title: Intranasal delivery of progesterone after transient ischemic stroke decreases mortality and provides neuroprotection.
abstract: Progesterone is a potential neuroprotective agent for cerebral stroke. One of the STAIR's recommendations is to test different routes of delivery of therapeutic agents. Here, we investigated the neuroprotective efficacy of intranasal delivery of progesterone in oleogel. Male mice were subjected to transient middle cerebral occlusion (MCAO) for 1 h. Mice received intranasal or intraperitoneal administrations of progesterone (8 mg/kg) at 1, 6, and 24 h post-MCAO. Plasma and brain levels of steroids were measured by gas chromatography-mass spectrometry 2 and 24 h after the last administration of progesterone. Behavioral and histopathological analyzes were performed at 48 h post-MCAO. For blood-brain barrier (BBB) permeability analysis, mice received one intranasal administration of progesterone or placebo at reperfusion and Evans Blue and sodium fluorescein extravasations were assessed at 4 h post-MCAO. Two hours after its nasal administration, progesterone reached elevated levels in brain and plasma and was bioconverted to its 5α-reduced metabolites and to 20α-dihydroprogesterone. However, brain levels of progesterone and its metabolites were about half those measured after intraperitoneal injections, whereas levels of 11-deoxycorticosterone and corticosterone were 5-times lower. In contrast, after 24 h, higher levels of progesterone were measured in brain and plasma after intranasal than after intraperitoneal delivery. Intranasal progesterone decreased the mortality rate, improved motor functions, reduced infarct, attenuated neuronal loss, and decreased the early BBB disruption. This study demonstrates a good bioavailability, a prolonged absorption and a good neuroprotective efficacy of intranasal delivery of progesterone, thus potentially offering an efficient, safe, non-stressful and very easy mode of administration in stroke patients.
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: magalie.frechou@inserm.fr.
authors.forename: Magalie
authors.initials: M
authors.lastname: Fréchou
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: zhang_shd@hotmail.com.
authors.forename: Shaodong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: philippe.liere@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: brigitte.delespierre@inserm.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Delespierre
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: soyed.nouha@yahoo.fr.
authors.forename: Nouha
authors.initials: N
authors.lastname: Soyed
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: antoine.pianos@inserm.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Pianos
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: michael.schumacher@inserm.fr.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.affiliation: M et P Pharma AG, Schynweg 7, P.O.Box 138, 6376 Emmetten, Switzerland. Electronic address: cu.mattern@bluewin.ch.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mattern
authors.affiliation: U1195 Inserm and University Paris-Sud, 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, France. Electronic address: rachida.guennoun@inserm.fr.
authors.forename: Rachida
authors.initials: R
authors.lastname: Guennoun
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000378:metabolism; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery; D007274:Injections, Intraperitoneal; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011374:Progesterone / Q000008:administration & dosage*; D011897:Random Allocation; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality
chemical_list: D018696:Neuroprotective Agents; D011374:Progesterone; D003345:Corticosterone
keywords: Corticosterone; Intranasal; Neuroprotection; Progesterone; Steroid; Stroke