Using behaviour to predict stroke severity in conscious rats: Post-stroke treatment with 3′, 4′-dihydroxyflavonol improves recovery

Roulston, Carli L; Callaway, Jennifer K.; Jarrott, Bevyn; Woodman, Owen L.; Dusting, Gregory J.

doi:10.1016/j.ejphar.2008.01.046

Cited by 26 publications

(47 citation statements)

References 42 publications

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“…Moreover, the severity of stroke can be controlled using a predetermined scale of behavioral indicators, which correlates with the degree of neuronal damage in this model. 25 The current results demonstrated a dose-related neuroprotective effect of CGP42112 that was more striking in the cortex than in the striatum. Consistent with our findings, it was previously reported, using this model, that there was less neuroprotection in the striatal region when compared with the cortical region, because the striatal region is generally considered to be the core of the infarct and refractory to therapeutic intervention.…”

Section: Discussionmentioning

confidence: 64%

“…23,24 ET-1 was infused through a 30-gauge injector protruding 3 mm beyond the end of the previously implanted guide cannula. Stroke was characterized by behavioral indicators 24,25 modified to be specific for the SHR strain. Typical behaviors that were observed were continuous contralateral or ipsilateral circling behavior; clenching, dragging, or failure to extend the forelimb contralateral to the side of ET-1 infusion; and forepaw shuffling, jaw flexing, or chin rubbing while circling.…”

Section: Stroke Inductionmentioning

confidence: 99%

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Angiotensin AT ₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

McCarthy

Vinh

Callaway

et al. 2009

Stroke

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Background and Purpose-The angiotensin II type 2 receptor (AT 2 R) is implicated to be neuroprotective in stroke, although this premise has not been directly tested. Therefore, we have examined the neuroprotective effect of AT 2 R stimulation after intracerebroventricular administration of AT 2 R agonist CGP42112 in a conscious rat model of stroke. Methods-Spontaneously hypertensive rats were treated with either CGP42112 (0.1 to 10 ng/kg/min intracerebroventricularly) alone or in combination with the AT 2 R antagonist PD123319 (36 ng/kg/min intracerebroventricularly) beginning 5 days before stroke induction. A focal reperfusion model of stroke was induced in conscious spontaneously hypertensive rats by administering endothelin-1 to the middle cerebral artery through a surgically implanted cannula. Behavioral tests were used to assess the severity of neurological deficit as a result of the ischemic event. Cortical and striatal infarct volumes were measured 72 hours poststroke. Results-Blood pressure was unaffected by treatments. CGP42112 dose-dependently reduced cortical infarct volume poststroke, and PD123319 abolished the neuroprotective effect of CGP42112. PD123319 had no effect on infarct volume alone. These results were consistent with the behavioral findings, indicating that CGP42112 reduced motor deficit on the ledged beam test at 72 hours poststroke and immunohistochemical analyses showing that CGP42112 increased neuronal survival and minimized the loss of AT 2 R expression in the infarcted region. Conclusion-Based on infarct, behavioral, and immunohistochemical data, these results indicate that centrally administered CGP42112 exhibits a neuroprotective effect, which was independent of blood pressure. Thus, for the first time, we have shown that central AT 2 R stimulation is neuroprotective in a conscious rat model of stroke.

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Section: Discussionmentioning

confidence: 64%

Section: Stroke Inductionmentioning

confidence: 99%

Angiotensin AT ₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

McCarthy

Vinh

Callaway

et al. 2009

Stroke

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102

100

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“…Infarct volume was calculated using the following formula: infarct volume = [left hemisphere volume − (right hemisphere volume − measured infarct volume)]/left hemisphere volume. Infarct volume in each rat was corrected to compensate for brain swelling in the ischemic hemisphere 22 by computing left and right hemisphere volume and applying the following formula: corrected infarct volume = left hemisphere volume − (right hemisphere volume − measured infarct volume). The infarction volume was expressed in cubic millimeters and as a percentage.…”

Section: Determining Infarct Volumementioning

confidence: 99%

CDK5 Knockdown Prevents Hippocampal Degeneration and Cognitive Dysfunction Produced by Cerebral Ischemia

Gutiérrez-Vargas

Múnera

Cardona‐Gómez

2015

J Cereb Blood Flow Metab

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Acute ischemic stroke is a cerebrovascular accident and it is the most common cause of physical disabilities around the globe. Patients may present with repeated ictuses, experiencing mental consequences, such as depression and cognitive disorders. Cyclindependent kinase 5 (CDK5) is a kinase that is involved in neurotransmission and plasticity, but its dysregulation contributes to cognitive disorders and dementia. Gene therapy targeting CDK5 was administered to the right hippocampus of ischemic rats during transient cerebral middle artery occlusion. Physiologic parameters (blood pressure, pH, pO 2 , and pCO 2 ) were measured. The CDK5 downregulation resulted in neurologic and motor improvement during the first week after ischemia. Cyclin-dependent kinase 5 RNA interference (RNAi) prevented dysfunctions in learning, memory, and reversal learning at 1 month after ischemia. These observations were supported by the prevention of neuronal loss, the reduction of microtubule-associated protein 2 (MAP2) immunoreactivity, and a decrease in astroglial and microglia hyperreactivities and tauopathy. Additionally, CDK5 silencing led to an increase in the expression of brain-derived neurotrophic factor (BDNF), its Tropomyosin Receptor kinase B (TRKB) receptor, and activation of cyclic AMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), which are important targets in neuronal plasticity. Together, our findings suggest that gene therapy based on CDK5 silencing prevents cerebral ischemia-induced neurodegeneration and motor and cognitive deficits.

