Altered in vitro and in vivo flumazenil binding in human epileptogenic neocortex

Ferenc Nagy, Diane C. Chugani, Csaba Juhász, Ednéa A. Da Silva, Otto Muzik, William Kupsky, Alexa Canady, Craig Watson, Jagdish Shah, Harry T. Chugani

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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 (B(max)) 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 B(max) 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 B(max) (P = .0047) in spiking cortex. A positive correlation was found between K(D) and B(max) values for 38 patients (r = 0.55, P < .0001), the magnitude of the K(D) increase being twice that of the B(max) 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 B(max) 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.

Original languageEnglish (US)
Pages (from-to)939-947
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume19
Issue number9
StatePublished - 1999
Externally publishedYes

Keywords

  • Benzodiazepine receptor
  • Epilepsy surgery
  • Flumazenil
  • Positron emission tomography

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

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    Nagy, F., Chugani, D. C., Juhász, C., Da Silva, E. A., Muzik, O., Kupsky, W., Canady, A., Watson, C., Shah, J., & Chugani, H. T. (1999). Altered in vitro and in vivo flumazenil binding in human epileptogenic neocortex. Journal of Cerebral Blood Flow and Metabolism, 19(9), 939-947.