Studies on benzodiazepine receptor subtypes in a model of chronic spontaneous petit mal-like seizures

doi:10.1016/0304-3940(88)90344-8

Neuroscience Letters

Volume 84, Issue 1, 11 January 1988, Pages 97-102

https://doi.org/10.1016/0304-3940(88)90344-8 Get rights and content

Abstract

Among the large variety of epilepsy models, differences in binding parameters on benzodiazepine (BZD) receptors could be demonstrated in some of them. A new model of petit mal-like seizures occurring spontaneously has been described in a strain of Wistar rats. The purpose of this study was to investigate the binding parameters on ‘central’ type and ‘peripheral’ type BZD receptor sites in epileptic and non-epileptic animals of this strain. Thus, using [³H]flunitrazepam as ligand, no modification was observed for ‘central’ type BZD sites in cortex, cerebellum and hippocampus. Nevertheless, using [³H]Ro 5-4864 as ligand, an important increase (125–150%) in the affinity constant on ‘peripheral’ type BZD sites was observed in epileptic rats, namely a lower affinity for the ligand on this receptor. Finally, no change occurred in the ratio between ‘central’ and ‘peripheral’ BZD receptor site apparent numbers.

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Anticonvulsant actions of nefiracetam on epileptic EL mice and their relation to peripheral-type benzodiazepine receptors
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Citation Excerpt :
This rank order of potencies is identical to that obtained from the behavioral experiments, suggesting that PBR might be targeted by nefiracetam and aniracetam. Involvement of PBRs in the brain has been reported as a possible seizure mechanism [3, 6, 13, 23]. PBRs in the brain are primarily found in glia cells [4, 31]and have a mitochondrial outer membrane localization [1, 17].
Anticonvulsant actions of the nootropic drug nefiracetam were studied using EL mice, an animal model of epilepsy, in which peripheral-type benzodiazepine receptors (PBRs) might be involved in their epileptogenesis. Nefiracetam, when administered orally to EL mice, inhibited convulsions induced by the PBR agonist, Ro 5-4864, with an ED₅₀ of 17.2 mg/kg, whereas it did not inhibit the drug-induced convulsions in control DDY mice. When administered intravenously (i.v.) to DDY mice, nefiracetam and other piracetam-like nootropics inhibited the Ro 5-4864-induced convulsions in the sequence of nefiracetam>aniracetam≫oxiracetam, piracetam. Spontaneous EL mouse seizures were also inhibited by these nootropics with a similar rank order of potencies. Binding studies for PBRs, performed on crude membranes of brain tissues of these mice, revealed that [ $^{3} H$ ]Ro 5-4864 and [ $^{3} H$ ]PK 11195 bindings were both inhibited by micromolar concentrations of nootropic agents in the sequence of nefiracetam>aniracetam≫oxiracetam, piracetam. The results suggest that nefiracetam may exert an anticonvulsant action through interacting with a low-affinity type of PBR in the brain, and could be developed as a promising therapeutic drug for neurological disorders including epilepsies.
Peripheral-type benzodiazepine receptors in association with epileptic seizures in EL mice
1996, Brain Research
Peripheral-type benzodiazepine receptors (PBR) in the brain were studied in association with epileptic seizures using EL mice, an animal model of epilepsy, and DDY mice as controls. Ro 5-4864 (i.p.), a specific agonist for PBR, elicited tonic-clonic convulsions in EL mice 2.6-times more potently than in DDY mice with CD₅₀s of 11.9 and 31.2 mg/kg for EL and DDY mice, respectively. In contrast, pentylenetetrazole (i.p.) exerted convulsant actions on EL and DDY mice in a less differential way with CD₅₀s of 29.2 and 48.1 mg/kg for EL and DDY mice, respectively. PK 11195 (i.v.), a specific antagonist for PBR, raised seizure thresholds of EL mice at a dose of 2 mg/kg. Binding assay revealed a 50% higher density of [³H]Ro 5-4864 binding sites in the mitochondrial fraction isolated from the cerebrum of EL mice in comparison with DDY mice. Similarly, a 40% higher density of [³H]flunitrazepam binding was observed in the mitochondrial fraction of EL mice. The results support the hypothesis that PBR, particularly those associated with mitochondria, are involved in the pathogenesis of epileptic seizures in EL mice.