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“…16 Stroke was characterized by behavioral indicators modified to be specific for the SHR strain. 13,17 Typical behaviors that were observed were continuous contralateral and ipsilateral circling behavior; clenching, dragging, or failure to extend the forelimb contralateral to the side of ET-1 infusion; chewing and jaw flexing; and shuffling with forepaws. Each stroke was graded based on these predetermined behavioral changes using a scale of 1 to 4, with 1 being a mild stroke and 4 being a severe stroke.…”

Section: Stroke Inductionmentioning

confidence: 99%

Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

McCarthy

Vinh²,

Broughton³

et al. 2012

Hypertension

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A ngiotensin II (Ang II) can bind to several receptor subtypes, thus, influencing an array of cardiovascular functions in the body. However, the 2 major receptor subtypes are the angiotensin II type 1 receptor (AT 1 R), which is thought to be responsible for most of the biological and pathological actions of Ang II, and the angiotensin II type 2 receptor (AT 2 R), which mainly opposes the actions of the AT 1 R.1 Several largescale clinical trials 2,3 have indicated that the use of AT 1 R antagonists as a method of blood pressure control in high-risk patients improves cardiac and vascular events, which results in a reduced risk of secondary events such as stroke. This is consistent with experimental studies reporting that central or peripheral pretreatment with an AT 1 R antagonist reduces postischemic inflammation and the size of the cerebral infarction together with improved behavioral symptoms. [4][5][6][7][8] Importantly, neuroprotection has been demonstrated to occur even with nonhypotensive doses of AT 1 R blockers. 9 The postulated nonvascular mechanisms of neuroprotection include inhibition of neuronal apoptosis 5 and reduced neuronal loss associated with inhibition of superoxide production and inflammation, 10 although there is likely to be a contribution from the AT 2 R during AT 1 R blockade.6,7 Indeed, several groups have reversed neuroprotection induced during AT 1 R blockade with the coadministration of an AT 2 R antagonist, suggesting that the AT 2 R is a pivotal component in the therapeutic action of AT 1 R antagonists. 6,7 In addition, mice lacking the AT 2 R show poorer outcome after stroke and are less receptive to the protective influence of AT 1 R antagonists.11,12 Thus, there is accumulating indirect evidence that suggests that the AT 2 R may have a cerebroprotective role during stroke, although little is known about direct AT 2 R stimulation in the brain.In this context, we have recently examined the neuroprotective effect of direct AT 2 R stimulation after intracerebroventricular (ICV) administration of the AT 2 R agonist CGP42112 in a conscious rat model of stroke. Our results indicate that, even in the absence of AT 1 R blockade, direct stimulation of the central AT 2 R for 5 days before and for 3 days after stroke dramatically reduces subsequent damage, both histologically and behaviorally, such that at 72 hours after stroke injury is minimal. 13 Given that patients normally present for treatment after a cerebrovascular event, a clinically relevant treatment needs to be effective when administered after a stroke has occurred. To this end, the current proof-of-principle study investigated the potential neuroprotective role of See Editorial Commentary, pp 1391-1392Abstract-We have demonstrated previously that pretreatment with an angiotensin II type 2 receptor (AT 2 R) agonist is neuroprotective against a subsequent stroke independent of any changes in blood pressure. Therefore, in the current study, we have examined the potential neuroprotective effect of AT 2 R stimulation initiated aft...

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Using behaviour to predict stroke severity in conscious rats: Post-stroke treatment with 3′, 4′-dihydroxyflavonol improves recovery

Cited by 26 publications

References 42 publications

Angiotensin AT ₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

Angiotensin AT ₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

CDK5 Knockdown Prevents Hippocampal Degeneration and Cognitive Dysfunction Produced by Cerebral Ischemia

Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

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Using behaviour to predict stroke severity in conscious rats: Post-stroke treatment with 3′, 4′-dihydroxyflavonol improves recovery

Cited by 26 publications

References 42 publications

Angiotensin AT 2 Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

Angiotensin AT 2 Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

CDK5 Knockdown Prevents Hippocampal Degeneration and Cognitive Dysfunction Produced by Cerebral Ischemia

Angiotensin II Type 2 Receptor Stimulation Initiated After Stroke Causes Neuroprotection in Conscious Rats

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Angiotensin AT ₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke

Angiotensin AT ₂ Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke