Inhibition of myosin light chain kinase reduces brain edema formation after traumatic brain injury

Luh, Clara; Kuhlmann, Christoph; Ackermann, Bianca; Timaru-Kast, Ralph; Luhmann, Heiko J.; Behl, Christian; Werner, Christian; Engelhard, Kristin; Thal, Serge C.

doi:10.1111/j.1471-4159.2009.06514.x

Cited by 50 publications

(48 citation statements)

References 31 publications

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“…13,18, Here, we show that MLCK is upregulated after TBI, peaking in the first 24 h. Up-regulation of MLCK results in endothelial cell contraction and disruption of the tight junctions, occludin 5, and claudin in bovine brain microvascular endothelial cells exposed to ethanol. 38 This allows albumin to extravasate from the microvasculature into the brain parenchyma.…”

Section: Discussionmentioning

confidence: 70%

“…; Sigma-Aldrich or comparable volume of 0.9% normal saline at 4 h after TBI and daily over the course of 5 days. 13,16 All animals were randomly assigned to saline versus ML-7 groups, and the investigator was blinded to treatment and experimental groups.…”

Section: Treatment and Experimental Protocolmentioning

confidence: 99%

“…12 Pretreatment with an inhibitor of MLCK has been shown to reduce cerebral edema after controlled cortical impact in a mouse model; however, the effects of treatment with an MLCK inhibitor after TBI are not known. 13 Here, we examined the effects of treatment with an MLCK inhibitor on cerebral edema and neurological functions after TBI in postnatal day 24 (PND-24) mice, a development state similar to a 7-to 8-year-old child. 14 …”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Myosin Light-Chain Kinase Attenuates Cerebral Edema after Traumatic Brain Injury in Postnatal Mice

Rossi

Todd

Bazán

et al. 2013

Journal of Neurotrauma

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Traumatic brain injury (TBI) in children less than 8 years of age leads to decline in intelligence and executive functioning. Neurological outcomes after TBI correlate to development of cerebral edema, which affect survival rates after TBI. It has been shown that myosin light-chain kinase (MLCK) increases cerebral edema and that pretreatment with an MLCK inhibitor (ML-7) reduces cerebral edema. The aim of this study was to determine whether inhibition of MLCK after TBI in postnatal day 24 (PND-24) mice would prevent breakdown of the blood-brain barrier (BBB) and development of cerebral edema and improve neurological outcome. We used a closed head injury model of TBI. ML-7 or saline treatment was administered at 4 h and every 24 h until sacrifice or 5 days after TBI. Mice were sacrificed at 24 h, 48 h, and 72 h and 7 days after impact. Mice treated with ML-7 after TBI had decreased levels of MLCK-expressing cells (20.7 -4.8 vs. 149.3 -40.6), less albumin extravasation (28.3 -11.2 vs. 116.2 -60.7 mm 2 ) into surrounding parenchymal tissue, less Evans Blue extravasation (339 -314 vs. 4017 -560 ng/g), and showed a significant difference in wet/dry weight ratio (1.9 -0.07 vs. 2.2 -0.05 g), compared to saline-treated groups. Treatment with ML-7 also resulted in preserved neurological function measured by the wire hang test (57 vs. 21 sec) and two-object novel recognition test (old vs. new, 10.5 touches). We concluded that inhibition of MLCK reduces cerebral edema and preserves neurological function in PND-24 mice.

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Section: Discussionmentioning

confidence: 70%

Section: Treatment and Experimental Protocolmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Myosin Light-Chain Kinase Attenuates Cerebral Edema after Traumatic Brain Injury in Postnatal Mice

Rossi

Todd

Bazán

et al. 2013

Journal of Neurotrauma

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“…For example, in bovine brain microvascular endothelial cells, intercellular gap formation, altered tight junction protein expression, and increased MLC phosphorylation in response to ethanol exposure and were prevented by treatment with ML-7 (20). MLCK-dependent BBB dysfunction also occured in mice and rats in response to hypoxia, brain tissue injury, or IL-17A exposure (23,26,28). In the present study, we found that MLC phosphorylation was strongly increased in response to exposure to IL-1␤, suggestive of a role for actomyosin contractility in barrier dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…In many examples, microvascular barrier dysfunction was mediated through increased endothelial MLCK-dependent actomyosin contractility (32,33,41). Likewise, in several studies (20,23,26,28) of BBB dysfunction during focal brain tissue injury, hypoxia, and other neuroinflammatory conditions, BBB dysfunction was shown to depend on MLCK activity. For example, in bovine brain microvascular endothelial cells, intercellular gap formation, altered tight junction protein expression, and increased MLC phosphorylation in response to ethanol exposure and were prevented by treatment with ML-7 (20).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium

