Central-type benzodiazepine receptors and epileptogenesis: Basic mechanisms and clinical validity

Purpose: gamma-Aminobutyric acid (GABA)-A/benzodiazepine receptors (BZRs) play an important inhibitory role in epileptogenesis. [123 I]Iomazenil (I-123-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 I-123-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 I-123-IMP SPECT (for regional cerebral blood flow). We also investigated in vitro autoradiography with I-123-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 I-123-IMZ and I-123-IMp SPECT. Consistent with those, marked reduction of I-125-IMZ binding was observed in hippocampal CA1-3 regions of the kainate model, which clearly paralleled pyramidal neuronal loss. In contrast, I-123-IMZ binding was increased in the dentate gyrus at I month but returned to the normal level at 3-6 months, when frequent spontaneous seizures appeared. The amygdala-kindling model demonstrated similar increases in I-125-IMZ binding in the dentate gyrus without any changes in other brain regions. In NE-CD patients, the epileptogenic foci showed decreased 121 I-IMZbinding with relatively normal I-123-IMp SPECT. I-125-IMZ binding also was decreased in the cerebral cortex, hippocampus (areas CA 1, 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.