2-chloroadenosine attenuates kainic acid-induced toxicity within the rat straitum: relationship to release of glutamate and Ca2+ influx.
1. The mechanism by which 2-chloroadenosine (2-chloroado) exerts a neuroprotective action against the excitotoxic effect of kainic acid (KA) when injected into the rat striatum was investigated. 2. Histological examination two weeks after a single injection of KA (2.2 nmol) into rat striatum revealed widespread neuronal damage. Co-injection of 2-chloroado (6-25 nmol) with the neurotoxin afforded dose-dependent neuroprotection. This effect was reversed by administration of an equimolar concentration of the adenosine receptor antagonist theophylline. 3. Both K+ (30 mM) and KA (1 mM) enhanced the release of endogenous glutamate from guinea-pig purified cerebrocortical synaptosomes in a predominantly (approximately 70%) Ca2+-dependent manner. 2-Chloroado (10 nM-1 microM) inhibited the release of glutamate evoked by both KA and K+. These effects were partially reversed by the selective A1-adenosine receptor antagonist 8-cyclopentyltheophylline (CPT) (1 microM). 4. Crude rat cortical synaptosomes were loaded with the fluorescent calcium indicator quin-2 and Ca2+ influx monitored following two successive depolarising stimuli (30 mM K+; 'S1' and 'S2'). 2-Chloroado (10 nM-1 microM) produced a dose-dependent reduction in the S2:S1 ratio when added before the S2 period of stimulation. This effect was reversed by 1 microM theophylline. However, KA (1 mM) failed to enhance Ca2+ influx in the same preparation. 5. These results suggest that the anti-excitotoxic action of 2-chloroado is mediated primarily through a specific presynaptic receptor mechanism involving reduction of transmitter glutamate release, possibly occurring through an inhibition of Ca2+ influx.
Arvin
B
B
Department of Physiology & Pharmacology, University of Southampton.
Neville
L F
LF
Pan
J
J
Roberts
P J
PJ
D015762:2-Chloroadenosine / Q000494:pharmacology*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005971:Glutamates / Q000378:metabolism*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D009252:NADPH Dehydrogenase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D005971:Glutamates; D015762:2-Chloroadenosine; D009252:NADPH Dehydrogenase; D000110:Acetylcholinesterase; D007608:Kainic Acid; D002118:Calcium