title: Rho kinase inhibition following traumatic brain injury in mice promotes functional improvement and acute neuron survival but has little effect on neurogenesis, glial responses or neuroinflammation.
abstract: Inhibition of the Rho/Rho kinase pathway has been shown to be beneficial in a variety of neural injuries and diseases. In this manuscript we investigate the role of Rho kinase inhibition in recovery from traumatic brain injury using a controlled cortical impact model in mice. Mice subjected to a moderately severe TBI were treated for 1 or 4 weeks with the Rho kinase inhibitor Y27632, and functional outcomes and neuronal and glial cell responses were analysed at 1, 7 and 35 days post-injury. We hypothesised that Y27632-treated mice would show functional improvement, with augmented recruitment of neuroblasts from the SVZ and enhanced survival of newborn neurons in the pericontusional cortex, with protection against neuronal degeneration, neuroinflammation and modulation of astrocyte reactivity and blood-brain-barrier permeability. While Rho kinase inhibition enhanced recovery of motor function after trauma, there were no substantial increases in the recruitment of DCX(+) neuroblasts or the number of BrdU(+) or EdU(+) labelled newborn neurons in the pericontusional cortex of Y27632-treated mice. Inhibition of Rho kinase significantly reduced the number of degenerating cortical neurons at 1day post-injury compared to saline controls but had no longer term effect on neuronal degeneration, with only modest effects on astrocytic reactivity and macrophage/microglial responses. Overall, this study showed that Rho kinase contributes to acute neurodegenerative processes in the injured cortex but does not play a significant role in SVZ neural precursor cell-derived adult neurogenesis, glial responses or blood-brain barrier permeability following a moderately severe brain injury.
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bye
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Christie
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Alisa
authors.initials: A
authors.lastname: Turbic
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Harleen S
authors.initials: HS
authors.lastname: Basrai
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia. Electronic address: turnley@unimelb.edu.au.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Turnley
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D002470:Cell Survival / Q000187:drug effects*; D000089662:Doublecortin Protein; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009443:Neuritis / Q000188:drug therapy* / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects; D016896:Treatment Outcome; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases
keywords: Astrocytic gliosis; Controlled cortical impact; Fasudil; Horizontal ladder test; Microglia; NeuN; Rho GTPase; Y27632