Allopregnanolone serum levels in female migraineurs

Background: Migraine and epilepsy are similar brain disorders in many aspects and for both, a neuronal hyperexcitability has been hypothesized. Cyclic changes in ovarian hormones are involved in exacerbating both migraine and epilepsy during perimenstrual period, leading to menstrually-related migraine and catamenial epilepsy, respectively. Ovarian hormones and derived neurosteroids can regulate important functions in neurons and glial cells in the brain; in particular, progesterone reduces seizure susceptibility partly through its conversion to allopregnanolone, a potent positive allosteric modulator of the GABA-A receptor [1]. In spite of their neuroprotective potential [2], the role of neurosteroids in migraine has not been thoroughly investigated. Therefore, we determined serum levels of testosterone, progesterone and allopregnanolone in three groups: women suffering from menstrually-related migraine (n=30), post-menopausal women suffering from migraine without aura (n=30) and non-headache control females (n=20). Methods: The enrolled migraineurs were patients afferent to the Headache Centre of Modena University Hospital; the control females were friends or relatives of the above patients. All women gave their written consent and the Ethical Committee of the Province of Modena approved the study. The fasting blood specimens were processed and then analyzed by HPLC-ESI-MS/MS. Results: Testosterone and progesterone levels were significantly higher in both non-headache control females and women suffering from menstrually-related migraine compared to post-menopausal women suffering from migraine without aura (P <0.005, t-test). Conversely, serum allopregnanolone levels were significantly lower in both women suffering from menstrually-related migraine (0.051 ng/mL; SD: 0.018) and post-menopausal women suffering from migraine without aura (0.025 ng/mL; SD: 0.013), compared to non-headache control females (0.078 ng/mL; SD 0.036, P <0.005, t-test). Conclusion: Women suffering from migraine presented low serum levels of allopregnanolone, a neurosteroid that modulates GABAergic inhibition. Consequently, the reduced GABAergic inhibition could inadequately protect women suffering from migraine against inflammatory and algogenic stimuli. In particular, it could contribute to the severity and poor response to treatments of migraine attacks. According to our preliminary results, a raise in the GABAergic transmission achieved by drugs increasing the biosynthetic pathway of inhibitory neurosteroids or the use of synthetic analogs could represent a possible novel therapeutic strategy for migraine management. [1] Meletti S., et al J. Neurochem. 2018; 147:275-284. [2] Reddy D.S., et al. Trends Pharmacol Sci. 2016;37:543-561.