Role of histaminergic neurons in development of epileptic seizures in EL mice

Abstract

The EL mouse is an animal model for hereditary temporal lobe epilepsy. When the mice receive weekly vestibular stimulation, e.g., 30 “tosses”, 10–15 cm vertically, they start to convulse after 1–2 weeks. The aim of this study was to evaluate the role of the histaminergic neurons in the regulation of seizure development in the EL mice. The obtained results indicated that administration of either histidine, a substrate for histamine synthesis, or metoprine (2,4-diamino-5-(3,4-dichlorophnyl)-6-methyl-pyrimidine), an inhibitor of histamine N-methyltransferase (HNMT), retarded the onset of seizure episodes in the mice. The co-administration of histidine and metoprine caused a more marked delay in it. The histamine levels in the brain significantly increased in response to any of these treatments. The intraperitoneal injection of diphenhydramine, a H1-antagonist accelerated the initiation of seizure episodes in the mice, whereas thioperamide, a H3-antagonist caused a delay in the response. There were significant increases in the brain histamine levels upon injection of any of these drugs with concomitant rises in the activity of the histidine decarboxylase (HDC). These results, taken together, suggest that the histaminergic neurons play crucial roles in the development of seizures in the EL mice. They inhibit convulsion in a H1-dependent fashion, while the neurons enhance it in a H3-receptor-mediated way.

Introduction

Mounting evidence indicates that central histaminergic neurons play important roles in the inhibition of convulsive disorders [1], [2], [3], [4], [5], [6], [7]. Many clinical experiences indicate that H1-antihistamines occasionally provoke convulsions not only in epileptic patients [1], but also in healthy children [2]. A variety of drugs, which may modulate the brain histamine levels, affect the development of seizures induced by chemical [3], [6] and electrical kindling [4], [5], [7]. The administration of either l-histidine, a precursor of histamine, or metoprine (2,4-diamino-5-(3,4-dichlorophnyl)-6-methyl-pyrimidine), an inhibitor of the histamine N-methyltransferase (HNMT), retarded seizure manifestation caused by the treatments through a probable increase in the brain histamine levels [4]. The histamine H1-antagonists, but not the H2-antihistamines, inhibited anti-convulsive effects of histidine and metoprine [4]. In addition, histamine H3-antagonists significantly attenuated the amygdaloid-kindled seizures [5]. Furthermore, the intracerebroventricular injection of histamine resulted in the inhibition of amygdaloid-kindled seizures [7].

The EL mouse is an established genetic model of human temporal lobe epilepsy [8], [9]. The mice manifest tonic–clonic seizures upon receiving periodically repeated vestibular stimuli such as being tossed upward or when subjected to seesaw movements [8], [9]. Several seizure frequency quantitative trait loci have been mapped on chromosome 2 as well as 9, which are associated with handling-induced seizures of EL mice [9]. However, seizure susceptibility of the mice seems to be complicated. It is influenced by a number of environmental factors including age, gender, maternal/paternal effects, prior handling, and seizure history [9]. In addition, emotional stress/fear response is also a likely trigger for seizure induction in EL mice [9]. The present studies were conducted to examine the role of the histaminergic neurons in the regulation of seizure manifestation of the EL mice. The obtained results suggest that the histaminergic neuron system has crucial roles in the inhibition of seizure episodes in the mice.