3. Histaminergic mechanisms in the CNS Brain histamine turnover and seizure behaviour in two mouse strains: Preliminary findings

Abstract

Epilepsy-prone strains of animal are often used as models for epilepsy. Susceptibility of the DBA/2 mouse to audiogenic seizures is age-related, beginning as soon as they can hear (~day 14) and is virtually lost by day 40 [1]. Controversy exists over the relationship between whole brain levels of 5-HT and noradrenaline and the audiogenic seizure susceptibility in the DBA/2 mouse [2]. Alterations in CNS histamine levels and function have been associated with epileptic seizures in rodents [3] and to date investigations into CNS histamine levels in this mouse strain have not been published. Thus we have measured levels of histamine and its major metabolite in 4 distinct brain regions in male DBA/2 mice compared with a nonaudiogenic-sensitive mouse strain (BKTO). Materials and methodsBoth audiogenic-sensitive (DBA/2) and non-audiogenic-sensitive (BKTO, Bantin & Kingman, Hull) mice were bred and housed at University of East London. Groups of 10 male mice of both strains, at 14, 21, 28, 35 and 42 days of age were killed by cervical dislocation. Brains were rapidly removed onto ice and dissected into 4 regions: cerebral cortex, hypothalamus, cerebellum and rest (mid-brain + brain stem). Perchloric acid (0.4 M) and EDTA (5 mM) were added to each sample. Samples were sonicated on ice and stored at -70°C. Histamine and t-methylhistamine were determined using an HPLC-fluorimetric method and GCMS [4]. Matched groups of mice were tested for audiogenic seizure susceptibility [5]. Data was analysed by ANOVA and appropriate post-tests. All animal work conformed to national animal legislation. Results and discussionBKTO mice did not exhibit audiogenic susceptibility. Maximal audiogenic susceptibility in the DBA/2 mouse occurred at day 21 and was almost lost 3 weeks later (Fig. 1 A). Our findings on the age-related audiogenic susceptibility of the DBA/2 mice agree with previous reports [1, 5].As assessment for audiogenic seizures might alter CNS histamine and t-methylhistamine levels, these were measured in mice which had not been subjected to any loud noises. Levels of histamine were highest in the hypothalamus (~10 nmol/g) and were similar in both strains with the highest levels being found on day 21 and then declining with age Inflamm. res. 52, Supplement 1 (2003) Fig. 1. Groups of 10 male DBA/2 & BKTO mice at weekly intervals were used to determine (A) mean audiogenic seizure scores by the method in [5] (1 = wild running, 2 = clonus, 3 = tonus, 4 = respiratory arrest. Inter-strain differences (Kruskal Wallis ANOVA) and (B) mean cerebellar histamine levels (pmol/g) + SD using HPLC-fluorimetry [4].

Central histaminergic signalling, neural excitability and epilepsy

“…Moreover, reductions in brain histamine were observed following amygdala kindling‐induced focal seizures using secondary generalized seizure rats, transauricular kindling rats, and 6‐Hz stimulation mice (Jahan et al, 2017; Kamei et al, 1998; Li et al, 2006). Research has also detected reduced histamine level in blood (Gholipoor et al, 2013; hyperthermia‐induced febrile seizure mice) and the hypothalamus (Tuomisto et al, 2003; audiogenic DBA/2 mice). Histamine levels in the striatum, hippocampus, amygdala, midbrain, thalamus, and hypothalamus of genetically epilepsy‐prone KM rats were significantly lower than in epilepsy‐resistant Wistar rats (Onodera et al, 1992).…”