Effect of recirculation on exacerbation of ischemic vascular lesions in rat brain.

Nishigaya, Kazuyuki; Yoshida, Yasuhiko; Sasuga, Motoi; Nukui, Hideaki; Ooneda, Genju

doi:10.1161/01.str.22.5.635

Cited by 68 publications

(31 citation statements)

References 20 publications

(8 reference statements)

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“…21 Unregulated blood flow and decreased cerebrovascular resistance may lead to edema formation and blood-brain barrier disruption. 18,20 Therefore, ONOO Ϫ -induced loss of myogenic activity may significantly contribute to brain injury after I/R.…”

Section: Discussionmentioning

confidence: 99%

Peroxynitrite Diminishes Myogenic Activity and Is Associated With Decreased Vascular Smooth Muscle F-Actin in Rat Posterior Cerebral Arteries

Maneen

Hannah

Vitullo

et al. 2006

Stroke

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Background and Purpose-This study investigated the effect of peroxynitrite (ONOO Ϫ ) on pressure-induced myogenic activity and vascular smooth muscle (VSM) actin of isolated posterior cerebral arteries (PCAs). Methods-Histochemical staining of nitrotyrosine (NT) was used to demonstrate the presence of ONOO Ϫ in the cerebrovasculature after 1 hour of middle cerebral artery occlusion with 30 minutes of reperfusion. To determine the effect of ONOO Ϫ on pressure-induced myogenic activity, third-order PCAs from nonischemic animals were isolated and mounted in an arteriograph chamber. Diameter in response to changes in pressure was determined in the absence and presence of ONOO Ϫ (10 Ϫ8 to 10 Ϫ4 mol/L). Filamentous actin (F-actin) and globular actin (G-actin) were quantified using confocal microscopy in PCAs with and without exposure to ONOO Ϫ . Results-NT staining of vascular cells was greater in ischemic brain versus sham animals (56Ϯ3% versus 35Ϯ3%;PϽ0.01). Addition of low concentrations of ONOO Ϫ (Յ10 Ϫ6 mol/L) to isolated PCAs caused constriction from 129Ϯ16 m to 115Ϯ15 m (PϽ0.01), whereas concentrations Ͼ10 Ϫ6 mol/L caused dilation of spontaneous tone and loss of myogenic activity in the physiological range of 50 to 125 mm Hg, increasing diameter from 130Ϯ6 to 201Ϯ5 m at 75 mm Hg (PϽ0.01). In addition, the diminished myogenic activity was associated with a 4.5-fold decrease in F-actin content of VSM and a 27% increase in G-actin content (PϽ0.01). Conclusions-This study demonstrates that ONOOϪ affects the myogenic activity of cerebral arteries and causes F-actin depolymerization in VSM, a consequence that could promote vascular damage during reperfusion injury and further brain injury.

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Section: Discussionmentioning

confidence: 99%

Peroxynitrite Diminishes Myogenic Activity and Is Associated With Decreased Vascular Smooth Muscle F-Actin in Rat Posterior Cerebral Arteries

Maneen

Hannah

Vitullo

et al. 2006

Stroke

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“…However, under excessive electrical activation and depolarization, associated with increased in- jpet.aspetjournals.org tracellular calcium accumulation, GRK3 levels and ␣ 2 -AR desensitization would be reduced, permitting maximum neuroprotection. Oxidative stress is a common trait of hypertension and plays an important role in hypertension-evoked brain injury by increasing the tissue concentrations of neurotransmitters and increasing cellular calcium ions influx (Nishigaya et al, 1991;Brown et al, 2004;Poulet et al, 2006). Therefore, calpain activation could cause increased degradation of GRK3 and render the ␣ 2 -AR resistant to desensitization by norepinephrine and EPI.…”

Section: Discussionmentioning

confidence: 99%

Role of 90-kDa Heat Shock Protein (Hsp 90) and Protein Degradation in Regulating Neuronal Levels of G Protein-Coupled Receptor Kinase 3

