Brain histamine in the WAG/Rij rat, an animal model of absence epilepsy
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IntroductionRats of WAG/Rij strain are widely used as a model of human absence epilepsy [1]. Recently, we reported that tissue histamine concentrations in a number of brain structures (e.g. in striatum, cortex, pons-medulla) were lower in WAG/Rij rats than in non-epileptic Wistar rats and that H 1 -receptors were denser in several regions of the epileptic rats (e.g. in brainstem nuclei) [2,3]. The purpose of the present study was to find out whether systemic administration of an H 1 -receptor antagonist had any effect on absence seizures in WAG/Rij rats. Materials and methodsTen male WAG/Rij rats (weight 220-350 g, age 5-7 months) were anaesthetized (chloral hydrate 4% solution, 10 ml/kg i.p; procaine 2% solution for soft tissue) and chronically implanted with epidural electrodes (stainless steel screws). The cortical electrodes were placed over the frontal and parieto-occipital regions of the neocortex with reference electrodes inserted over the cerebellum. Animals were allowed to recover from the surgery at least for 10 days. EEGs were recorded in freely moving animals. An index of epileptic activity, taken as a percentage of time occupied by the generalized spike-wave discharges [4] (spike-wave index, SWI), was calculated for each rat individually from the baseline EEGs recorded for 30-45 min. After i.p. pyrilamine injection (pyrilamine maleate, 20 mg/kg) EEG was monitored for 45-60 min. All experiments were performed according to institutional and national guidelines of animal care.Statistical analysis was performed by Kruskal-Wallis ANOVA and the Wilcoxon matched pairs test. Results are presented as the medians and ranges. Results and discussionNo general effect of pyrilamine on absence epileptic phenomena was found. Instead, both aggravation (post-injection SWI higher than basal SWI) and reduction (post-injection SWI lower than basal SWI) of the seizure activity were observed. Furthermore, statistical analysis revealed that Inflamm. res. 54, Supplement 1 (2005) S40-S41 increased or decreased epileptic activity after administration of pyrilamine corresponded to low and high basal level of absence seizures in individual rats, respectively (Fig. 1). Rats reacting with increment of absence seizures (N 1 = 5) had basal SWI of 1.5% (range 0.4%-2.4%), whereas the rats reacting with decrement of absence seizures (N 2 = 5) had basal SWI of 7.1% (range 5.4%-12%). The difference in the basal SWI between these two groups was statistically significant (N 1,2 = 5, p = 0.009 according to the Kruskal-Wallis ANOVA by ranks). The treatment effects were also significant (N 1,2 = 5, p = 0.04 for both groups, Wilcoxon matched pairs test). In the rats with low basal SWI (see above) the median SWI increased up to 3.5% (range: 2.4%-8.3%), in the rats with high basal SWI (see above) the median SWI decreased down to 0.6% (range 0%-4.9%).Pyrilamine in the dose of 20 mg/kg has been reported to induce electroencephalographic and behavioural convulsions in non-epileptic rats [5]. In our experiments with WAG/Rij rats no signs of behaviou...
IntroductionRats of WAG/Rij strain are widely used as a model of human absence epilepsy [1]. Recently, we reported that tissue histamine concentrations in a number of brain structures (e.g. in striatum, cortex, pons-medulla) were lower in WAG/Rij rats than in non-epileptic Wistar rats and that H 1 -receptors were denser in several regions of the epileptic rats (e.g. in brainstem nuclei) [2,3]. The purpose of the present study was to find out whether systemic administration of an H 1 -receptor antagonist had any effect on absence seizures in WAG/Rij rats. Materials and methodsTen male WAG/Rij rats (weight 220-350 g, age 5-7 months) were anaesthetized (chloral hydrate 4% solution, 10 ml/kg i.p; procaine 2% solution for soft tissue) and chronically implanted with epidural electrodes (stainless steel screws). The cortical electrodes were placed over the frontal and parieto-occipital regions of the neocortex with reference electrodes inserted over the cerebellum. Animals were allowed to recover from the surgery at least for 10 days. EEGs were recorded in freely moving animals. An index of epileptic activity, taken as a percentage of time occupied by the generalized spike-wave discharges [4] (spike-wave index, SWI), was calculated for each rat individually from the baseline EEGs recorded for 30-45 min. After i.p. pyrilamine injection (pyrilamine maleate, 20 mg/kg) EEG was monitored for 45-60 min. All experiments were performed according to institutional and national guidelines of animal care.Statistical analysis was performed