Evidence for the Role of Mitogen-Activated Protein Kinase Signaling Pathways in the Development of Spinal Cord Injury

Abstract

Mitogen-activated protein kinase (MAPK) signaling pathways involve two closely related MAPKs, known as extracellular signal-regulated kinase (ERK)1 and ERK2. The aim of the present study was to evaluate the contribution of MAPK3/MAPK1 in the secondary damage in experimental spinal cord injury (SCI) in mice. To this purpose, we used 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059), which is an inhibitor of MAPK3/MAPK1. Spinal cord trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, and apoptosis. PD98059 treatment (10 mg/kg i.p.) at 1 and 6 h after the SCI significantly reduced 1) the degree of spinal cord inflammation and tissue injury (histological score), 2) neutrophil infiltration (myeloperoxidase activity), 3) nitrotyrosine formation, 4) proinflammatory cytokines expression, 5) nuclear factor-B activation, 6) phospho-ERK1/2 expression, and 6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, Fas ligand, Bax, and Bcl-2 expression). Moreover, PD98059 significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. Taken together, our results clearly demonstrate that PD98059 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.Spinal cord injury (SCI) is a highly debilitating pathology (Maegele et al., 2005). Although innovative medical care has improved patient outcome, advances in pharmacotherapy for the purpose of limiting neuronal injury and promoting regeneration have been limited. The complex pathophysiology of SCI may explain the difficulty in finding a suitable therapy. The primary traumatic mechanical injury to the spinal cord causes the death of a number of neurons that cannot be recovered and regenerated. Studies indicate that neurons continue to die for hours following traumatic SCI (Profyris et al., 2004). The events that characterize this successive phase to mechanical injury are called "secondary damage." Secondary damage is determined by a large number of cellular, molecular, and biochemical cascades. Considerable recent data suggest the presence of a local inflammatory response, which amplifies secondary damage.Moreover, various evidence has suggested that resident microglia and macrophages originating from blood are two key cell types related to the occurrence of neuronal degeneration in CNS after traumatic injury. In particular, when SCI occurs, microglia in parenchyma is activated, and macrophages in circulation can cross the blood-brain barrier to act as intrinsic spinal phagocytes. Therefore, these cells can release various neurotrophic peptides such as brain-derived neurotrophic factor (Batchelor et al., 2002), and laminin, which are excellent substrates for growing neuritis. Concomitantly, different proinflammatory mediators, ...

Tocotrienol alleviates inflammation and oxidative stress in a rat model of spinal cord injury via suppression of transforming growth factor-β

“…The two damage mechanisms of primary and secondary SCI may combine to seriously affect human health and quality of life; potentially causing disabling injuries (14). Primary SCI occurs instantly after injury of spinal cord tissue due to exposure to external forces, and is an irreversible form of damage (17). On the basis of primary injury in the spinal cord tissue, the progressive, self-destructive cascade amplification destruction process caused by a variety of factors is known as secondary SCI; the degree of damage is substantially more than in primary SCI (17)(18)(19).…”

“…Primary SCI occurs instantly after injury of spinal cord tissue due to exposure to external forces, and is an irreversible form of damage (17). On the basis of primary injury in the spinal cord tissue, the progressive, self-destructive cascade amplification destruction process caused by a variety of factors is known as secondary SCI; the degree of damage is substantially more than in primary SCI (17)(18)(19). The present study further showed that BBB scores and contused volume in rats post-SCI were improved and suppressed by treatment with tocotrienol, respectively.…”

Effect of PD98059, a Selective MAPK3/MAPK1 Inhibitor, on Acute Lung Injury in Mice

“…bolus) 1h aftercarrageenan administration of saline (N=10). The doses of PD98059 (10 mg kg') used here were based on previous in vivo studies that demonstrated a regulation of inflammation process (13)(14).…”

Temporospatial expression of fibulin-1 after acute spinal cord injury in rats

“…It has been reported that ERK1/2 is activated in models of reperfusion and excitotoxic SCI, 31,32 and ERK activation is involved in post-SCI neuronal survival. 33,34 Fibulin-1 was previously established as a modulator of FN-stimulated ERK signaling, and it suppresses FN-regulated cell adhesion and motility. Furthermore, research by Selwyn et al showed that fibulin-1 can alter ECM-mediated cell signaling through inhibiting ERK activation.…”