The effect of age, sex and strains on the performance and outcome in animal models of stroke

Zhang, Hongxia; Lin, Siyang; Chen, Xudong; Gu, Lei; Zhu, Xiaohong; Zhang, Yinuo; Reyes, Kassandra; Wang, Brian; Jin, Kunlin

doi:10.1016/j.neuint.2018.10.005

Cited by 27 publications

(30 citation statements)

References 164 publications

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“…Stroke outcome is also altered in preclinical models of age and comorbidity. For example, neurological impairment and recovery after experimental stroke is often worse in older animals compared with their younger counterparts 27 28. Hypertension and diabetes are very common in the elderly and both have been shown to worsen outcome in experimental stroke models 27 29.…”

Section: Why Should We Consider Comorbidities?mentioning

confidence: 99%

Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?

McCann¹,

Lawrence²

2020

BMJ Open Science

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Stroke is a significant cause of mortality and morbidity for which there are limited treatment options. Virtually all drug interventions that have been successful preclinically in experimental stroke have failed to translate to an effective treatment in the clinical setting. In this review, we examine one of the factors likely contributing to this lack of translation, the failure of preclinical studies to consider fully the advanced age and comorbidities (eg, hypertension or diabetes) present in most patients with stroke. Age and comorbidities affect the likelihood of suffering a stroke, disease progression and the response to treatment. Analysing data from preclinical systematic reviews of interventions for ischaemic stroke we show that only 11.4% of studies included an aged or comorbid model, with hypertension being the most frequent. The degree of protection (% reduction in infarct volume) varied depending on the comorbidity and the type of intervention. We consider reasons for the lack of attention to comorbid and aged animals in stroke research and discuss the value of testing a potential therapy in models representing a range of comorbidities that affect patients with stroke. These models can help establish any limits to a treatment’s efficacy and inform the design of clinical trials in appropriate patient populations.

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Section: Why Should We Consider Comorbidities?mentioning

confidence: 99%

Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?

McCann¹,

Lawrence²

2020

BMJ Open Science

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“…Recent communication with the parents of these patients, who are now an average of 21 years old, revealed no notable symptom exacerbation. It is therefore possible that the SWIP P1019R mouse model either exhibits differences from human patients or may predict future disease progression for these individuals, given that we observed significant worsening at 5-6 months old in mice (which is thought to be equivalent to ∼30-35 years old in humans) (Dutta and Sengupta, 2016; Zhang et al, 2019).…”

Section: Resultsmentioning

confidence: 98%

Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

Courtland

Bradshaw

Waitt

et al. 2020

Preprint

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Mutation of the WASH complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. Remarkably, a retrospective analysis of SWIPP1019R patients confirms motor deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

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“…After excluding seven studies, 11 were included in the current systematic review (Figure 1; Table 1). 12–22 Eight studies used rats and three employed mice. Four studies induced stroke by occluding the middle cerebral artery for two hours, 12,14,17,21 seven induced permanent cerebral ischaemia by inserting a filament into the middle cerebral artery, 15,16,18,19 or intravenous thrombus injection.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have examined the effect of upregulating or administering angpt-1 on the outcome of ischaemic stroke in rodent models, but findings have been inconsistent. 12–22 The current study systematically reviewed the efficacy of upregulating or administering angpt-1 in improving recovery from experimentally induced ischaemic stroke in rodent models.…”

Section: Introductionmentioning

confidence: 99%

The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: A meta-analysis

Moxon

Trollope

Dewdney

et al. 2019

J Cereb Blood Flow Metab

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Clinical studies report that low circulating angiopoietin-1 concentration at presentation predicts worse outcomes after ischaemic stroke. Upregulating angiopoietin-1 may therefore have therapeutic benefit for ischaemic stroke. This systematic review assessed whether upregulating angiopoietin-1 improved outcomes in rodent models of ischaemic stroke. Random-effects models quantified the effect of angiopoietin-1 upregulation on stroke severity in terms of the size of cerebral infarction and the extent of blood–brain barrier permeability. Eleven studies utilising rat and mouse models of ischaemic stroke fulfilled the inclusion criteria. Meta-analyses demonstrated that angiopoietin-1 upregulation significantly reduced cerebral infarction size (standardised mean difference: –3.02; 95% confidence intervals: –4.41, –1.63; p < 0.001; n = 171 animals) and improved blood–brain barrier integrity (standardized mean difference: –2.02; 95% confidence intervals: –3.27, –0.77; p = 0.002; n = 129 animals). Subgroup analyses demonstrated that angiopoietin-1 upregulation improved outcomes in models of transient, not permanent cerebral ischaemia. Six studies assessed the effect of angiopoietin-1 upregulation on neurological function; however, inter-study heterogeneity prevented meta-analysis. In conclusion, published rodent data suggest that angiopoietin-1 upregulation improves outcome following temporary cerebral ischaemia by reducing cerebral infarction size and improving blood–brain barrier integrity. Additional research is required to examine the effect of angiopoietin-1 upregulation on neurological function during stroke recovery and investigate the benefit and risks in patients.

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The effect of age, sex and strains on the performance and outcome in animal models of stroke

Cited by 27 publications

References 164 publications

Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?

Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?

Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: A meta-analysis

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