by Kruskal-Wallis ANOVA and the Wilcoxon matched pairs test. Results are presented as the medians and ranges. Results and discussionNo general effect of pyrilamine on absence epileptic phenomena was found. Instead, both aggravation (post-injection SWI higher than basal SWI) and reduction (post-injection SWI lower than basal SWI) of the seizure activity were observed. Furthermore, statistical analysis revealed that Inflamm. res. 54, Supplement 1 (2005) S40-S41 increased or decreased epileptic activity after administration of pyrilamine corresponded to low and high basal level of absence seizures in individual rats, respectively (Fig. 1). Rats reacting with increment of absence seizures (N 1 = 5) had basal SWI of 1.5% (range 0.4%-2.4%), whereas the rats reacting with decrement of absence seizures (N 2 = 5) had basal SWI of 7.1% (range 5.4%-12%). The difference in the basal SWI between these two groups was statistically significant (N 1,2 = 5, p = 0.009 according to the Kruskal-Wallis ANOVA by ranks). The treatment effects were also significant (N 1,2 = 5, p = 0.04 for both groups, Wilcoxon matched pairs test). In the rats with low basal SWI (see above) the median SWI increased up to 3.5% (range: 2.4%-8.3%), in the rats with high basal SWI (see above) the median SWI decreased down to 0.6% (range 0%-4.9%).Pyrilamine in the dose of 20 mg/kg has been reported to induce electroencephalographic and behavioural convulsions in non-epileptic rats [5]. In our experiments with WAG/Rij rats no signs of behaviou...
Increased density of H 1 histamine receptors in brain regions of rats with absence epilepsy
Absence epilepsy is a generalized non-convulsive form of epilepsy, characterized by spontaneous paroxysmal loss of consciousness associated with spike-wave discharges (SWDs) in EEG. The rats of the WAG/Rij strain are used as an animal model for this pathology [1].H 1 histamine receptors are supposed to play an important role in the histaminergic regulation of epilepsy: H 1 receptor binding is increased in the epileptic foci in humans [2], systemic kainic acid administration induces significant increase of H 1 receptor mRNA expression in caudate-putamen and dentate gyrus of rats [3], H 1 antagonists potentiate seizures in the EL mouse model of temporal lobe epilepsy [4].Relatively high density of H 1 receptors was found in brain regions, known to be involved in absence epilepsy -such as thalamic nuclei, superior colliculus, substantia nigra [5]. Our previous finding on negative correlation between tissue level of histamine and propensity of absence epilepsy in WAG/Rij rats [6], motivated us to investigate the possible involvement of H 1 receptor in the regulation of absence epilepsy phenomena. MethodsMale rats of the WAG/Rij (N = 8) and Wistar (N = 8) strain, weighing 250 -300 g, housed 4 -5 in a cage, with food and water ad libitum, under natural dark-light regimes (about 12 h of daylight) were used. The rats were decapitated, brains quickly removed and frozen in isopentane, on top of dry ice. Sagital slices (14 mm) were cut at -18°C, from the following levels: L = 3,4; 1,9; 0,9 according to the Rat Brain Atlas of Paxinos, then they were dried overnight at room temperature and kept at -20°C until use. The sections were incubated with 5 nM [H 3 ] pyrilamine (specific activity 30.0 Ci/mmol) either alone (total binding) or with 2 mM triprolidine (for non-specific binding) for 60 min at 4°C, rinsed and exposed to tritium-sensitive film, together with standards (Amersham). Local optical densities of the autoradiographs were measured within anatomically defined regions by the MCID image analysis device and software (St. Catharines, Ca). Statistical Analysis: in 22 out of 24 brain regions tested the mean values of the H 1 receptor density were higher in WAG/Rij rats than in Wistar rats. In other regions studied, no significant differences in the mean values were found but the Fisher's Exact test revealed, that the rat strains differed in frequency of exceeding the averaged values in the following structures: prefrontal (p = 0.041), frontal (p = 0.045) and occipital cortex (p < 0.001); dentate gyrus (p = 0.044), caudoputamen (p = 0.026), lateral thalamus (p = 0.042), medial thalamus (p = 0.013), ventral tegmental area (p = 0.004), substantia nigra (p = 0.011), hypothalamus (p = 0.026), region of optic chiasm (p = 0.003), inferior colliculus (p = 0.002). No difference was found in: CA1 hippocampal field, amygdala, nucleus accumbens, septum, solitary tract, peduncolopontine nuclei, reticular thalamic nucleus, bed nucleus of stria terminalis.The results indicate a pronounced increase of H 1 histamine receptor density in fou...
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