Genetic and Pharmacological Inhibition of p38? Improves Locomotor Recovery after Spinal Cord Injury.

ABSTRACT: One of the mitogen-activated protein kinases, p38? plays a crucial role in various inflammatory diseases and apoptosis of various types of cells. In this study, we investigated the pathophysiological roles of p38? in spinal cord injury (SCI), using a mouse model. Lateral hemisection at T9 of the SC was performed in wild type (WT) and p38?^+/- mice (p38?^-/- showed embryonic lethality). p38?^+/- 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 p38?^+/- 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 p38?^+/- 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 p38?^+/- 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 p38?^+/- mice compared with the case of WT mice. At the same time point, astrocytic scar formation was less apparent in p38?^+/- than in WT mice, while compaction of inflammatory immune cells associated with the wound contraction was more apparent in p38?^+/- than in WT mice. Furthermore, we verified the effectiveness of oral administration of SB239063, a p38? inhibitor on the hindlimb locomotor recovery after SCI. These results suggest that p38? deeply contributes to the pathogenesis of SCI and that inhibition of p38? is a beneficial strategy to recovery from SCI.

SUBMITTER: Umezawa H 

PROVIDER: S-EPMC5313485 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature