An alternative surgical approach reduces variability following filament induction of experimental stroke in mice

Trotman‐Lucas, Melissa; Kelly, Michael; Janus, Justyna; Fern, Robert; Gibson, Claire L.

doi:10.1242/dmm.029108

Cited by 20 publications

(33 citation statements)

References 35 publications

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“…Here, the degree of weight loss over 49 days did not directly correlate with initial damage at 48 h, suggesting that post-stroke weight loss may be caused by factors secondary to the initial injury, and develop during recovery. Experimental models of stroke involving permanent external carotid ligation have been proposed to cause feeding difficulties that result in weight loss [59,60]. Although food intake is likely to be reduced in the initial few days after stroke, we observed that when weight loss was maximal (day 14), food intake was not different (in obese) or increased (in controls) compared to pre-surgery, which is in agreement with others showing no reduction in food intake 7 days after stroke in mice [54].…”

Section: Discussionmentioning

confidence: 99%

Stroke Induces Prolonged Changes in Lipid Metabolism, the Liver and Body Composition in Mice

Haley

White

Roberts

et al. 2019

Transl. Stroke Res.

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During recovery, stroke patients are at risk of developing long-term complications that impact quality of life, including changes in body weight and composition, depression and anxiety, as well as an increased risk of subsequent vascular events. The aetiologies and time-course of these post-stroke complications have not been extensively studied and are poorly understood. Therefore, we assessed long-term changes in body composition, metabolic markers and behaviour after middle cerebral artery occlusion in mice. These outcomes were also studied in the context of obesity, a common stroke co-morbidity proposed to protect against post-stroke weight loss in patients. We found that stroke induced long-term changes in body composition, characterised by a sustained loss of fat mass with a recovery of lean weight loss. These global changes in response to stroke were accompanied by an altered lipid profile (increased plasma free fatty acids and triglycerides) and increased adipokine release at 60 days. After stroke, the liver also showed histological changes indicative of liver damage and a decrease in plasma alanine aminotransferase (ALT) was observed. Stroke induced depression and anxiety-like behaviours in mice, illustrated by deficits in exploration, nest building and burrowing behaviours. When initial infarct volumes were matched between mice with and without comorbid obesity, these outcomes were not drastically altered. Overall, we found that stroke induced long-term changes in depressive/anxiety-like behaviours, and changes in plasma lipids, adipokines and the liver that may impact negatively on future vascular health.

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Section: Discussionmentioning

confidence: 99%

Stroke Induces Prolonged Changes in Lipid Metabolism, the Liver and Body Composition in Mice

Haley

White

Roberts

et al. 2019

Transl. Stroke Res.

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“…In order to allow animals to progress through the functional tests we used non-invasive MRI scanning for quantification of lesion volume. MRI has been shown, in animal stroke models, to detect the evolving ischemic damage and allows a multi-parametric analysis of tissue status [13, 32]. T2 weighted images allow tissue damage to be characterized which reflects final infarct volume, correlates with clinical deficit and identifies tissue damage early following stroke.…”

Section: Discussionmentioning

confidence: 99%

“…As described previously in detail [13] MRI scanning was performed on a 9.4T Agilent scanner (Agilent Technologies, Santa Clare, CA, USA) with a 310 mm bore diameter and 12 cm inner-diameter gradient (600 mT/m maximum gradient strength), interfaced with a DirectDrive Console. Diffusion tensor imaging (DTI) and T2-weighted (T2w) images were acquired at 48h post-MCAO.…”

Section: Methodsmentioning

confidence: 99%

Pre-stroke surgery is not beneficial to normotensive rats undergoing sixty minutes of transient focal cerebral ischemia

et al. 2018

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Experimental stroke in rodents, via middle cerebral artery occlusion (MCAO), can be associated with a negative impact on wellbeing and mortality. In hypertensive rodents, pre-stroke craniotomy increased survival and decreased body weight loss post-MCAO. Here we determined the effect, in normotensive Sprague-Dawley rats following 60 minutes MCAO, with or without pre-surgical craniotomy, on post-stroke outcomes in terms of weight loss, neurological deficit, lesion volume and functional outcomes. There was no effect of pre-stroke craniotomy on indicators of wellbeing including survival rate (P = 0.32), body weight loss (P = 0.42) and neurological deficit (P = 0.75). We also assessed common outcome measures following experimental stroke and found no effect of pre-stroke craniotomy on lesion volume as measured by T2-weighted MRI (P = 0.846), or functional performance up to 28 days post-MCAO (staircase test, P = 0.32; adhesive sticker test, P = 0.49; cylinder test, P = 0.38). Thus, pre-stroke craniotomy did not improve animal welfare in terms of body weight loss and neurological deficit. However, it is important, given that a number of drug delivery studies utilise the craniotomy procedure, to note that there was no effect on lesion volume or functional outcome following experimental stroke.

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“…109 The group utilised Longa's 42 transient iMCAO method in rats, with both filament insertion and MSC injection via a transected ECA, with the CCA temporarily tied for the duration of iMCAO. 109 CCA repair, reported previously to be successful in rats, 110,111 alongside our recent method development in mice, 101,105 would negate the requirement to transect the ECA, therefore, removing the negative welfare outcomes reported following ECA transection. 102,103,110 Although many IA stem cell delivery experimental models utilise rats, there are examples of these studies conducted in mice.…”

Section: Scientific Applications Of Refinementsmentioning

confidence: 91%

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

Trotman‐Lucas

Gibson

2021

F1000Res

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Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers.

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An alternative surgical approach reduces variability following filament induction of experimental stroke in mice

Cited by 20 publications

References 35 publications

Stroke Induces Prolonged Changes in Lipid Metabolism, the Liver and Body Composition in Mice

Stroke Induces Prolonged Changes in Lipid Metabolism, the Liver and Body Composition in Mice

Pre-stroke surgery is not beneficial to normotensive rats undergoing sixty minutes of transient focal cerebral ischemia

A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

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