Neuroprotection mediated by changes in the endothelial actin cytoskeleton

Laufs, Ulrich; Endres, Matthias; Stagliano, Nancy E.; Amin‐Hanjani, Sepideh; Chui, Dao-Shan; Yang, Shui-Xiang; Simoncini, Tommaso; Yamada, Masaru; Rabkin, Elena; Allen, Philip G.; Huang, Paul L.; Böhm, Michael; Schoen, Frederick J.; Moskowitz, Michael A.; Liao, James K.

doi:10.1172/jci9639

Cited by 264 publications

(181 citation statements)

References 46 publications

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“…In addition to the leukocyte-based mechanism outlined above, Slit might exert its anti-chemotactic effect by negative regulation of Rho GTPase signaling in endothelial cells, which also express Slit receptors (Park et al, 2003;Wang et al, 2003). The inhibition of Rho-mediated cascades by Slit engagement of these receptors could lead to increased expression and activity of endothelial nitric oxide synthase (Laufs et al, 2000), a potent antiinflammatory mediator (Altay et al, 2004;Kubes et al, 1991), and decreased ICAM-1-mediated signaling (Adamson et al, 1999) within the endothelial cell.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, there is substantial evidence that Rho GTPases are involved in synaptic remodeling and maintenance (Govek et al, 2005), and relative changes in their active/inactive state are associated with dendritic plasticity (Nakayama et al, 2000;Pilpel et al, 2004). Moreover, inhibition of Rho GTPases or their effectors protects against ischemia/reperfusion injury in vivo in both brain (Laufs et al, 2000;Trapp et al, 2001) and other tissues (Bao et al, 2004). Based on these findings, we offer the speculation that modulation of Rho GTPase signaling cascades by Slit has the net effect of maintaining cellular integrity and functioning in ischemic brain secondary to its ability to prevent or reduce synaptic disruption and other changes in dendritic morphology crucial to neuronal viability (Hasbani et al, 2001;Park et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

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Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFα application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygenglucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFα and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFα. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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“…There is ample evidence that the neuroprotective effect of statins/statin-induced upregulation of eNOS activity is at least in part mediated by inhibition of rho kinase (Laufs and Liao, 1998;Laufs et al, 1999Laufs et al, , 2000a. Rho kinase (ROCK) is a serine-threonine kinase whose activity is modulated by isoprenoid intermediate geranygeranylpyrophosphate (GGPP).…”

Section: Rho Kinase (Rock)-inhibitorsmentioning

confidence: 99%

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Terpolilli¹,

Moskowitz

Plesnila³

2012

J Cereb Blood Flow Metab

128

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Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

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“…Endothelial nitric oxide synthase activity was determined by measuring nitrite accumulation or the conversion of [ 3 H]L-arginine into [ 3 H]L-citrulline in the presence or absence of the competitive NOS inhibitor N(G)-nitro-Larginine methylester (L-NAME) (1 mmol/L), as described (Laufs et al, 2000). Cells were homogenized in ice-cold PBS containing 1 mmol/L EDTA.…”

Section: Measurement Of Endothelial Nitric Oxide Synthase Activitymentioning

confidence: 99%

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

Kim

Sawada

Soydan

et al. 2008

J Cereb Blood Flow Metab

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Recent studies suggest that dipyridamole (DP) may exert stroke protective effects beyond platelet inhibition. The purpose of this study is to determine whether statin and DP could enhance stroke protection through nitric oxide (NO)-dependent vascular effects. Mice were pretreated with DP (10 to 60 mg/kg, q 12 h, 3 days) alone or in combination with a statin (simvastatin; 0.1 to 20 mg/kg per day, 14 days) before transient intraluminal middle cerebral artery occlusion. Although simvastatin (1 mg/kg per day, 14 days) increased endothelial NO synthase (eNOS) activity by 25% and DP (30 mg/kg, q12 h, 3 days) increased aortic cGMP levels by 55%, neither statin nor DP alone, at these subtherapeutic doses, increased absolute cerebral blood flow (CBF) or conferred stroke protection. However, the combination of subtherapeutic doses of simvastatin and DP increased CBF by 50%, decreased stroke volume by 54%, and improved neurologic motor deficits, all of which were absent in eNOS-deficient mice. In contrast, treatment with aspirin (10 mg/kg per day, 3 days) did not augment the neuroprotective effects of DP and/or simvastatin. These findings indicate that statin and DP exert additive NO-dependent vascular effects and suggest that the combination of statin and DP has greater benefits in stroke protection than statin alone through vascular protection.

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Neuroprotection mediated by changes in the endothelial actin cytoskeleton

Cited by 264 publications

References 46 publications

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Additive Effects of Statin and Dipyridamole on Cerebral Blood Flow and Stroke Protection

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