Anticonvulsant effect of carnosine on penicillin-induced epileptiform activity in rats

Abstract

Carnosine is a compound of naturally-occurring dipeptide that synthesized by the carnosine synthetase from β-alanine and l-histidine. Recent reports claim that carnosine plays an important role in the control of epilepsy but its involvement in anticonvulsant functions remains unknown. In this study, we investigated the effects of carnosine in a rat model of epilepsy using the intracortical penicillin injection method. Thirty minutes after penicillin injection, the doses of 125, 250, 500, 1000 mg/kg carnosine and 90 min before penicillin injection the dose of 500 mg/kg carnosine were administered intraperitoneally. The epileptiform activity was verified by electrocorticographic (ECoG) recordings. The mean spike frequency of penicillin-induced epileptiform activity was significantly decreased in all carnosine-treated rats when compared with those of penicillin-injected. The dose of 500 mg/kg for carnosine treated and pretreated rats was found to be the most effective dose in reducing the frequency of penicillin-induced epileptiform activity. There was no significant difference in the mean onset of epileptiform activity between penicillin and 500 mg/kg carnosine pretreated groups. These findings indicate that carnosine has an anticonvulsant effect on penicillin-induced epilepsy in rats. Thus, our data support the hypothesis that carnosine may be a potential anticonvulsant drug for clinical therapy of epilepsy in the future.

Introduction

Epilepsy is a chronic neurological disorder and characterized by chronic recurrent paroxysmal changes in neurologic functions caused by abnormalities in the electrical activity of the brain (Dichter, 1994). Conventional treatment of epilepsy consists primarily of anticonvulsant medications. Although these drugs often control or reduce the frequency of seizures, approximately one-third of patients still have uncontrolled seizures, and an even larger percentage suffer from chronic treatment side effects of currently available antiepileptic drugs (AEDs) (Löscher and Leppik, 2002). Thus, more effective and safer new therapeutics are needed.

Carnosine is a compound of naturally-occurring dipeptide that synthesized by the carnosine synthetase from β-alanine and l-histidine. Its main function serves as a reservoir for histidine, which is a precursor of histamine (Kasziba et al., 1988). It is highly concentrated in the muscle and brain of mammals (O et al., 1988, Bonfanti et al., 1999) and can easily cross the blood–brain barrier (BBB) from the periphery (Matsukura and Tanaka, 2000). Carnosine is thought to play many prominent roles such as anti-inflammatory agent, free radical scavenger (Boldyrev et al., 1999), and protein glycosylation inhibitor (Quinn et al., 1992, Hipkiss, 2005). In addition, carnosine may also serve as a neurotransmitter in the olfactory bulb (Margolis, 1974). To date, only a few studies have been published on the understanding about the anticonvulsant role of carnosine in the experimental epilepsy models (Jin et al., 2005, Wu et al., 2006, Zhu et al., 2007). Jin et al. (2005) have reported that intraperitoneal injection of carnosine significantly decreases seizure stage, after discharge duration and also prolongs generalized seizure latency of amygdaloid-kindled seizures which mimics human complex partial epilepsy with secondary generalization. Wu et al. (2006) have also shown that carnosine had significantly decreased the seizure stage, and prolonged the latencies for myoclonic jerks, in a dose- and time-dependent manner in the pentylenetetrazol (PTZ)-induced seizures, an animal model of human myoclonic, generalized tonic-clonic seizures, in rats. Furthermore, carnosine also increased remarkably the level of histamine in the hippocampus and amygdala from 1 to 2 h after carnosine injection in the amygdaloid-kindled rats (Jin et al., 2005). These results provide more evidences to support that carnosine could be metabolically transformed into histamine in the brain. Although histamine plays an important role in the pathogenesis of epilepsy (Kamei et al., 2000, Chen et al., 2002, Vinogradova et al., 2007), it cannot cross the BBB from the periphery. Thus, carnosine may be an endogenous anticonvulsant factor and could be used as a new potential antiepileptic drug in the future. However, anticonvulsant effect of carnosine should be exhibited more clearly in the different types of experimental epilepsy models.

Animal models have played a key role in the discovery and characterization of all the antiepileptic drugs. However, it is most likely that no single model system could be useful for all types of epilepsy. Topical administration of penicillin G is an experimental model commonly used to produce epileptic foci and interictal activity, both in the motor cortex (Collins, 1978, Bostanci and Bagirici, 2006) and the amygdala (Fernandez-Guardiola et al., 1995, Gonzalez-Trujano et al., 2006) that resembles focal interictal spikes recorded in the human cortex (Prince, 1972, Fisher, 1989). Administration of carnosine by different routes and doses modified convulsive activity in PTZ (Wu et al., 2006, Zhu et al., 2007), and amygdale-kindled (Jin et al., 2005) models of epilepsy. However, the data concerning the effects of carnosine on penicillin-induced epileptic activity under ECoG monitoring are still not sufficiently reported in the currently available literature. In the present study, therefore, we used intracortical penicillin injection method to induce epileptiform activity and investigated the effects of carnosine on this epilepsy model in Wistar rats.