Effects of probenecid on the elicitation of spreading depression in the rat striatum

Spreading depression (SD) is a wave of cellular depolarization which contributes to neuronal damage in experimental focal ischaemia, and may also underlie the migraine aura. The purpose of this study was to examine the effects of probenecid, an inhibitor of organic anion transport, on K+-evoked SD in vivo. Microdialysis electrodes were implanted in the rat striatum, and recurrent SD elicited by perfusion of artificial cerebrospinal fluid containing 160 mM K+ for 20 min. Probenecid was administered either directly through the microdialysis probe, starting 50 min before application of high K+, or intravenously. SD was markedly reduced by perfusion of 5 mM probenecid through the microdialysis probe. In contrast, a high intravenous dose of probenecid (250 mg/kg) only slightly inhibited SD elicitation 90 min after treatment, despite clear changes in the amplitude and spectrum of the electroencephalogram, as early as 10 min after drug administration, confirming that probenecid readily penetrated the central nervous system. As SD is inhibited by hypercapnia, we have examined the possibility that probenecid may inhibit SD through extracellular acidification subsequent to blockade of lactate transport. Perfusion of 1-20 mM probenecid increased dose-dependently the dialysate levels of lactate, but without extracellular acidosis since the dialysate pH was not significantly reduced. How probenecid inhibits SD deserves further investigation because it may help identify novel strategies to suppress this phenomenon, now recognized deleterious to neuronal function and survival.