SB203580, a p38 mitogen-activated protein kinase inhibitor, fails to improve functional outcome following a moderate spinal cord injury in rat

Stirling, David P.; Liu, J.; Plunet, Ward T.; Steeves, John D.; Tetzlaff, Wolfram

doi:10.1016/j.neuroscience.2008.05.007

Cited by 18 publications

(16 citation statements)

References 40 publications

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“…Previous studies report increased levels of p38 after TBI and spinal cord injury (SCI) (Mori et al, 2002; Xu et al, 2006; Stirling et al, 2008; Ghasemlou et al, 2010) However, preclinical experiments using small molecule p38 inhibitors have demonstrated mixed results, with a lack of neuroprotection following a focal TBI (Mori et al, 2002), or moderate SCI (Stirling et al, 2008), while showing protection in a mild SCI (Xu et al, 2006). A recent study using mice deficient in MK2, a direct downstream substrate of p38, demonstrated reduced inflammation and improved locomotor recovery following SCI (Ghasemlou et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The p38α MAPK Regulates Microglial Responsiveness to Diffuse Traumatic Brain Injury

Bachstetter¹,

Rowe

Kaneko³

et al. 2013

J. Neurosci.

110

109

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Neuropathology following traumatic brain injury (TBI) is the result of both the immediate impact injury and secondary injury mechanisms. Unresolved post-traumatic glial activation is a secondary injury mechanism that contributes to a chronic state of neuroinflammation in both animal models of TBI and human head injury patients. We recently demonstrated, using in vitro models, that p38α MAPK signaling in microglia is a key event in promoting cytokine production in response to diverse disease-relevant stressors and subsequent inflammatory neuronal dysfunction. From these findings, we hypothesized that the p38α signaling pathway in microglia could be contributing to the secondary neuropathologic sequelae following a diffuse TBI. Mice where microglia were p38α deficient (p38α KO) were protected against TBI induced motor deficits and synaptic protein loss. In wild type (WT) mice, diffuse TBI produced microglia morphological activation that lasted for at least 7 days; however, p38α KO mice failed to activate this response. Unexpectedly, we found that the peak of the early, acute phase cytokine and chemokine levels was increased in injured p38α KO mice compared to injured WT mice. The increased cytokine levels in the p38α KO mice could not be accounted for by more infiltration of macrophages or neutrophils, or increased astrogliosis. By 7 days after injury, the cytokine and chemokine levels remained elevated in injured WT mice but not in p38α KO mice. Together, these data suggest that p38α balances the inflammatory response by acutely attenuating the early proinflammatory cytokine surge, while perpetuating the chronic microglia activation after TBI.

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Section: Discussionmentioning

confidence: 99%

The p38α MAPK Regulates Microglial Responsiveness to Diffuse Traumatic Brain Injury

Bachstetter¹,

Rowe

Kaneko³

et al. 2013

J. Neurosci.

110

109

View full text Add to dashboard Cite

show abstract

“…In addition to neurons and oligodendrocytes, activation of p38 was observed in activated microglia/macrophages, infiltrated neutrophils, and reactive astrocytes forming a glial scar after SCI [ 39 , 40 , 59 , 60 ]. Several reports have described the mechanism of p38-mediated SCI development.…”

Section: Involvement Of P38 In the Pathogenesis Of Scimentioning

confidence: 99%

Stress-Activated Protein Kinases in Spinal Cord Injury: Focus on Roles of p38

Kasuya

Umezawa

Hatano

2018

IJMS

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Spinal cord injury (SCI) consists of three phases—acute, secondary, and chronic damages—and limiting the development of secondary damage possibly improves functional recovery after SCI. A major component of the secondary phase of SCI is regarded as inflammation-triggered events: induction of cytokines, edema, microglial activation, apoptosis of cells including oligodendrocytes and neurons, demyelination, formation of the astrocytic scar, and so on. Two major stress-activated protein kinases (SAPKs)—c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK)—are activated in various types of cells in response to cellular stresses such as apoptotic stimuli and inflammatory waves. In animal models of SCI, inhibition of either JNK or p38 has been shown to promote neuroprotection-associated functional recovery. Here, we provide an overview on the roles of SAPKs in SCI and, in particular, the pathological role of p38 will be discussed as a promising target for therapeutic intervention in SCI.

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“…Peroxynitrite, which is produced by the interaction of nitric oxide (NO) and superoxide ions (O 2 Á À ), is implicated in tissue damage after SCI (Xiong et al, 2007;Xiong and Hall, 2009). Reducing levels of NO by inhibition of inducible nitric oxide synthase (iNOS), attenuates the loss of neurons Xu et al, 2006), and p38 signaling (Stirling et al, 2008), seen after SCI. Inhibition of iNOS via application of SB203580 was not effective at enhancing SC survival in vitro after H 2 O 2 administration, or in vivo following transplantation.…”

Section: Lipid Peroxidase Inhibitionmentioning

confidence: 99%

A Calpain Inhibitor Enhances the Survival of Schwann CellsIn Vitroand after Transplantation into the Injured Spinal Cord

Hill

Guller

Raffa

et al. 2010

Journal of Neurotrauma

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Despite the diversity of cells available for transplantation into sites of spinal cord injury (SCI), and the known ability of transplanted cells to integrate into host tissue, functional improvement associated with cellular transplantation has been limited. One factor potentially limiting the efficacy of transplanted cells is poor cell survival. Recently we demonstrated rapid and early death of Schwann cells (SCs) within the first 24 h after transplantation, by both necrosis and apoptosis, which results in fewer than 20% of the cells surviving beyond 1 week. To enhance SC transplant survival, in vitro and in vivo models to rapidly screen compounds for their ability to promote SC survival are needed. The current study utilized in vitro models of apoptosis and necrosis, and based on withdrawal of serum and mitogens and the application of hydrogen peroxide, we screened several inhibitors of apoptosis and necrosis. Of the compounds tested, the calpain inhibitor MDL28170 enhanced SC survival both in vitro in response to oxidative stress induced by application of H 2 O 2 , and in vivo following delayed transplantation into the moderately contused spinal cord. The results support the use of calpain inhibitors as a promising new treatment for promoting the survival of transplanted cells. They also suggest that in vitro assays for cell survival may be useful for establishing new compounds that can then be tested in vivo for their ability to promote transplanted SC survival.

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SB203580, a p38 mitogen-activated protein kinase inhibitor, fails to improve functional outcome following a moderate spinal cord injury in rat

Cited by 18 publications

References 40 publications

The p38α MAPK Regulates Microglial Responsiveness to Diffuse Traumatic Brain Injury

The p38α MAPK Regulates Microglial Responsiveness to Diffuse Traumatic Brain Injury

Stress-Activated Protein Kinases in Spinal Cord Injury: Focus on Roles of p38

A Calpain Inhibitor Enhances the Survival of Schwann CellsIn Vitroand after Transplantation into the Injured Spinal Cord

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