Research ReportAnticonvulsant effect of carnosine on penicillin-induced epileptiform activity in rats
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.
Section snippets
Results
Baseline activities of each animal were recorded before the administration of intracortical penicillin (Fig. 1A). Intracortical injection of penicillin (500 IU) induced an epileptiform ECoG activity characterized by bilateral spikes and spike wave complexes. The ECoG activity had reached a constant level as to frequency and amplitude in the 25 ± 3 min and carnosine was administrated 30 min after penicillin injection.
Discussion
In the present study, we investigated the effects of carnosine on the penicillin-induced epileptiform activity in rats. The mean spike frequency of epileptiform activity was significantly decreased in all the carnosine-treated rats compared with those penicillin-injected. A few studies have been published based on the anticonvulsant role of carnosine, thus the present investigation is the first report on the anticonvulsant effect of carnosine on penicillin-induced focal epilepsy.
We used the
Animals and chemicals
Adult male Wistar rats (270–300 g) were obtained from Experimental Research Centre of Ondokuz Mayis University (Samsun, Turkey). The animal studies were carried out according to the guidelines of European Community Council for experimental animal care. Animals were housed individually on a 12-h light:12-h dark cycle (lights on at 07.00 h), at a temperature of 20 ± 2 °C and 50% humidity. Food and water were given ad libitum. Rats were assigned to the following experiments and groups: (1)
Acknowledgment
This study was supported by The Research Fund of Ondokuz Mayis University.
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2020, NeuropharmacologyCitation Excerpt :A more recent study of human epilepsy found 224 genes with differential DNA methylation persons with epilepsy and controls (Wang et al., 2016). Among the candidate genes, ATPGD1 - which codes for carnosine synthase 1 - showed hypermethylation in conjunction with decreased mRNA levels, implicating a defect in carnosine, which is known for its anticonvulsant and neuroprotective properties (Jin et al., 2005; Kozan et al., 2008). Another hypermethylated gene, which showed reduced expression, TUBB2B, is implicated in tubulinopathies, which can include cortical malformations leading to epilepsy (Chang, 2015).
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2019, Toxicology and Applied PharmacologyCitation Excerpt :It also provides cells with an antioxidant system that functions in the cytosolic environment, where water soluble oxidation mediators are often present in high concentrations (Garibala and Sinclair, 2000). Previous studies highlighted the potential neuroprotective ability of carnosine as a supportive treatment against neurotoxins (Kozan et al., 2008), effect that can be mediated by virtue of its antioxidants and anti-inflammatory effects (Hipkiss, 2009; Shiheit et al., 2010; Cheng et al., 2011). The aim of the current study is to assess the potential prophylactic effect of exogenous antioxidant “L-carnosine” on oxaliplatin-induced peripheral neuropathy in colorectal cancer patients and to assess the possible role of the Nrf-2 and NF-κB pathways.
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2011, NeuropeptidesCitation Excerpt :This result may indicate that the effect of carnosine is more of a manifest on granule cell excitability than on the strength of perforant path-granule cell synapses. The anticonvulsant effect of carnosine was shown on penicillin-induced epileptiform activity in rats (Kozan et al., 2008) and pentylenetetrazol-induced seizures in mice (Zhu et al., 2007). The perforant path consists of distinct lateral (LPP) and medial (MPP) subdivisions which arise in the entorhinal cortex and innervate, in a laminar manner, the outer and middle third of the granule cell dendritic tree, respectively (Bramham et al., 1997).
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2009, Advances in Food and Nutrition ResearchCitation Excerpt :Some anticonvulsants also upregulate carnosine levels in mouse brain and homocarnosine levels in human brain (Petroff et al., 1998, 2006). Both carnosine and homocarnosine also have anticonvulsant activity in mice, rats, and humans (Jin et al., 2005; Kozan et al., 2008; Petroff et al., 1998; Wu et al., 2006; Zhu et al., 2007). It is also thought, however, that carnosine's anticonvulsant action is exerted via a carnosine–histidine–histamine pathway (Zhu et al., 2007) activating histaminergic, GABAergic, and glutamicergic systems (Kozan et al., 2008).