EFFECTS OF PROBENECID ON THE ELICITATION OF SPREADING DEPRESSION IN THE RAT STRIATUM

Spreading depression (SD) is a wave of cellular depolarization which c ontributes to neuronal damage in experimental focal ischaemia, and may also underlie the migraine aura. The purpose of this study was to exa mine the effects of probenecid, an inhibitor of organic anion transpor t, on K+-evoked SD in vivo. Microdialysis electrodes were implanted in the rat striatum, and recurrent SD elicited by perfusion of artificia l 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 marked ly reduced by perfusion of 5 mM probenecid through the microdialysis p robe. In contrast, a high intravenous dose of probenecid (250 mg/kg) o nly slightly inhibited SD elicitation 90 min after treatment, despite clear changes in the amplitude and spectrum of the electroencephalogra m, as early as 10 min after drug administration, confirming that probe necid readily penetrated the central nervous system. As SD is inhibite d 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 pr obenecid inhibits SD deserves further investigation because it may hel p identify novel strategies to suppress this phenomenon, now recognize d deleterious to neuronal function and survival. (C) 1997 Elsevier Sci ence B.V.