title: Plasminogen deficiency causes reduced corticospinal axonal plasticity and functional recovery after stroke in mice.
abstract: Tissue plasminogen activator (tPA) has been implicated in neurite outgrowth and neurological recovery post stroke. tPA converts the zymogen plasminogen (Plg) into plasmin. In this study, using plasminogen knockout (Plg-/-) mice and their Plg-native littermates (Plg+/+), we investigated the role of Plg in axonal remodeling and neurological recovery after stroke. Plg+/+ and Plg-/- mice (n = 10/group) were subjected to permanent intraluminal monofilament middle cerebral artery occlusion (MCAo). A foot-fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to anterogradely label the corticospinal tract (CST). Animals were euthanized 4 weeks after stroke. Neurite outgrowth was also measured in primary cultured cortical neurons harvested from Plg+/+ and Plg-/- embryos. In Plg+/+ mice, the motor functional deficiency after stroke progressively recovered with time. In contrast, recovery in Plg-/- mice was significantly impaired compared to Plg+/+ mice (p<0.01). BDA-positive axonal density of the CST originating from the contralesional cortex in the denervated side of the cervical gray matter was significantly reduced in Plg-/- mice compared with Plg+/+ mice (p<0.05). The behavioral outcome was highly correlated with the midline-crossing CST axonal density (R2>0.82, p<0.01). Plg-/- neurons exhibited significantly reduced neurite outgrowth. Our data suggest that plasminogen-dependent proteolysis has a beneficial effect during neurological recovery after stroke, at least in part, by promoting axonal remodeling in the denervated spinal cord.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America; Department of Physics, Oakland University, Rochester, Michigan, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D001522:Behavior, Animal; D002478:Cells, Cultured; D002574:Cervical Vertebrae / Q000473:pathology; D004622:Embryo, Mammalian / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D016501:Neurites / Q000378:metabolism; D009473:Neuronal Plasticity; D010958:Plasminogen / Q000172:deficiency* / Q000378:metabolism; D011712:Pyramidal Tracts / Q000473:pathology* / Q000503:physiopathology*; D020127:Recovery of Function; D020521:Stroke / Q000150:complications / Q000503:physiopathology*
chemical_list: D010958:Plasminogen
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