Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury

Lu, Kwok Tung; Wang, Yi Wen; Wo, Yu Yuan P.; Yang, Yi

doi:10.1016/j.neulet.2005.05.057

Cited by 62 publications

(46 citation statements)

References 27 publications

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“…The changes in vessel reactivity followed by reperfusion could induce hypoxic stress on the endothelium, resulting in BBBD (43). Molecular analysis following pFUS+MB-induced vasospasm (31) has not been investigated adequately, but the increases in protein expression or mRNA reported here in HSP70, TNFα, IL1α, IL1β, VEGF, and EPO would be consistent with decreased perfusion and reperfusion within the targeted parenchyma (9,12,19,(44)(45)(46)(47). The rapid increase in TNFα and other proinflammatory factors indicates an acute involvement of NVU elements in response to hypoxia or injury (14,48).…”

Section: Discussionmentioning

confidence: 87%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

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

332

388

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MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1-7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells. The BBB consists of specialized endothelial cells connected through various tight junction proteins (TJP), astrocyte endplates, and a basement membrane. These components form part of the neurovascular unit (NVU) that is comprised of vessels, pericytes, microglia, astrocytes, and neurons along with the extracellular matrix (1,3,4,8). BBBD secondary to ischemia or trauma leads to increases in endothelial caveolae and down-regulation of TJP, transcytosis of plasma proteins (i.e., albumin), and vasogenic edema (1,6,(8)(9)(10)(11). The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12-15). The release of CCTFs and inte...

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Section: Discussionmentioning

confidence: 87%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

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

332

388

View full text Add to dashboard Cite

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“…42 Down-regulation of these cytokines by injecting receptor antibodies reduces the number of infiltrating inflammatory cells and reduces neural cell death, leading to improved functional recovery after traumatic central nervous system injury. 7,43 In the present study, we fractionated infiltrating neutrophils, monocytes/macrophages, and resident microglial cells and successfully isolated them from the injured spinal cord to analyze their individual gene expression profiles. Our results demonstrated that these inflammatory cells directly contribute to the dramatic upregulation of proinflammatory cytokines/chemokines at the lesion area (Figure 4, A-C, see Supplemental Figure S2 available at http://ajp.amjpathol.org).…”

Section: Discussionmentioning

confidence: 99%

The LTB4-BLT1 Axis Mediates Neutrophil Infiltration and Secondary Injury in Experimental Spinal Cord Injury

Saiwai

Ohkawa

Yamada

et al. 2010

The American Journal of Pathology

155

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Traumatic injury in the central nervous system induces inflammation; however, the role of this inflammation is controversial. Precise analysis of the inflammatory cells is important to gain a better understanding of the inflammatory machinery in response to neural injury. Here, we demonstrated that leukotriene B4 plays a significant role in mediating leukocyte infiltration after spinal cord injury. Using flow cytometry, we revealed that neutrophil and monocyte/macrophage infiltration peaked 12 hours after injury and was significantly suppressed in leukotriene B4 receptor 1 knockout mice. Similar findings were observed in mice treated with a leukotriene B4 receptor antagonist. Further, by isolating each inflammatory cell subset with a cell sorter, and performing quantitative reverse transcription-PCR, we demonstrated the individual contributions of more highly expressed subsets, ie, interleukins 6 and 1␤, tumor necrosis factor-␣, and FasL, to the inflammatory reaction and neural apoptosis. Inhibition of leukotriene B4 suppressed leukocyte infiltration after injury, thereby attenuating the inflammatory reaction, sparing the white matter, and reducing neural apoptosis, as well as inducing better functional recovery. These findings are the first to demonstrate that leukotriene B4 is involved in the pathogenesis of spinal cord injury through the amplification of leukocyte infiltration, and provide a potential therapeutic Spinal cord injury (SCI) causes severe motor/sensory dysfunction with limited functional recovery. Mechanical trauma rapidly leads to blood-brain barrier disruption, neuronal cell death, edema, axonal damage, and demyelination, followed by a cascade of secondary injuries that expand the inflammatory reaction, which is characterized by immune cell infiltration and activation of systemic immunity at the lesion area.

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“…Studies show that ERK activation promotes neuronal death and worsens neurologic outcomes in ischemic (Ozawa et al, 1999;Lu et al, 2010) and traumatic brain injury (Raghupathi et al, 2003;Clausen et al, 2004;Lu et al, 2005). PHLPP1 targeting strategies that decrease total protein levels may inadvertently promote cell death by freeing PHLPP1-LRR-mediated ERK inhibition (which in turn might induce deleterious ERK activation).…”

Section: Phlpp Inhibitors Are Promising New Neuroprotective Agentsmentioning

confidence: 99%

Pharmacological Inhibition of Pleckstrin Homology Domain Leucine-Rich Repeat Protein Phosphatase Is Neuroprotective: Differential Effects on Astrocytes

Jackson

Verrier

Drábek

et al. 2013

J Pharmacol Exp Ther

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Pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) inhibits protein kinase B (AKT) survival signaling in neurons. Small molecule pan-PHLPP inhibitors (selective for PHLPP1 and PHLPP2) may offer a translatable method to induce AKT neuroprotection. We tested several recently discovered PHLPP inhibitors (NSC117079 and NSC45586; benzoic acid,-2-hydroxy-,sodium salt.) in rat cortical neurons and astrocytes and compared the biochemical response of these agents with short hairpin RNA (shRNA)-mediated PHLPP1 knockdown (KD). In neurons, both PHLPP1 KD and experimental PHLPP inhibitors activated AKT and ameliorated staurosporine (STS)-induced cell death. Unexpectedly, in astrocytes, both inhibitors blocked AKT activation, and NSC117079 reduced viability. Only PHLPP2 KD mimicked PHLPP inhibitors on astrocyte biochemistry. This suggests that these inhibitors could have possible detrimental effects on astrocytes by blocking novel PHLPP2-mediated prosurvival signaling mechanisms. Finally, because PHLPP1 levels are reportedly high in the hippocampus (a region prone to ischemic death), we characterized hippocampal changes in PHLPP and several AKT targeting prodeath phosphatases after cardiac arrest (CA)-induced brain injury. PHLPP1 levels increased in rat brains subjected to CA. None of the other AKT inhibitory phosphatases increased after global ischemia (i.e., PHLPP2, PTEN, PP2A, and PP1). Selective PHLPP1 inhibition (such as by shRNA KD) activates AKT survival signaling in neurons and astrocytes. Nonspecific PHLPP inhibition (by NSC117079 and NSC45586) only activates AKT in neurons. Taken together, these results suggest that selective PHLPP1 inhibitors should be developed and may yield optimal strategies to protect injured hippocampal neurons and astrocytesnamely from global brain ischemia.

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Extracellular signal-regulated kinase-mediated IL-1-induced cortical neuron damage during traumatic brain injury

Cited by 62 publications

References 27 publications

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

The LTB4-BLT1 Axis Mediates Neutrophil Infiltration and Secondary Injury in Experimental Spinal Cord Injury

Pharmacological Inhibition of Pleckstrin Homology Domain Leucine-Rich Repeat Protein Phosphatase Is Neuroprotective: Differential Effects on Astrocytes

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