title: Genetic and Pharmacological Inhibition of p38α Improves Locomotor Recovery after Spinal Cord Injury.
abstract: One of the mitogen-activated protein kinases, p38α plays a crucial role in various inflammatory diseases and apoptosis of various types of cells. In this study, we investigated the pathophysiological roles of p38α in spinal cord injury (SCI), using a mouse model. Lateral hemisection at T9 of the SC was performed in wild type (WT) and p38α+/-mice (p38α-/-showed embryonic lethality). p38α+/-mice showed a better functional recovery from SCI-associated paralyzed hindlimbs compared to WT mice at 7 days post-injury (dpi), which remained until 28 dpi (an end time point of monitoring the behavior). In histopathological analysis at 28 dpi, there was more axonal regeneration with remyelination on the caudal side of the lesion epicenter in p38α+/-mice than in WT mice. At 7 dpi, infiltration of inflammatory cells into the lesion and expression of cytokines in the lesion were reduced in p38α+/-mice compared with WT mice. At the same time point, the number of apoptotic oligodendrocytes in the white matter at the caudal boarder of the lesion of p38α+/-mice was lower than that of WT mice. At 14 dpi, more neural and oligodendrocyte precursor cells in the gray matter and white matter, respectively, were observed around the lesion epicenter of p38α+/-mice compared with the case of WT mice. At the same time point, astrocytic scar formation was less apparent in p38α+/-than in WT mice, while compaction of inflammatory immune cells associated with the wound contraction was more apparent in p38α+/-than in WT mice. Furthermore, we verified the effectiveness of oral administration of SB239063, a p38α inhibitor on the hindlimb locomotor recovery after SCI. These results suggest that p38α deeply contributes to the pathogenesis of SCI and that inhibition of p38α is a beneficial strategy to recovery from SCI.
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biomedical Science, Graduate School of Medicine, Chiba UniversityChiba, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Umezawa
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biomedical Science, Graduate School of Medicine, Chiba UniversityChiba, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba UniversityChiba, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biomedical Science, Graduate School of Medicine, Chiba UniversityChiba, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Yoshioka
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biomedical Science, Graduate School of Medicine, Chiba UniversityChiba, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Chemical Biology Core Facility and Antibiotics Laboratory, RIKEN Advanced Science Institute Saitama, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Sudo
authors.affiliation: Corporate Research & Development, Ube Industries, Ltd Ube, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hagihara
authors.affiliation: Department of Biomedical Science, Graduate School of Medicine, Chiba University Chiba, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biomedical Science, Graduate School of Medicine, Chiba UniversityChiba, Japan.
authors.forename: Yoshitoshi
authors.initials: Y
authors.lastname: Kasuya
keywords: p38 mitogen-activated protein kinases; recovery of locomotor activity; spinal cord injury (SCI); tissue degeneration; tissue regeneration