Central-type benzodiazepine receptors and epileptogenesis: basic mechanisms and clinical validity.
OBJECTIVE
Gamma-aminobutyric acid (GABA)-A/benzodiazepine receptors (BZRs) play an important inhibitory role in epileptogenesis. [123I]Iomazenil (123I-IMZ) is a specific ligand for central-type (or neuronal-type) BNRs and is available for single-photon emission computed tomography (SPECT) in brain disorders. We demonstrated alterations of central-type BZRs in human focal epilepsies and their experimental models.


METHODS
We examined interictal 123I-IMZ SPECT in patients with mesial temporal lobe epilepsy (MTLE; n = 19) with hippocampal sclerosis and neocortical epilepsy with focal cortical dysplasia (NE-CD; n = 18), and compared those with magnetic resonance imaging (MRI) and 123I-IMP SPECT (for regional cerebral blood flow). We also investigated in vitro autoradiography with (123)I-IMZ at various time courses in the intraamygdala kainate, amygdala kindling, and in-utero irradiation models.


RESULTS
In MTLE patients, the epileptogenic hippocampus often showed decreases in both 123I-IMZ and 123I-IMP SPECT. Consistent with those, marked reduction of 125I-IMZ binding was observed in hippocampal CA1-3 regions of the kainate model, which clearly paralleled pyramidal neuronal loss. In contrast, 125I-IMZ binding was increased in the dentate gyrus at 1 month but returned to the normal level at 3-6 months, when frequent spontaneous seizures appeared. The amygdala-kindling model demonstrated similar increases in 125I-IMZ binding in the dentate gyrus without any changes in other brain regions. In NE-CD patients, the epileptogenic foci showed decreased 123I-IMZ binding with relatively normal 123I-IMP SPECT. 125I-IMZ binding also was decreased in the cerebral cortex, hippocampus (areas CA1, 2, and 4), and caudate/putamen of the in-utero irradiation model.


CONCLUSIONS
These results indicate that central-type BZRs neuroimaging is useful for detection of epileptogenic foci, but their alterations differ between epilepsy subtypes and time-courses.
Department of Neuropsychiatry, Faculty of Medicine, Kagawa Medical University, Kagawa, Japan. neuropsy@kms.ac.jp
Kiyoshi
K
Morimoto
Hiroshi
H
Tamagami
Kazumi
K
Matsuda
D000328:Adult; D000679:Amygdala / Q000502:physiology; D000818:Animals; D001345:Autoradiography; D002540:Cerebral Cortex / Q000002:abnormalities / Q000098:blood supply / Q000503:physiopathology; D018891:Dentate Gyrus / Q000000981:diagnostic imaging / Q000196:embryology / Q000503:physiopathology; D004195:Disease Models, Animal; D004828:Epilepsies, Partial / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D004833:Epilepsy, Temporal Lobe / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology; D005260:Female; D005442:Flumazenil / Q000031:analogs & derivatives*; D006624:Hippocampus / Q000098:blood supply / Q000000981:diagnostic imaging / Q000503:physiopathology; D006801:Humans; D007457:Iodine Radioisotopes; D007608:Kainic Acid; D007696:Kindling, Neurologic / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D019579:Neocortex / Q000098:blood supply / Q000503:physiopathology; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D012039:Regional Blood Flow; D015899:Tomography, Emission-Computed, Single-Photon / Q000706:statistics & numerical data
D007457:Iodine Radioisotopes; D011963:Receptors, GABA-A; D005442:Flumazenil; C063038:iomazenil; D007608:Kainic Acid