Effect of Focal Cerebral Infarctions on Lesional RhoA and RhoB Expression

Brabeck, Christine; Mittelbronn, Michel; Bekure, Kubrom; Meyermann, Richard; Schluesener, Hermann J.; Schwab, Jan M.

doi:10.1001/archneur.60.9.1245

Cited by 36 publications

(31 citation statements)

References 20 publications

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“…Similar increases in RhoA protein levels previously have been reported in stroke brain sections and in various cellular components of rodent cerebrovasculature after exposure to global ischemia. 8,9 In the latter study, suppression of neuronal RhoA levels via hyperbaric oxygen confirms the ability of ischemia to regulate GTPase expression. 9 Consistent with increases in Rho kinase protein levels, cells exposed to OGD also possessed higher levels of Rho kinase activity.…”

Section: Discussionsupporting

confidence: 52%

Small GTPase RhoA and Its Effector Rho Kinase Mediate Oxygen Glucose Deprivation-Evoked In Vitro Cerebral Barrier Dysfunction

Allen

Srivastava

Bayraktutan

2010

Stroke

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Background and Purpose-Enhanced vascular permeability attributable to disruption of blood-brain barrier results in the development of cerebral edema after stroke. Using an in vitro model of the brain barrier composed of human brain microvascular endothelial cells and human astrocytes, this study explored whether small GTPase RhoA and its effector protein Rho kinase were involved in permeability changes mediated by oxygen-glucose deprivation (OGD), key pathological phenomena during ischemic stroke. Methods and Results-OGD increased RhoA and Rho kinase protein expressions in human brain microvascular endothelial cells and human astrocytes while increasing or unaffecting that of endothelial nitric oxide synthase in respective cells. Reperfusion attenuated the expression and activity of RhoA and Rho kinase in both cell types compared to their counterparts exposed to equal periods of OGD alone while selectively increasing human brain microvascular endothelial cells endothelial nitric oxide synthase protein levels. OGD compromised the barrier integrity as confirmed by decreases in transendothelial electric resistance and concomitant increases in flux of permeability markers sodium fluorescein and Evan's blue albumin across cocultures. Transfection of cells with constitutively active RhoA also increased flux and reduced transendothelial electric resistance, whereas inactivation of RhoA by anti-RhoA Ig electroporation exerted opposite effects. In vitro cerebral barrier dysfunction was accompanied by myosin light chain overphosphorylation and stress fiber formation. Reperfusion and treatments with a Rho kinase inhibitor Y-27632 significantly attenuated barrier breakdown without profoundly altering actin structure. Conclusions-Increased RhoA/Rho kinase/myosin light chain pathway activity coupled with changes in actin cytoskeleton account for OGD-induced endothelial barrier breakdown. (Stroke.

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Section: Discussionsupporting

confidence: 52%

Small GTPase RhoA and Its Effector Rho Kinase Mediate Oxygen Glucose Deprivation-Evoked In Vitro Cerebral Barrier Dysfunction

Allen

Srivastava

Bayraktutan

2010

Stroke

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“…Furthermore, the involvement of RhoB in programmed cell death (Liu et al, 2000) may occur via activation of mDia2 (Kamasani et al, 2007). Indeed, RhoB is emerging as a key player in CNS injury (Brabeck et al, 2003(Brabeck et al, , 2004 and aging (Yoon et al, 2007). Evidence that RhoB modulates Alzheimer's diseaserelated genes suggests a link between this GTPase and dementia (Kamasani and Prendergast, 2005).…”

