Animal Models of Stroke for Preclinical Drug Development: A Comparative Study of Flavonols for Cytoprotection

Roulston, Carli L; McCann, Sarah; Weston, Robert M.; Jarrott, Bevyn

doi:10.1007/978-1-4419-9530-8_25

Cited by 3 publications

(2 citation statements)

References 122 publications

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“…Stereotaxic application of endothelin-1 to the middle cerebral artery is now a well established method of focal ischemia in conscious rats [22] with recent adaption of the model for use in primates [23]. This is the first study to examine the effects of apocynin in an animal model where stroke is induced in the conscious rat, where treatment afforded protection to the cortex 3 days after reperfusion, but failed to reduce damage to subcortical structures.…”

Section: Discussionmentioning

confidence: 99%

Targeting Oxidative Stress Injury after Ischemic Stroke in Conscious Rats: Limited Benefits with Apocynin Highlight the Need to Incorporate Long Term Recovery

Weston

Lin

Dusting

et al. 2013

Stroke Research and Treatment

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NADPH oxidase is a major source of superoxide anion following stroke and reperfusion. This study evaluated the effects of apocynin, a known antioxidant and inhibitor of Nox2 NADPH, on neuronal injury and cell-specific responses to stroke induced in the conscious rat. Apocynin treatment (50 mg/kg i.p.) commencing 1 hour prior to stroke and 24 and 48 hours after stroke significantly reduced infarct volume in the cortex by ~ 60%, but had no effect on striatal damage or neurological deficits. In situ detection of reactive oxygen species (ROS) using dihydroethidium fluorescence revealed that increased ROS detected in OX-42 positive cells following ischemia was reduced in apocynin-treated rats by ~ 51%, but surprisingly increased in surrounding NeuN positive cells of the same rats by ~ 27%, in comparison to the contralateral hemisphere. Reduced ROS from activated microglia/macrophages treated with apocynin was associated with reduced Nox2 immunoreactivity without change to the number of cells. These findings confirm the protective effects of apocynin and indicate a novel mechanism via reduced Nox2 expression. We also reveal compensatory changes in neuronal ROS generation as a result of Nox2 inhibition and highlight the need to assess long term individual cell responses to inhibitors of oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Targeting Oxidative Stress Injury after Ischemic Stroke in Conscious Rats: Limited Benefits with Apocynin Highlight the Need to Incorporate Long Term Recovery

Weston

Lin

Dusting

et al. 2013

Stroke Research and Treatment

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“…More extensive clinical trials are currently underway which may result in the approval of edaravone for use in additional countries [ 52 ]. Optimism also remains surrounding the use of flavonols for acute stroke treatment, which we have reviewed previously [ 61 ]. Extensive experimental and epidemiological evidence suggest that intake of food rich in antioxidant flavonoids (both flavonols and flavanols) is associated with improvement of endothelial function and better outcomes in the face of cardiovascular disease [ 62 , 63 ].…”

Section: Antioxidants For Strokementioning

confidence: 99%

NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

McCann

Roulston

2013

Brain Sciences

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Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.

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A Complete Guide to Using the Endothelin-1 Model of Stroke in Conscious Rats for Acute and Long-Term Recovery Studies

Abeysinghe

Roulston

2018

Methods in Molecular Biology

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Multiple methods exist to model permanent and transient ischemia under anesthesia in animals, however most human strokes occur while conscious. The use of endothelin-1 as a vasoconstrictor applied to the perivascular surface of the middle cerebral artery is one of the only methods for inducing stroke in conscious animals. Here, we describe standard operating procedures for stereotaxic placement of an ET-1 guide probe above the middle cerebral artery, induction of stroke in conscious rats, predictive outcome scoring during stroke, and neurological behavioral tests that we use to monitor transient and continuing deficits. The inclusion of long term neurological assessment is of particular importance when taking into consideration the effects of stroke on brain remodeling.

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Animal Models of Stroke for Preclinical Drug Development: A Comparative Study of Flavonols for Cytoprotection

Cited by 3 publications

References 122 publications

Targeting Oxidative Stress Injury after Ischemic Stroke in Conscious Rats: Limited Benefits with Apocynin Highlight the Need to Incorporate Long Term Recovery

Targeting Oxidative Stress Injury after Ischemic Stroke in Conscious Rats: Limited Benefits with Apocynin Highlight the Need to Incorporate Long Term Recovery

NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives

A Complete Guide to Using the Endothelin-1 Model of Stroke in Conscious Rats for Acute and Long-Term Recovery Studies

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