title: Subacute intranasal administration of tissue plasminogen activator promotes neuroplasticity and improves functional recovery following traumatic brain injury in rats.
abstract: Traumatic brain injury (TBI) is a major cause of death and long-term disability worldwide. To date, there are no effective pharmacological treatments for TBI. Recombinant human tissue plasminogen activator (tPA) is the effective drug for the treatment of acute ischemic stroke. In addition to its thrombolytic effect, tPA is also involved in neuroplasticity in the central nervous system. However, tPA has potential adverse side effects when administered intravenously including brain edema and hemorrhage. Here we report that tPA, administered by intranasal delivery during the subacute phase after TBI, provides therapeutic benefit. Animals with TBI were treated intranasally with saline or tPA initiated 7 days after TBI. Compared with saline treatment, subacute intranasal tPA treatment significantly 1) improved cognitive (Morris water maze test) and sensorimotor (footfault and modified neurological severity score) functional recovery in rats after TBI, 2) reduced the cortical stimulation threshold evoking ipsilateral forelimb movement, 3) enhanced neurogenesis in the dentate gyrus and axonal sprouting of the corticospinal tract originating from the contralesional cortex into the denervated side of the cervical gray matter, and 4) increased the level of mature brain-derived neurotrophic factor. Our data suggest that subacute intranasal tPA treatment improves functional recovery and promotes brain neurogenesis and spinal cord axonal sprouting after TBI, which may be mediated, at least in part, by tPA/plasmin-dependent maturation of brain-derived neurotrophic factor.
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Meng
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
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Yanlu
authors.initials: Y
authors.lastname: Zhang
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 Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: An
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Asim
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States of America.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001369:Axons / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000819:agonists / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D011712:Pyramidal Tracts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010959:Tissue Plasminogen Activator