title: Blockage of A2A and A3 adenosine receptors decreases the desensitization of human GABA(A) receptors microtransplanted to Xenopus oocytes.
abstract: We previously found that the endogenous anticonvulsant adenosine, acting through A(2A) and A(3) adenosine receptors (ARs), alters the stability of currents (I(GABA)) generated by GABA(A) receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether ARs alter the stability (desensitization) of I(GABA) expressed in focal cortical dysplasia (FCD) and in periglioma epileptic tissues. The experiments were performed with tissues from 23 patients, using voltage-clamp recordings in Xenopus oocytes microinjected with membranes isolated from human MTLE and FCD tissues or using patch-clamp recordings of pyramidal neurons in epileptic tissue slices. On repetitive activation, the epileptic GABA(A) receptors revealed instability, manifested by a large I(GABA) rundown, which in most of the oocytes (approximately 70%) was obviously impaired by the new A(2A) antagonists ANR82, ANR94, and ANR152. In most MTLE tissue-microtransplanted oocytes, a new A(3) receptor antagonist (ANR235) significantly improved I(GABA) stability. Moreover, patch-clamped pyramidal neurons from human neocortical slices of periglioma epileptic tissues exhibited altered I(GABA) rundown on ANR94 treatment. Our findings indicate that antagonizing A(2A) and A(3) receptors increases the I(GABA) stability in different epileptic tissues and suggest that adenosine derivatives may offer therapeutic opportunities in various forms of human epilepsy.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti & Dipartimento di Fisiologia Umana e Farmacologia-Centro di Eccellenza BEMM, Universita' di Roma La Sapienza, I00185 Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Roseti
authors.forename: Eleonora
authors.initials: E
authors.lastname: Palma
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Martinello
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.forename: Roberta
authors.initials: R
authors.lastname: Morace
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Esposito
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Cantore
authors.forename: Antonietta
authors.initials: A
authors.lastname: Arcella
authors.forename: Felice
authors.initials: F
authors.lastname: Giangaspero
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Addolorata
authors.initials: A
authors.lastname: Mascia
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Di Gennaro
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Quarato
authors.forename: Mario
authors.initials: M
authors.lastname: Manfredi
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristalli
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Eusebi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D054220:Malformations of Cortical Development / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C502530:8-ethoxy- 9-ethyladenine; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D011963:Receptors, GABA-A; D000225:Adenine