Positive impact of pre-stroke surgery on survival following transient focal ischemia in hypertensive rats

Ord, Emily N.J.; Shirley, Rachel; Kralingen, Josie C van; Graves, Alice; McClure, John; Wilkinson, Michael; McCabe, Chris; Macrae, I. Mhairi; Work, Lorraine M.

doi:10.1016/j.jneumeth.2012.09.001

Cited by 9 publications

(11 citation statements)

References 18 publications

(19 reference statements)

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“…Body temperature was maintained at 37 ± 0.5°C. Animals underwent pre-stroke burrhole surgery 35 before transient middle cerebral artery occlusion (tMCAO, 45 min). Briefly, a silicone-coated monofilament (Doccol Corporation, USA) was advanced through the common carotid artery to block the origin of the MCA 36 .…”

Section: Methodsmentioning

confidence: 99%

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

Chouchani

Pell

Gaude

et al. 2014

Nature

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2,210

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Ischaemia-reperfusion (IR) injury occurs when blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death, and aberrant immune responses through generation of mitochondrial reactive oxygen species (ROS)1-5. Although mitochondrial ROS production in IR is established, it has generally been considered a non-specific response to reperfusion1,3. Here, we developed a comparative in vivo metabolomic analysis and unexpectedly identified widely conserved metabolic pathways responsible for mitochondrial ROS production during IR. We showed that selective accumulation of the citric acid cycle (CAC) intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase (SDH), which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. Upon reperfusion, the accumulated succinate is rapidly re-oxidised by SDH, driving extensive ROS generation by reverse electron transport (RET) at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo IR injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of IR injury. Furthermore, these findings reveal a novel pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation upon subsequent reperfusion is a potential therapeutic target to decrease IR injury in a range of pathologies.

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Section: Methodsmentioning

confidence: 99%

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

Chouchani

Pell

Gaude

et al. 2014

Nature

Self Cite

2,210

2,226

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“…A refinement for intraluminal filament-induced transient MCA occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) has been reported, which reduces mortality and post-stroke associated weight loss. 156 SHRSP rats exhibit many of the co-morbidities associated with stroke clinically including hypertension, altered glucose handling and elevated inflammatory signalling. The refinement involves an additional general anaesthetic, a cranial burr hole and durotomy six days prior to transient MCA occlusion and was identified by chance in an earlier study which required a general anaesthetic and stereotaxic injection of a substance one week prior to stroke.…”

Section: Refinement For Specific Modelsmentioning

confidence: 99%

The IMPROVE Guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments)

Sert

Alfieri

Allan

et al. 2017

J Cereb Blood Flow Metab

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134

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Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information).

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“…Interestingly, this prestroke surgery reduces subsequent stroke-related mortality. 24 Briefly, the head was secured in a stereotactic frame, a 1 mm cranial burrhole made, and a 24G needle connected to a Hamilton syringe used to pierce the dura and administer virus into the cortex. After a 2-minute rest period, 2.1 mL virus suspension was injected for 5 minutes, with a subsequent 2-minute rest period before slow needle retraction.…”

Section: Virus and Drug Administrationmentioning

confidence: 99%

Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

Ord

Shirley

McClure

et al. 2013

J Cereb Blood Flow Metab

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We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/ reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO þ control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO þ Ngb-expressing CAV-2, CAVNgb; tMCAO þ SP600125; tMCAO þ CAVNgb þ SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression þ SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb þ SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb þ SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.

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Positive impact of pre-stroke surgery on survival following transient focal ischemia in hypertensive rats

Cited by 9 publications

References 18 publications

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS

The IMPROVE Guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments)

Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats

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