2-Chloroadenosine attenuates kainic acid-induced toxicity within the rat striatum: relationship to release of glutamate and Ca2+ influx

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Abstract
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 μm) 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 μm). 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 μm) produced a dose-dependent reduction in the S2:S1 ratio when added before the S2 period of stimulation. This effect was reversed by 1 μm 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.