Understanding Secondary Injury

Borgens, Richard B.; Liu-Snyder, Peishan

doi:10.1086/665457

Cited by 172 publications

(129 citation statements)

References 223 publications

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“…Nonetheless, it is known that oligodendrocytes are especially vulnerable to mechanical trauma (10,26,27), and that neuroinflammation may exacerbate WMI following TBI (15,21). The present study improves our understanding of white matter pathophysiology by showing that microglia/macrophages exert protective or destructive effects on oligodendrocytes depending on M2 or M1 polarization status, respectively.…”

Section: Discussionsupporting

confidence: 51%

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Wang

Shi

Jiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

320

292

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Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/ macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3β in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3β may be more subtle than previously thought, in that GSK3β can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction.T raumatic brain injury (TBI) often leads to catastrophic neurological disabilities and sometimes ends in death (1). TBI results not only in gray matter damage, but also in severe white matter injury (WMI), thereby disrupting signal transmission and eliciting poor functional outcomes (2, 3). WMI in TBI patients is strongly correlated with neurological deficits, and diffusion tensor imaging of white matter offers prognostic value for neurological status (2-4). At present, there are no satisfactory therapies to protect TBI patients against either gray matter injury or WMI. Furthermore, most preclinical TBI studies greatly emphasize gray matter over white matter, which may contribute to the many disappointing results in clinical trials to date (5).Previous studies have shown that histone deacetylase (HDAC) inhibitors mitigate WMI after ischemia (6, 7). HDACs allow DNA to be wrapped more tightly around histones, thereby blocking gene transcription and acting in opposition to histone acetyltransferases that promote gene transcription (8, 9). Some HDAC inhibitors preferentially promote the transcription of neuroprotective genes. We...

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Section: Discussionsupporting

confidence: 51%

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Wang

Shi

Jiang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

320

292

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“…A spinal cord injury (SCI) refers to any damage to the spinal cord that is caused by a trauma instead of disease [1]. SCI includes a primary mechanic injury followed by a much more complicated secondary injury process involving inflammation, oxidation and excitotoxicity [1].…”

Section: Introductionmentioning

confidence: 99%

“…SCI includes a primary mechanic injury followed by a much more complicated secondary injury process involving inflammation, oxidation and excitotoxicity [1].…”

Section: Introductionmentioning

confidence: 99%

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RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Walker

et al. 2016

Mol Neurobiol

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Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A 2 (cPLA 2 ), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10 th thoracic (T10) vertebral level. We found that coadministration of TNF-α and glutamate induced spinal neuron death, and activation of RhoA, Rho kinase and cPLA 2 . Inhibition of RhoA, Rho kinase and cPLA 2 significantly reduced TNF-α/glutamate-induced cell death by 33%, 52% and 43%, respectively (p < 0.001). Inhibition of RhoA and Rho kinase also significantly down-regulated cPLA 2 activation by 66% and 60%, respectively (p < 0.01). Furthermore, inhibition of RhoA and Rho kinase reduced the release of arachidonic acid, a downstream substrate of cPLA 2 . The immunofluorescence staining showed that ROCK 1 or ROCK 2, two isoforms of Rho kinase, was co-localized with cPLA 2 in neuronal cytoplasm. Interestingly, co-immunoprecipitation (Co-IP) assay showed that ROCK 1 or ROCK 2 , bonded directly with cPLA 2 and phospho-cPLA 2 . When the Rho kinase inhibitor Y27632 was applied in mice with T10 contusion injury, it significantly decreased cPLA 2 activation and expression, and reduced injury-induced apoptosis in the lesion area. Taken together, our results reveal a novel mechanism of RhoA/Rho kinase-mediated neuronal death through regulating cPLA 2 activation.

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“…Secondary mechanisms involve a cascade of vascular, cellular and biochemical events, such as hemorrhage, edema, ischemia, cell death and oxidative stress. 1 The development of intramedullary hemorrhage exacerbates necrosis, causes swelling in the spinal cord, and higher intramedullary pressure under constraint from the meninges. The hemorrhagic necrosis and fluid accumulation at the lesion site also aggravate secondary injury.…”

Section: Introductionmentioning

confidence: 99%

Optimal time window of myelotomy in rats with acute traumatic spinal cord injury: a preliminary study

et al. 2013

Spinal Cord

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Objectives: Pathophysiological mechanisms underlying spinal cord injury (SCI) partially involve edema and formation of a hematoma. Myelotomy seems to be a promising intervention. However, the appropriate timing of myelotomy is still unknown in SCI. Here we aimed to determine the timing of microsurgical myelotomy in an animal model of SCI. Methods: The SCI model was contusion-induced with a new york university impactor. Sixty-five adult female rats were randomly divided into the following groups: laminectomy alone (the 'sham group', SG), laminectomy plus contusion (the 'contusion group', CG) or laminectomy plus contusion followed by myelotomy at 8, 24 or 48 h (8 h-MTG [myelotomy-treated group], 24 h-MTG or 48 h-MTG). Functional recovery was evaluated via the open field test and the inclined plane test every week after SCI. The percentage of spared white matter area (SWMA) and ultrastructure characteristics of the injured dorsolateral spinal cord were determined on the 42nd day after SCI. Results: Compared with the CG, myelotomy at 8 h-MTG or 24 h-MTG greatly improved the BASSO-BEATTIE-BRESNAHAN scores (Po0.008), whereas the 48 h-MTG showed less efficacy (P ¼ 0.023). All myelotomy groups showed higher mean angle values in an inclined plane test (Po0.005) and had greater percentages of SWMA than the CG. Rats in the 24 h-MTG showed a higher intraaxonal fraction and myelin fraction than those in 48 h-MTG (Po0.005). Conclusion: Myelotomy up to 48 h after SCI improves recovery in rats. The potential time window of myelotomy may be between 8 and 24 h after SCI.

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Understanding Secondary Injury

Cited by 172 publications

References 223 publications

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Optimal time window of myelotomy in rats with acute traumatic spinal cord injury: a preliminary study

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