Effect of systemic kynurenine on cortical spreading depression and its modulation by sex hormones in rat

Abstract

BackgroundThe aura symptoms in migraine are most likely due to cortical spreading depression (CSD). CSD is favored by NMDA receptor activation and increased cortical excitability. The latter probably explains why migraine with aura may appear when estrogen levels are high, like during pregnancy. Kynurenic acid, a derivative of tryptophan metabolism, is an endogenous NMDA receptor antagonist whose cerebral concentrations can be augmented by systemic administration of its precursor l-kynurenine. ObjectiveTo determine if exogenous administration of l-kynurenine is able to influence KCl-induced CSD in rat, if the effect is sex-dependent and if it differs in females between the phases of the estrous cycle. MethodsAdult Sprague–Dawley rats (n=8/group) received intraperitoneal (i.p.) injections of l-kynurenine (L-KYN, 300mg/kg), L-KYN combined with probenecid (L-KYN+PROB) that increases cortical concentration of KYNA by blocking its excretion from the central nervous system, probenecid alone (PROB, 200mg/kg) or NaCl. Cortical kynurenic acid concentrations were determined by HPLC (n=7). Thirty minutes after the injections, CSDs were elicited by application of 1M KCl over the occipital cortex and recorded by DC electrocorticogram. In NaCl and L-KYN groups, supplementary females were added and CSD frequency was analyzed respective to the phases of the estrous cycle determined by vaginal smears. ResultsIn both sexes, PROB, L-KYN and L-KYN+PROB increased cortical kynurenic acid level. PROB, L-KYN and L-KYN+PROB with increasing potency decreased CSD frequency in female rats, while in males such an effect was significant only for L-KYN+PROB. The inhibitory effect of L-KYN on CSD frequency in females was most potent in diestrus. Conclusionl-Kynurenine administration suppresses CSD, most likely by increasing kynurenic acid levels in the cortex. Females are more sensitive to this suppressive effect of l-kynurenine than males. These results emphasize the role of sex hormones in migraine and open interesting novel perspectives for its preventive treatment.