Article

Blockage of A2A and A3 adenosine receptors decreases the desensitization of human GABA(A) receptors microtransplanted to Xenopus oocytes.

Istituto Pasteur-Fondazione Cenci Bolognetti & Dipartimento di Fisiologia Umana e Farmacologia-Centro di Eccellenza BEMM, Universita' di Roma La Sapienza, I00185 Rome, Italy.
Proceedings of the National Academy of Sciences (impact factor: 9.68). 09/2009; 106(37):15927-31. DOI:10.1073/pnas.0907324106 pp.15927-31
Source: PubMed

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.

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Keywords

adenosine derivatives
 
ANR94 treatment
 
antagonizing A(2A)
 
different epileptic tissues
 
endogenous anticonvulsant adenosine
 
epileptic GABA(A)
 
epileptic human mesial temporal lobe
 
epileptic tissue slices
 
FCD tissues
 
focal cortical dysplasia
 
human epilepsy
 
human neocortical slices
 
large I(GABA)
 
membranes
 
patch-clamped pyramidal neurons
 
periglioma epileptic tissues
 
periglioma epileptic tissues exhibited
 
pyramidal neurons
 
various forms
 
Xenopus oocytes microinjected