title: Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage.
abstract: In models of acute brain injury, progesterone improves recovery through several mechanisms including modulation of neuroinflammation. Secondary injury from neuroinflammation is a potential therapeutic target after intracerebral hemorrhage (ICH). For potential translation of progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal collagenase (0.05-0.075 U) or autologous whole blood (35 μl) injection. Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively. Hematoma volume, brain water content (cerebral edema), complementary immunohistochemistry, multiplex cytokine arrays, and inflammatory proteins were assessed at prespecified time points after injury. Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory cytokines and Toll-like receptor-associated proteins were also decreased after progesterone (4 mg/kg) treatment (p < 0.01). Progesterone-treated young female mice showed no detectable effects. Exogenous progesterone improved short- and long-term neurobehavioral recovery and modulated neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.
authors.affiliation: Multidisciplinary Neuroprotection Laboratories, Duke University, Durham, N.C., USA.
authors.forename: Beilei
authors.initials: B
authors.lastname: Lei
authors.forename: Haichen
authors.initials: H
authors.lastname: Wang
authors.forename: Seongtae
authors.initials: S
authors.lastname: Jeong
authors.forename: Justin T
authors.initials: JT
authors.lastname: Hsieh
authors.forename: Mohammed
authors.initials: M
authors.lastname: Majeed
authors.forename: Hana
authors.initials: H
authors.lastname: Dawson
authors.forename: Huaxin
authors.initials: H
authors.lastname: Sheng
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.forename: Michael L
authors.initials: ML
authors.lastname: James
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D006406:Hematoma / Q000209:etiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D011374:Progesterone / Q000097:blood / Q000627:therapeutic use*; D011372:Progestins / Q000627:therapeutic use*; D051193:Toll-Like Receptors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D011372:Progestins; D051193:Toll-Like Receptors; D011374:Progesterone