Cephalic Pain Unit of GIGA-Neurosciences, Liège University, CHU Sart Tilman, T4, +1, 4000 Liege, Belgium.
Exp Neurol. 2012 Aug;236(2):207-14. doi: 10.1016/j.expneurol.2012.05.002. Epub 2012 May 14.
The 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.
To 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.
Adult Sprague-Dawley rats (n=8/group) received intraperitoneal (i.p.) injections of L-kynurenine (L-KYN, 300 mg/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, 200 mg/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.
In 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.
L-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.
偏头痛中的先兆症状很可能是由于皮质扩散性抑制（CSD）引起的。CSD 受到 NMDA 受体激活和皮质兴奋性增加的影响。后者可能解释了为什么偏头痛伴先兆可能在雌激素水平升高时出现，例如在怀孕期间。犬尿氨酸酸是色氨酸代谢的衍生物，是一种内源性 NMDA 受体拮抗剂，其脑浓度可以通过系统给予其前体 L-犬尿氨酸来增强。
确定外源性给予 L-犬尿氨酸是否能够影响大鼠的 KCl 诱导的 CSD，其作用是否具有性别依赖性，以及在雌性动物的发情周期的不同阶段是否存在差异。
成年 Sprague-Dawley 大鼠（每组 8 只）接受腹腔内（i.p.）注射 L-犬尿氨酸（L-KYN，300mg/kg）、L-KYN 与丙磺舒（L-KYN+PROB）的组合，丙磺舒通过阻止其从中枢神经系统排泄来增加犬尿氨酸酸的皮质浓度，单独给予丙磺舒（PROB，200mg/kg）或生理盐水。通过 HPLC 测定皮质犬尿氨酸酸浓度（n=7）。注射后 30 分钟，通过在枕叶皮质上施加 1M KCl 来引发 CSD，并通过 DC 脑电描记术记录。在生理盐水和 L-KYN 组中，加入补充的雌性动物，并根据阴道涂片确定的发情周期阶段分析 CSD 频率。
在两性中，PROB、L-KYN 和 L-KYN+PROB 均增加了皮质犬尿氨酸酸水平。PROB、L-KYN 和 L-KYN+PROB 依次增加其效力，降低雌性大鼠的 CSD 频率，而在雄性动物中，这种作用仅对 L-KYN+PROB 显著。L-KYN 对雌性动物 CSD 频率的抑制作用在发情间期最为强烈。
L-犬尿氨酸酸的给药抑制 CSD，很可能是通过增加皮质中的犬尿氨酸酸水平。雌性动物比雄性动物对 L-犬尿氨酸酸的这种抑制作用更为敏感。这些结果强调了性激素在偏头痛中的作用，并为其预防性治疗开辟了有趣的新视角。
