Abstract
Migraine is sexually dimorphic and associated in 20–30% of patients with an aura most likely caused by cortical spreading depression (CSD). We have previously shown that systemic L-kynurenine (L-KYN), the precursor of kynurenic acid, suppresses CSD and that this effect depends on the stage of the estrous cycle in female rats. The objectives here are to determine the influence of ovarian hormones on KCl-induced CSD and its suppression after L-KYN by directly modulating estradiol or progesterone levels in ovariectomized rats. Adult female rats were ovariectomized and subcutaneously implanted with silastic capsules filled with progesterone or 17β-estradiol mixed with cholesterol, with cholesterol only or left empty. Two weeks after the ovariectomy/capsule implantation, the animals received an i.p. injection of L-KYN (300 mg/kg) or NaCl as control. Thirty minutes later CSDs were elicited by applying KCl over the occipital cortex and recorded by DC electrocorticogram for 1 hour. The results show that both estradiol and progesterone increase CSD frequency after ovariectomy. The suppressive effect of L-KYN on CSD frequency, previously reported in normal cycling females, is not found anymore after ovariectomy, but reappears after progesterone replacement therapy. Taken together, these results emphasize the complex role of sex hormones on cortical excitability. The CSD increase by estradiol and, more surprisingly, progesterone may explain why clinically migraine with aura appears or worsens during pregnancy or with combined hormonal treatments.
Highlights
Migraine is the most common neurological disorder and occurs in about 15% of the population with a female/male ratio of 3/1 [1]
At the parieto-occipital level, ovariectomized females treated since 2 weeks with E2 had a higher cortical spreading depression (CSD) frequency than those treated with cholesterol
L-KYN had no significant influence on CSD frequency in ovariectomized females neither at the parieto-occipital site (ANOVA treatment effect F(1,34) = 0.44, N.S.) (Fig.1), nor at the frontal site (ANOVA treatment effects F(1,34) = 1.30, N.S.) (Table 1)
Summary
Migraine is the most common neurological disorder and occurs in about 15% of the population with a female/male ratio of 3/1 [1]. Migraine in women is influenced by menarche, menstruation, pregnancy, menopause, oral contraceptive use, and hormonal replacement therapy [3]. May differentially modulate migraine with aura (MA) and without aura (MO). In contrast to MO, MA is favored by hyperestrogenic states: it can appear during pregnancy [4] and is worsened by oral contraceptives [5]. It has been shown that gonadal steroids can modulate CSD susceptibility. In female mice CSD thresholds are lower than in males [8]. The increased susceptibility to CSD of female FHM1 knock-in mice is abolished by ovariectomy whereafter it is partially restored by estradiol treatment [10]
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