title: Increased pCREB expression and the spontaneous epileptiform activity in a BCNU-treated rat model of cortical dysplasia.
abstract: OBJECTIVE
  Cortical dysplasias (CDs) represent a wide range of cortical abnormalities that closely correlate with intractable epilepsy. Rats prenatally exposed to 1-3-bis-chloroethyl-nitrosurea (BCNU) represent an injury-based model that reproduces many histopathologic features of human CD. Previous studies reported in vivo hyperexcitability in this model, but in vivo epileptogenicity has not been confirmed.
  
  
  METHODS
  To determine whether cortical and hippocampal lesions lead to epileptiform discharges and/or seizures in the BCNU model, rats at three different ages (3, 5, and 9 months old) were implanted for long-term video electroencephalographic recording. At the end of the recording session, brain tissue was processed for histologic and immunohistochemical investigation including cAMP response element binding protein (CREB) phosphorylation, as a biomarker of epileptogenicity.
  
  
  RESULTS
  BCNU-treated rats showed spontaneous epileptiform activity (67%) in the absence of a second seizure-provoking hit. Such activity originated mainly from one hippocampus and propagated to the ipsilateral neocortex. No epileptiform activity was found in age-matched control rats. The histopathologic investigation revealed that all BCNU rats with epileptiform activity showed neocortical and hippocampal abnormalities; the presence and the severity of these lesions did not correlate consistently with the propensity to generate epileptiform discharges. Epileptiform activity was found only in cortical areas of BCNU-treated rats in which a correlation between brain abnormalities and increased pCREB expression was observed.
  
  
  CONCLUSIONS
  This study demonstrates the in vivo occurrence of spontaneous epileptiform discharges in the BCNU model and shows that increased pCREB expression can be utilized as a reliable biomarker of epileptogenicity.
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pennacchio
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Noé
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Vadym
authors.initials: V
authors.lastname: Gnatkovsky
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Ramona Frida
authors.initials: RF
authors.lastname: Moroni
authors.affiliation: Scientific Department, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Zucca
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Regondi
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Inverardi
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: de Curtis
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, IRCCS Foundation Neurological Institute "C. Besta", Milano, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Frassoni
mesh_terms: D000367:Age Factors; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism*; D064026:Calbindins / Q000378:metabolism; D002330:Carmustine / Q000009:adverse effects*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D054220:Malformations of Cortical Development / Q000188:drug therapy*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology; D051381:Rats
chemical_list: D018906:Antineoplastic Agents, Alkylating; D064026:Calbindins; D005904:Glial Fibrillary Acidic Protein; D050882:CREB-Binding Protein; D002330:Carmustine
keywords: BCNU; CREB phosphorylation; Cortical dysplasia; Electroencephalography; Epilepsy; Immunohistochemistry