyperexcitability, ideally in a way that is specific to abnormal cells. Most drugs currently used in the treatment of epilepsy act through a limited number of molecular targets and mechanisms such as the enhancement of γ -aminobutyric acid (GABA)ergic function or voltage-gated potassium channels, or the inhibition of voltage-gated sodium channels or calcium T-channels (1-3). Although the currently used drugs are effective in many individuals, the continued occurrence of seizures in a large proportion of patients suggests that agents with other mechanisms of action should be considered. Increas- E-mail: ehb2z@virginia.edu ing information suggests that the pharmacology of epileptic systems may be quite different from that of normal brains, observations that suggest that the identification of new therapies should involve models that better represent the human condition.Glutamate receptors, especially N-methyl-D-aspar...

Clinical and histopathologic correlates of 11C-alpha-methyl-l-tryptophan (AMT) PET abnormalities in children with intractable epilepsy

“…Our findings also highlight the possibility that molecular neuroimaging with PET using selected tracers may assist in the elucidation of various underlying mechanisms of epilepsy. Several pharmacologic approaches to treating epilepsy with agents aimed at the kynurenine pathway in animal models have been reported (Chiarugi et al., 1995; Wu et al., 2002; Nemeth et al., 2004; Zhang et al., 2005). Based on these studies, pharmacologic agents are currently under development targeting the kynurenine pathway as a new option for the treatment of epilepsy.…”

α-Methyl- L -Tryptophan: Mechanisms for Tracer Localization of Epileptogenic Brain Regions

“…Nemeth et al administered kynurenine with probenecid to rats with pentylenetetrazol-induced seizures and showed marked inhibition of electrophysiological and behavioral seizure activity [80]. Zhang and colleagues have administered 4-chlorokynurenine, which is converted by astrocytes to the NMDA glycine-site antagonist 7-chlorokynurenic acid, to rats with kainate-induced seizures [81] and in chronic limbic epilepsy [82]. 4-chloro-kynurenine administration in kainate-treated rats delayed seizure onset, reduced total time in seizures and prevented lesions in the piriform cortex in the CA1 region of the hippocampus.…”