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[Mitochondrial benzodiazepine receptors (MBR) in association with neurological disorders]
M Yoshii1, Y Nakamoto, S Watabe
1Department of Neurophysiology, Tokyo Institute of Psychiatry, Japan.
Abstract:
Ro 5-4864, a specific agonist of the peripheral-type benzodiazepine receptor (PBR), elicited convulsions 2.6 times more potently in EL mice (an animal model of epilepsy) than in DDY mice (control animal). A binding assay revealed a 50% higher density of [3H] Ro 5-4864 binding sites in the mitochondrial fraction (i.e., mitochondrial benzodiazepine receptors; MBR) of the brain tissues in EL mice as compared with DDY mice. On an elevated plus-maze, EL mice showed fear responses similar to those increased in DDY mice after PBR stimulation, suggesting a hyperfunction of MBR underlying the abnormal behaviors of EL mice. In fluorometric studies using NG108-15 cells, Ro 5-4864 depolarized mitochondrial membranes and, possibly as a consequence of this, raised intracellular Ca2+. Finally, we propose that MBR could be a major target of therapy for various neurological disorders, so drugs such as "mitochondrial membrane stabilizers" should be developed.
Insights
Peripheral-type benzodiazepine receptor (PBR) agonists like Ro 5-4864 are more potent in epilepsy model mice. This suggests mitochondrial benzodiazepine receptors (MBR) hyperfunction may underlie epilepsy and related neurological disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Peripheral-type benzodiazepine receptor (PBR) agonists, such as Ro 5-4864, are known to affect neurological function.
- Epilepsy is a complex neurological disorder with various underlying mechanisms.
- Mitochondrial benzodiazepine receptors (MBR) are a subtype of PBR located in mitochondria.
Purpose of the Study:
- To investigate the role of peripheral-type benzodiazepine receptors (PBR) in an animal model of epilepsy (EL mice).
- To compare the PBR agonist sensitivity and MBR density between epileptic and control mice.
- To explore the potential of MBR as a therapeutic target for neurological disorders.
Main Methods:
- Administered Ro 5-4864, a PBR agonist, to EL mice (epilepsy model) and DDY mice (control).
- Conducted binding assays to quantify [3H] Ro 5-4864 binding sites in brain mitochondrial fractions.
- Utilized an elevated plus-maze to assess fear responses and fluorometric studies to examine mitochondrial membrane potential and intracellular calcium levels in NG108-15 cells.
Main Results:
- Ro 5-4864 elicited convulsions 2.6 times more potently in EL mice compared to DDY mice.
- EL mice exhibited a 50% higher density of mitochondrial benzodiazepine receptors (MBR) in brain tissues.
- PBR stimulation in EL mice led to fear responses and mitochondrial depolarization, with increased intracellular Ca2+.
Conclusions:
- Mitochondrial benzodiazepine receptor (MBR) hyperfunction may be implicated in the abnormal behaviors observed in EL mice, an epilepsy model.
- MBR represent a potential therapeutic target for neurological disorders.
- Development of drugs like "mitochondrial membrane stabilizers" could offer new treatment strategies for neurological conditions.