Altered in vitro and in vivo flumazenil binding in human epileptogenic neocortex.
In vitro and in vivo parameters of flumazenil (FMZ) binding were measured in spiking and nonspiking neocortex identified by intraoperative electrocorticography in epileptic patients who underwent cortical resection for seizure control. In vitro measures of receptor affinity (K(D)), number (Bmax) and laminar distribution for [3H]-FMZ binding in the epileptic focus (n = 38) were compared to nonspiking cortex from a subgroup of the patients (n = 12) and to tissue obtained from trauma patients (n = 5). The in vitro binding parameters were compared to in vivo [11C]-FMZ binding measured with positron emission tomography (PET) (n = 19). The Bmax was higher in the 38 spiking tissues as compared to the 12 nonspiking tissues (P = .012). Paired comparison of spiking versus nonspiking binding in the 12 patients from whom nonspiking tissue was available showed increases in both K(D) (P = .037) and Bmax (P = .0047) in spiking cortex. A positive correlation was found between K(D) and Bmax values for 38 patients (r = 0.55, P < .0001), the magnitude of the K(D) increase being twice that of the Bmax increase. In addition, there was a significant correlation between the asymmetry indices of the in vivo FMZ binding on PET and in vitro K(D) of spiking cortex (n = 19, r = 0.52, P = .02). The laminar distribution of [3H]-FMZ showed increased FMZ binding in cortical layers V-VI in spiking cortex compared to nonspiking and control cortex. The increased receptor number in spiking cortical layers V-VI may be a compensatory mechanism to decreased GABAergic input. The increased Bmax in spiking cortex was accompanied by a larger decrease in the affinity of FMZ for the receptor suggesting that decreased FMZ binding in the epileptic focus measured with PET is due to a decrease in the affinity of the tracer for the receptor.
Nagy
F
F
Department of Pediatrics, Children's Hospital of Michigan, The Detroit Medical Center, Wayne State University, USA.
Chugani
D C
DC
Juhász
C
C
da Silva
E A
EA
Muzik
O
O
Kupsky
W
W
Canady
A
A
Watson
C
C
Shah
J
J
Chugani
H T
HT
D000293:Adolescent; D000328:Adult; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000503:physiopathology / Q000601:surgery*; D005260:Female; D005442:Flumazenil / Q000008:administration & dosage*; D018757:GABA Modulators / Q000008:administration & dosage*; D058787:GABA-A Receptor Antagonists; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000187:drug effects* / Q000503:physiopathology* / Q000601:surgery; D011963:Receptors, GABA-A / Q000502:physiology; D014055:Tomography, Emission-Computed
D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D005442:Flumazenil