Salim

Eikenburg²

2006

J Pharmacol Exp Ther

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Cellular levels of G protein-coupled receptor kinase (GRK)3 determine the sensitivity of the ␣ 2A/B -adrenoceptor (␣ 2 -AR) to agonist-induced down-regulation. Using human neuroblastoma BE(2)-C cells, this study examines how cellular GRK3 levels are affected by several mechanisms reported to influence stability and degradation of other GRKs. We first examined the interaction between the 90-kDa heat shock protein (Hsp90) and GRK3; Hsp90 reportedly affects the maturation and stability of GRK2. In unstimulated cells, GRK3 coimmunoprecipitates with Hsp90, suggesting a physical interaction. Moreover, when GRK3 protein expression was increased by 24-h epinephrine (EPI) treatment, Hsp90 protein expression increased with a similar but slightly delayed time course. To investigate the influence of Hsp90 on GRK3 protein stability, we determined the effect of the Hsp90 inhibitor geldanamycin (GA) on cellular GRK3 levels. GA eliminated the interaction between Hsp90 with GRK3 and produced a rapid, proteasome-mediated, 70% decrease in GRK3 levels within 24 h. To investigate the influence of Hsp90 on up-regulation of GRK3 expression, we examined the effect of GA on EPI-induced up-regulation. GA reduced the absolute increase in GRK3; however, the percentage of increase in GRK3 by EPI was not significantly different in the absence versus presence of GA (141 Ϯ 41 versus 94 Ϯ 12%). Finally, we examined the influence of Ca 2ϩ -activated proteases on cellular GRK3. Treatment with the calcium ionophore ionomycin produced a rapid decrease in GRK3 levels that was inhibited by the calpain inhibitor calpeptin. In conclusion, several mechanisms influence the degradation of GRK3 and therefore have the potential to affect GPCR signaling by regulating GRK3 levels in neurons.

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“…This hypoperfusion following transient ischemia is thought to stem from multiple mechanisms, including microvascular damage and cerebrovascular occlusion from cellular elements (Aspey et al, 1989;Dietrich et al, 1987;Mori et al, 1992;Nishigaya et al, 1991). In addition to these observed changes, hemoconcentration, red blood cell sludging, hyperviscosity, and platelet plugging tend to occur as well in the reperfusion phase, further exacerbating the damage seen in ischemia/reperfusion injury (Choudhri et al, 1998).…”

Section: Inflammatory Responsementioning

confidence: 99%

Mechanisms of Neuroprotection Underlying Physical Exercise in Ischemia - Reperfusion Injury

Dornbos¹,

Ding²

2012

Brain Injury - Pathogenesis, Monitoring, Recovery and Management

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Mechanisms of Neuroprotection Underlying Physical Exercise in Ischemia -Reperfusion Injury 301 neuroprotection after exercise has stopped.Another study revealed that the neuroprotective effects of exercise preconditioning appear to be long-lasting, showing that 3 weeks after cessation of exercise, rats still maintained lower levels of neurologic deficit and decreased stroke volume when compared to non-exercise rats (Ding et al., 2004b). Future human studies ought to determine the exact duration needed for maximal endogenous neuroprotection. Preconditioning modalitiesWhile various modalities, such as treadmill running, voluntary running, simple and complex exercise, have been shown to provide variable amounts of neuroprotection. When comparing forced exercise on a treadmill to voluntary running on a running wheel, rats forced to exercise on a treadmill tend to have better neurologic outcomes after stroke (Hayes et al., 2008). Previous studies have shown that forced exercise on a treadmill is slower but more constant than voluntary exercise occurs in shorter spurts with faster speed, although the total distance is equal in the two groups (Noble et al., 1999). This neuroprotection in forced exercise subjects led to decreased stroke volume, lessened neurologic deficit, upregulation of heat shock proteins, increased neurogenesis and cerebral metabolism (Hayes et al., 2008;Kinni et al., 2011;Leasure and Jones, 2008). These findings show that moderate exercise over a longer time period conveys more efficient and greater neuroprotection than more vigorous exercise over shorter time periods. In addition to the studies assessing forced and voluntary exercise, differences have also been established when comparing simple and complex exercise. This study analyzed simple exercise as the repetitive movements of treadmill running, whereas complex exercise constituted enriched activities which required both balance and coordination (Ding et al., 2003). Following ischemia/reperfusion injury, rats preconditioned with complex exercise demonstrated increased synaptogenesis and improved neurologic outcomes when compared to simple treadmill exercise (Ding et al., 2003;Jones et al., 1999). Simple exercise training also alleviates much of the injury following ischemia/reperfusion, but its benefit is less pronounced than what is observed with complex exercise training. Although no human studies have definitively shown the most effective means of exercise for enhanced neuroprotection, these animal studies provide a solid framework for the development of appropriate exercise regimens. Moderate exercise intensity, including components of balance, coordination and stress, taking place over a sustained duration seem to be the most neuroprotective when compared to other exercise modalities and intensities.

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Effect of recirculation on exacerbation of ischemic vascular lesions in rat brain.

Cited by 68 publications

References 20 publications

Peroxynitrite Diminishes Myogenic Activity and Is Associated With Decreased Vascular Smooth Muscle F-Actin in Rat Posterior Cerebral Arteries

Peroxynitrite Diminishes Myogenic Activity and Is Associated With Decreased Vascular Smooth Muscle F-Actin in Rat Posterior Cerebral Arteries

Role of 90-kDa Heat Shock Protein (Hsp 90) and Protein Degradation in Regulating Neuronal Levels of G Protein-Coupled Receptor Kinase 3

Mechanisms of Neuroprotection Underlying Physical Exercise in Ischemia - Reperfusion Injury

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