Blockage of A2A and A3 adenosine receptors decreases the desensitization of human GABA(A) receptors microtransplanted to Xenopus oocytes.
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.
Roseti
Cristina
C
Istituto Pasteur-Fondazione Cenci Bolognetti & Dipartimento di Fisiologia Umana e Farmacologia-Centro di Eccellenza BEMM, Universita' di Roma La Sapienza, I00185 Rome, Italy.
Palma
Eleonora
E
Martinello
Katiuscia
K
Fucile
Sergio
S
Morace
Roberta
R
Esposito
Vincenzo
V
Cantore
Gianpaolo
G
Arcella
Antonietta
A
Giangaspero
Felice
F
Aronica
Eleonora
E
Mascia
Addolorata
A
Di Gennaro
Giancarlo
G
Quarato
Pier Paolo
PP
Manfredi
Mario
M
Cristalli
Gloria
G
Lambertucci
Catia
C
Marucci
Gabriella
G
Volpini
Rosaria
R
Limatola
Cristina
C
Eusebi
Fabrizio
F
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
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