A3 adenosine receptor antagonists delay irreversible synaptic failure caused by oxygen and glucose deprivation in the rat CA1 hippocampus in vitro.
The role of adenosine A3 receptor activation during ischaemia-like conditions produced by oxygen and glucose deprivation (OGD) was evaluated with extracellular recordings from the CA1 region of rat hippocampal slices. In all, 7 min of OGD evoked tissue anoxic depolarisation (AD, peak at approximately 7 min from OGD start, n=20) and were invariably followed by irreversible loss of electrically evoked field epsps (fepsps, n=42).The selective adenosine A3 antagonists 3-propyl-6-ethyl-5[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridinecarboxylate (MRS 1523, 1-100 nM, n=31), N-[9-chloro-2-(2-furanyl)[1,2,4]-triazolo[1,5-c]quinazolin-5-yl]benzeneacetamide (MRS 1220, 100 nM, n=7), N-(2-methoxyphenyl)-N'-[2-(3-pyrindinyl)-4-quinazolinyl]-urea, (VUF 5574, 100 nM, n=3) and 5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride (1 nM, n=4), prevented the irreversible failure of neurotransmission induced by 7 min OGD (n=45) and the development of AD in 20 out of 22 monitored slices. When tested on OGD episodes of longer duration (8-10 min, n=18), 100 nM MRS 1523 prevented or delayed the appearance of AD and exerted a protective effect on neurotransmission for episodes of up to 9 min duration. In the absence of AD, the fepsp recovery was almost total, regardless of OGD episode duration. These findings support the notion that A3 receptor stimulation is deleterious during ischaemia and suggest that selective A3 receptor block may substantially increase the resistance of the CA1 hippocampal region to ischaemic damage.
Pugliese
Anna Maria
AM
Dipartimento di Farmacologia Preclinica e Clinica, Universita' di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy.
Coppi
Elisabetta
E
Spalluto
Giampiero
G
Corradetti
Renato
R
Pedata
Felicita
F
D000200:Action Potentials / Q000187:drug effects; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007003:Hypoglycemia / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043684:Receptor, Adenosine A3 / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
C419146:2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; C110041:9-chloro-2-(2-furyl)-5-phenylacetylamino(1,2,4)triazolo(1,5-c)quinazoline; D058918:Adenosine A3 Receptor Antagonists; D011725:Pyridines; D011799:Quinazolines; D043684:Receptor, Adenosine A3; D014230:Triazoles