Histamine H 2 -receptor modulation in two mouse models of seizure susceptibility

Abstract

IntroductionHistamine H 1 -receptor antagonists are known to influence seizure susceptibility in humans [1] and mice [2]. However, the evidence for the role of the histamine H 2 -receptor in seizures is poor and conflicting [3]. Using the histamine H 2 -agonist dimaprit and histamine H 2 -antagonist zolantidine, histamine H 2 -receptor modulation was evaluated in 2 mouse seizure models. These models were chemically-induced, pentylenetetrazol (leptazol), which produced both clonic and tonic seizures and the audiogenic susceptible DBA/2 strain of mouse [4]. Materials and methods Chemically induced-seizures in miceEither a subcutaneous (s.c.) injection of leptazol (55-60 mg/kg) which caused clonic seizures in 40-80% of the control group or a intravenous (i.v.) infusion (0.61 ml/min into the tail vein) of 0.5% w/v leptazol solution which caused both clonic and tonic seizures were used. The leptazol was administered 20 min after treatment to groups of BK/TO or CD1 mice (30-60 g) after treatment with saline (10 ml/kg) or drug (s.c.). Audiogenic seizures in DBA/2 mice25 -29 days old DBA/2 mice(5-13 g) were exposed to auditory stimulation 20 min after s. c. injection of either vehicle or drug. For up to a maximum of 45 s a bell was rung (95 dB) 30 cm above the mice. The resulting behaviours were scored: 1 = wild running, 2 = clonus, 3 = tonus and 4 = respiratory arrest RA [6]. Results and discussionDimaprit (0.3-3 mg/kg) produced a bell shaped dose-related decrease in the s.c. leptazol-seizure model in male BK/TO mice (n = 30-60) (Fig. 1), with significant anticonvulsant effects at 0.3 and 3.0 mg/kg (p < 0.01) and at 1 mg/kg (p < 0.001) in the occurrence of seizure incidence. The severity (total of seizures observed within each of the groups) of the seizures was also reduced in a dose-related manner with both 0.3 and 3 mg/kg showing significant differences (p < 0.05) and 1 mg/kg (p < 0.01). However, zolantidine (3 and 10 mg/kg) was ineffective in this model in male BK/TO mice (n = 20-50).In the leptazol infusion model in female BK/TO mice, dimaprit (1 mg/kg) increased the leptazol dose needed to evoke tonic seizures by nearly 50% (65.73 ± 4.66 mg/kg in the controls compared to 92.46 ± 9.86 mg/kg (p < 0.05)). Fig. 1. Effect of dimaprit (s.c.) on the incidence of clonic seizures resulting from subcutaneous administration of leptazol (55 -60mg/kg) in male BK/TO mice (n = 30 -60). * p < 0.01, ** p < 0.001.Whereas, zolantidine (10 mg/kg) reduced the amount of leptazol needed to evoke clonic seizure in female CD1 mice (n = 15-17) by over 10% (43.94 ± 2.61 mg/kg in the controls, compared with 38.13 ± 1.40 mg/kg in the dosed group (p < 0.05)) (n = 15-17).In audiogenic susceptible mice, dimaprit (0.3-3mg/kg) produced a bell-shaped dose-dependent effect. The mean seizure score of 3.20 in the controls was reduced to 2.25 in the dimaprit group (1 mg/kg). Dimaprit (0.3-1 mg/kg) significantly reduced wild running in the mice (p < 0.05) and at 1 mg/kg, a significant difference in RA was seen (p < 0.05) (Table 1a). Zolantidine (3 and 10...

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

“…1 A). Our findings on the age-related audiogenic susceptibility of the DBA/2 mice agree with previous reports [1,5].…”

“…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.…”

“…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].…”