Section: Introductionmentioning

confidence: 99%

A Role for RhoB in Synaptic Plasticity and the Regulation of Neuronal Morphology

McNair¹,

Spike²,

Guilding³

et al. 2010

J. Neurosci.

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Actin-rich dendritic spines are the locus of excitatory synaptic transmission and plastic events such as long-term potentiation (LTP).Morphological plasticity of spines accompanies activity-dependent changes in synaptic strength. Several Rho GTPase family members are implicated in regulating neuronal and, in particular, spine structure via actin and the actin-binding protein cofilin. However, despite expression in hippocampus and cortex, its ability to modulate actin-regulatory proteins, and its induction during aging, RhoB has been relatively neglected. We previously demonstrated that LTP is associated with specific RhoB activation. Here, we further examined its role in synaptic function using mice with genetic deletion of the RhoB GTPase (RhoB Ϫ/Ϫ mice). Normal basal synaptic transmission accompanied reduced paired-pulse facilitation and post-tetanic potentiation in the hippocampus of RhoB Ϫ/Ϫ mice. Early phase LTP was significantly reduced in RhoB Ϫ/Ϫ animals, whereas the later phase was unaffected. In wild-type mice (RhoB ϩ/ϩ ), Western blot analysis of potentiated hippocampus showed significant increases in phosphorylated cofilin relative to nonpotentiated slices, which were dramatically impaired in RhoB Ϫ/Ϫ slices. There was also a deficit in phosphorylated Lim kinase levels in the hippocampus from RhoB Ϫ/Ϫ mice. Morphological analysis suggested that lack of RhoB resulted in increased dendritic branching and decreased spine number. Furthermore, an increase in the proportion of stubby relative to thin spines was observed. Moreover, spines demonstrated increased length along with increased head and neck widths. These data implicate RhoB in cofilin regulation and dendritic and spine morphology, highlighting its importance in synaptic plasticity at a structural and functional level.

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“…Understanding the signaling mechanisms of ROCK inhibition mediated NOG opens up the possibility for developing novel strategies to promote axon regeneration in vivo. Clinically, the use of a ROCK inhibitor may be useful for developing therapies in CNS following damage by Alzheimer's disease [44], spinal cord injury [45], traumatic brain injury [46] and stroke [47].…”

Section: Discussionmentioning

confidence: 99%

Direct Rho-associated kinase inhibiton induces cofilin dephosphorylation and neurite outgrowth in PC-12 cells

Zhang¹,

Ottens²,

Larner³

et al. 2006

Cellular and Molecular Biology Letters

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Axons fail to regenerate in the adult central nervous system (CNS) following injury. Developing strategies to promote axonal regeneration is therapeutically attractive for various CNS pathologies such as traumatic brain injury, stroke and Alzheimer's disease. Because the RhoA pathway is involved in neurite outgrowth, Rho-associated kinases (ROCKs), downstream effectors of GTP-bound Rho, are potentially important targets for axonal repair strategies in CNS injuries. We investigated the effects and downstream mechanisms of ROCK inhibition in promoting neurite outgrowth in a PC-12 cell model. Robust neurite outgrowth (NOG) was induced by ROCK inhibitors Y-27632 and H-1152 in a time-and dose-dependent manner. Dramatic cytoskeletal Unauthenticated Download Date | 5/10/18 6:54 PM CELLULAR & MOLECULAR BIOLOGY LETTERS 13 reorganization was noticed upon ROCK inhibition. NOG initiated within 5 to 30 minutes followed by neurite extension between 6 and 10 hours. Neurite processes were then sustained for over 24 hours. Rapid cofilin dephosphorylation was observed within 5 minutes of Y-27632 and H-1152 treatment. Re-phosphorylation was observed by 6 hours after Y-27632 treatment, while H-1152 treatment produced sustained cofilin dephosphorylation for over 24 hours. The results suggest that ROCK-mediated dephosphorylation of cofilin plays a role in the initiation of NOG in PC-12 cells.

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Effect of Focal Cerebral Infarctions on Lesional RhoA and RhoB Expression

Abstract: Inhibition of Rho is a promising lead for the development of new pharmacologic interventions in FCI. Because the observed up-regulation of RhoA and RhoB was still detectable months after FCI, we speculate that even delayed treatment with Rho inhibitors might be a therapeutic option.

Cited by 36 publications

References 20 publications

Small GTPase RhoA and Its Effector Rho Kinase Mediate Oxygen Glucose Deprivation-Evoked In Vitro Cerebral Barrier Dysfunction

Small GTPase RhoA and Its Effector Rho Kinase Mediate Oxygen Glucose Deprivation-Evoked In Vitro Cerebral Barrier Dysfunction

A Role for RhoB in Synaptic Plasticity and the Regulation of Neuronal Morphology

Direct Rho-associated kinase inhibiton induces cofilin dephosphorylation and neurite outgrowth in PC-12 cells

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