GABAA-receptor-mediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema in the rat meninges.
1. The effects of progesterone, its A-ring-reduced metabolites, allopregnanolone, tetrahydroxydeoxycorticosterone and the synthetic neuroactive steroid alphaxalone were evaluated in a rat model of plasma extravasation within the meninges following unilateral electrical stimulation (ES) of the trigeminal ganglion (0.6 mA, 5 ms, 5 min) or substance P administration (1 nmol kg-1, i.v.). 2. When administered 55 min prior to electrical stimulation, progesterone (> or = 500 micrograms, s.c.) dose-dependently decreased plasma extravasation within the meninges (ED50: 650 micrograms) but not within conjunctiva and tongue. Promegestone (R5020), a non-metabolized progesterone agonist (1000 micrograms, i.p.) was ineffective. The administration of progestrone (> or = 500 micrograms s.c.) 55 min prior to substance P partially suppressed plasma extravasation within the meninges (ED50: 550 micrograms). 3. The GABAA-antagonist, bicuculline (ED50: 8.2 micrograms kg-1, i.p.) but not the GABAB-antagonist, phaclofen (100 micrograms kg-1, i.p.) attenuated the effects of progesterone after electrical stimulation and substance P administration. 4. The metabolites of progesterone, allopregnanolone (3 alpha-hydroxy-5 alpha- pregnan-20-one (THP); ED50: 0.58 micrograms kg-1, i.p.), tetrahydroxydeoxycorticosterone (3 alpha,21- dihydroxy-5 alpha-pregnan-20-one (THDOC); ED50: 1.2 micrograms kg-1, i.p.) as well as the synthetic steroid alphaxalone (3 alpha-hydroxy-5 alpha-pregnane-11,20-dione; ED50: 1.8 micrograms kg-1, i.p.) suppressed plasma extravasation dose-dependently following ES, whereas the epimer of allopregnanolone, 3 beta-hydroxy-5 alpha-pregnan-20-one (100 micrograms kg-1, i.p.), did not. Extravasation caused by SP administration was partially suppressed by allopregnanolone (> or = 1 microgram kg-1, i.p.) (ED50: 2.1 micrograms kg-1). 5. The effect of progesterone (1000 micrograms, s.c.) and allopregnanolone (100 micrograms kg-1, i.p.) on neurogenic plasma extravasation was reversed by bicuculline (10 micrograms kg-1, i.p.) or by a congener, bicuculline-methiodide (10 micrograms kg-1, i.p.) which does not cross the blood brain barrier. 6. Progesterone (1000 micrograms, s.c.) had no effect on mean arterial blood pressure or heart rate when measured for 60 min after administration. 7. These results indicate that neurosteroid modulation of a GABAA-receptor located outside the blood brain barrier suppresses neurogenic and substance P-induced plasma extravasation within the meninges. The findings are consistent with previously reported data showing that valproic acid and muscimol inhibit meningeal oedema by bicuculline-sensitive mechanisms. Drugs which activate GABAA-receptors and its modulatory sites might be clinically effective in the treatment of migraine and cluster headache.
Limmroth
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Stroke and Neurovascular Regulation, Massachusetts General Hospital, Charlestown 02129, USA.
Lee
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Moskowitz
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D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D002199:Capillary Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D007536:Isomerism; D008297:Male; D008578:Meninges / Q000187:drug effects* / Q000378:metabolism; D011280:Pregnanolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*; D012710:Serum Albumin, Bovine; D013373:Substance P / Q000494:pharmacology
D018756:GABA Antagonists; D011963:Receptors, GABA-A; D012710:Serum Albumin, Bovine; D013373:Substance P; D011374:Progesterone; D011280:Pregnanolone; D001640:Bicuculline