GABA<inf>A</inf> sodium independent receptor sites in a strain of rats presenting generalized non-convulsive seizures
1992, Neuroscience Letters
The role of gamma-aminobutyric acid (GABA), a major inhibitor neurotransmitter in the central nervous system (CNS), is well established in the genesis and the control of epilepsies. The purpose of this work was to study the binding parameters of the Na⁺-independent GABA receptors in the brain of a strain of rats presenting spontaneous generalized non-convulsive seizures. The high- and low-affinity binding sites were evaluated in cerebral cortex, cerebellum, and hippocampus using [³H]muscimol. No significant modification was observed for the B_max and the K_d of high-affinity binding sites, although a slight decrease of B_max was noted in the three brain areas in rats with seizures. Concerning the low-affinity binding sites, significant decreases were observed in the values of B_max in the cortex, cerebellum, and hippocampus of animals with spontaneous seizures, without modification of K_d values. Such changes could be considered to be involved in some of the physiological and behaviour activities observed in this strain of rats.
GABAergic neurotransmission in the C57BL 10, sps sps mouse mutant: A model of absence seizures
1991, Experimental Neurology
The $C57BL 10, sps sps$ mouse mutant displays generalized absence seizure-like behavior. In these mice, glutamic acid decarboxylase activity is reduced in the cortex and hippocampus. Tritiated flunitrazepam binding (³H-flu) is reduced in these areas, as well as in midbrain, cerebellum, and pons-medulla. Quantitative [³H]-flunitrazepam binding autoradiography confirms these observations. GABA uptake by synaptosomes from $sps sps$ mice is also reduced in all the areas studied. Potassium-stimulated, Ca²⁺-dependent release of radioactivity from synaptosomes preloaded with [¹⁴C]-GABA is reduced in the hippocampus, increased in midbrain and pons-medulla, but remains unaltered in the cortex. These results suggest region-specific alterations in GABAergic neurotransmission that may be responsible for the absence-like seizures in $C57BL 10, sps sps$ mice.
The benzodiazepine receptor in cultured astrocytes from genetically epilepsy-prone rats
1990, Brain Research
Peripheral-type benzodiazepine (BZD) receptors were studied in cultured astrocytes derived from genetically epilepsy-prone and control rats. Scatchard analysis of the binding of [³H]Ro 5-4864 to astrocyte homogenates from epilepsy-prone rats showed 38% fewer BZD receptors (B_max) as compared to controls. No significant change in affinity (K_d) was observed. These findings suggest that the astrocyte peripheral-type BZD receptor may be involved in some forms of epilepsy.
The C57BL/10Bg sps/sps mouse: A mutant with absence-like seizures; neurochemical and behavioral correlates
1990, Neuroscience Letters
C57BL/10Bg sps/sps mice display behavioral arrest, similar to generalized absence seizures [7]. Compared with the parent strain C57BL/10Bg SPS/SPS, the activities of glutamate decarboxylase (GAD, E. C. 2.6.1.15), GABA aminotransferase (GABA-T, E. C. 2.6.1.19), aspartate aminotransferase (ASP-T, E. C. 2.6.1.1), and glutamate dehydrogenase (GDH, E. C. 1.4.1.3) in whole brain crude supernatant were significantly reduced in the sps/sps mice. Alanine aminotransferase activity (ALA-T, E. C. 2.6.1.2), was not altered in any of the strains, and normalization of GAD, GABA-T and GDH activities by that of ALA-T, further revealed significant differences between the normal strain (SPS/SPS), the heterozygotes (SPS/sps), and behavioral arrest (sps/sps) mice. These results suggest the possible involvement of GABAergic and glutamatergic neurotransmission in the absence-like behavior displayed by sps/sps mice.
Open field behavior of C57BL/10Bg sps/sps mice is characterized by periods of marked inactivity which easily distinguish affected homozygotes, from their heterozygotes littermates.

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Studies on benzodiazepine receptor subtypes in a model of chronic spontaneous petit mal-like seizures

Abstract

Life Sci.

J. Biol. Chem.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Neurosci. Lett.

Life Sci.

Life Sci.