Rigor

Beard

Litovka

et al. 2012

American Journal of Physiology-Cell Physiology

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Rigor RR, Beard RS Jr, Litovka OP, Yuan SY. Interleukin-1␤-induced barrier dysfunction is signaled through PKC-in human brain microvascular endothelium. Am J Physiol Cell Physiol 302: C1513-C1522, 2012. First published March 7, 2011 doi:10.1152/ajpcell.00371.2011.-Blood-brain barrier dysfunction is a serious consequence of inflammatory brain diseases, cerebral infections, and trauma. The proinflammatory cytokine interleukin (IL)-1␤ is central to neuroinflammation and contributes to brain microvascular leakage and edema formation. Although it is well known that IL-1␤ exposure directly induces hyperpermeability in brain microvascular endothelium, the molecular mechanisms mediating this response are not completely understood. In the present study, we found that exposure of the human brain microvascular endothelium to IL-1␤ triggered activation of novel PKC isoforms ␦, , and , followed by decreased transendothelial electrical resistance (TER). The IL-1␤-induced decrease in TER was prevented by small hairpin RNA silencing of PKC-or by treatment with the isoform-selective PKC inhibitor Gö6976 but not by PKC inhibitors that are selective for all PKC isoforms other than PKC-. Decreased TER coincided with increased phosphorylation of regulatory myosin light chain and with increased proapoptotic signaling indicated by decreased uptake of mitotracker red in response to IL-1␤ treatment. However, neither of these observed effects were prevented by Gö6976 treatment, indicating lack of causality with respect to decreased TER. Instead, our data indicated that the mechanism of decreased TER involves PKC--dependent phosphorylation of the tight junction protein zona occludens (ZO)-1. Because IL-1␤ is a central inflammatory mediator, our interpretation is that inhibition of PKC-or inhibition of ZO-1 phosphorylation could be viable strategies for preventing blood-brain barrier dysfunction under a variety of neuroinflammatory conditions.

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Albumin causes increased myosin light chain kinase expression in astrocytes via p38 mitogen-activated protein kinase

et al. 2011

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Myosin light chain kinase (MLCK) plays an important role in the reorganization of the cytoskeleton leading to disruption of vascular barrier integrity in multiple organs including the blood brain barrier (BBB) after traumatic brain injury (TBI). MLCK has been linked to transforming growth factor (TGF) and rho kinase signaling pathways, but the mechanisms regulating MLCK expression following TBI are not well understood. Albumin leaks into the brain parenchyma following TBI, activates glia and has been linked to TGF-β receptor signaling. We investigated the role of albumin in the increase in MLCK in astrocytes and the signaling pathways involved in this increase. Following midline closed-skull TBI in mice, there was a significant increase in MLCK-immunoreactive (IR) cells and albumin extravasation, which was prevented by treatment with the MLCK inhibitor ML-7. Using immunohistochemical methods, we identified the MCLK-IR cells as astrocytes. In primary astrocytes, exposure to albumin increased both isoforms of MLCK, 130 and 210. Inhibition of the TGF-β receptor partially prevented the albumin-induced increase in both isoforms, which was not prevented by inhibition of smad3. Inhibition of p38 MAPK, but not ERK, JNK or rho kinase also prevented this increase. These results are further evidence of a role of MCLK in the mechanisms of BBB compromise following TBI, and identify astrocytes as a cell type, in addition to endothelium in the BBB which express MLCK. These findings implicate albumin, acting through p38 MAPK, in a novel mechanism by which activation of MLCK following TBI may lead to compromise of the BBB. Keywords myosin light chain kinase; blood brain barrier; astrocyte; traumatic brain injury; transforming growth factor

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Inhibition of myosin light chain kinase reduces brain edema formation after traumatic brain injury

Cited by 50 publications

References 31 publications

Inhibition of Myosin Light-Chain Kinase Attenuates Cerebral Edema after Traumatic Brain Injury in Postnatal Mice

Inhibition of Myosin Light-Chain Kinase Attenuates Cerebral Edema after Traumatic Brain Injury in Postnatal Mice

Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium

Albumin causes increased myosin light chain kinase expression in astrocytes via p38 mitogen-activated protein kinase

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