Large animal ischemic stroke models: replicating human stroke pathophysiology

Kaiser, Erin E.; West, Franklin D.

doi:10.4103/1673-5374.274324

Cited by 56 publications

(28 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The STAIR recommendations suggested the use of large animal models over a decade ago, however large animal model use has remained limited with only a few stroke studies in dogs, sheep, and pigs ( 33 , 53 ). Some of the most significant limiting factors in using the pig stroke model are cost and accessibility as compared to widely popular rodent models.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Magnetic Resonance Imaging and Gait Analysis Indicate Similar Outcomes Between Yucatan and Landrace Porcine Ischemic Stroke Models

et al. 2021

View full text Add to dashboard Cite

The Stroke Therapy Academic Industry Roundtable (STAIR) has recommended that novel therapeutics be tested in a large animal model with similar anatomy and physiology to humans. The pig is an attractive model due to similarities in brain size, organization, and composition relative to humans. However, multiple pig breeds have been used to study ischemic stroke with potentially differing cerebral anatomy, architecture and, consequently, ischemic stroke pathologies. The objective of this study was to characterize brain anatomy and assess spatiotemporal gait parameters in Yucatan (YC) and Landrace (LR) pigs pre- and post-stroke using magnetic resonance imaging (MRI) and gait analysis, respectively. Ischemic stroke was induced via permanent middle cerebral artery occlusion (MCAO). MRI was performed pre-stroke and 1-day post-stroke. Structural and diffusion-tensor sequences were performed at both timepoints and analyzed for cerebral characteristics, lesion diffusivity, and white matter changes. Spatiotemporal and relative pressure gait measurements were collected pre- and 2-days post-stroke to characterize and compare acute functional deficits. The results from this study demonstrated that YC and LR pigs exhibit differences in gross brain anatomy and gait patterns pre-stroke with MRI and gait analysis showing statistical differences in the majority of parameters. However, stroke pathologies in YC and LR pigs were highly comparable post-stroke for most evaluated MRI parameters, including lesion volume and diffusivity, hemisphere swelling, ventricle compression, caudal transtentorial and foramen magnum herniation, showing no statistical difference between the breeds. In addition, post-stroke changes in velocity, cycle time, swing percent, cadence, and mean hoof pressure showed no statistical difference between the breeds. These results indicate significant differences between pig breeds in brain size, anatomy, and motor function pre-stroke, yet both demonstrate comparable brain pathophysiology and motor outcomes post-stroke. The conclusions of this study suggest pigs of these different breeds generally show a similar ischemic stroke response and findings can be compared across porcine stroke studies that use different breeds.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Heart rate, respiratory rate, and temperature were recorded at each time point. Banamine (2.2 mg/kg) was administered IM for postoperative pain, acute inflammation, and fever management every 12 h for the first 24 h, and every 24 h for 3 days post-stroke ( 13 , 33 ).…”

Section: Methodsmentioning

confidence: 99%

Magnetic Resonance Imaging and Gait Analysis Indicate Similar Outcomes Between Yucatan and Landrace Porcine Ischemic Stroke Models

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Finally, in order to limit for potential confounders, we did not employ specific sepsis therapies, such as antibiotics, since it has been shown that they can modify BBB [82], influence central nervous system inflammation [83,84], and induce seizures [85]; on the other hand, this do not allow an entire translation of our results to clinical practice. Furthermore, albeit sheep is a promising surrogate for modelling human brain diseases [86], interspecies differences limit the generalization of animals studies results to humans.…”

Section: Discussionmentioning

confidence: 99%

Cerebral autoregulation and neurovascular coupling are progressively impaired during septic shock: an experimental study

Ferlini

Créteur

et al. 2020

ICMx

View full text Add to dashboard Cite

Background: Alteration of the mechanisms of cerebral blood flow (CBF) regulation might contribute to the pathophysiology of sepsis-associated encephalopathy (SAE). However, previous clinical studies on dynamic cerebral autoregulation (dCA) in sepsis had several cofounders. Furthermore, little is known on the potential impairment of neurovascular coupling (NVC) in sepsis. The aim of our study was to determine the presence and time course of dCA and NVC alterations in a clinically relevant animal model and their potential impact on the development of SAE. Methods: Thirty-six anesthetized, mechanically ventilated female sheep were randomized to sham procedures (sham, n = 15), sepsis (n = 14), or septic shock (n = 7). Blood pressure, CBF, and electrocorticography were continuously recorded. Pearson's correlation coefficient Lxa and transfer function analysis were used to estimate dCA. NVC was assessed by the analysis of CBF variations induced by cortical gamma activity (Eγ) peaks and by the magnitude-squared coherence (MSC) between the spontaneous fluctuations of CBF and Eγ. Cortical function was estimated by the alpha-delta ratio. Wilcoxon signed rank and rank sum tests, Friedman tests, and RMANOVA test were used as appropriate. Results: Sepsis and sham animals did not differ neither in dCA nor in NVC parameters. A significant impairment of dCA occurred only after septic shock (Lxa, p = 0.03, TFA gain p = 0.03, phase p = 0.01). Similarly, NVC was altered during septic shock, as indicated by a lower MSC in the frequency band 0.03-0.06 Hz (p < 0.001). dCA and NVC impairments were associated with cortical dysfunction (reduction in the alpha-delta ratio (p = 0.03)). Conclusions: A progressive loss of dCA and NVC occurs during septic shock and is associated with cortical dysfunction. These findings indicate that the alteration of mechanisms controlling cortical perfusion plays a late role in the pathophysiology of SAE and suggest that alterations of CBF regulation mechanisms in less severe phases of sepsis reported in clinical studies might be due to patients' comorbidities or other confounders. Furthermore, a mean arterial pressure targeting therapy aiming to optimize dCA might not be sufficient to prevent neuronal dysfunction in sepsis since it would not improve NVC.

show abstract

“…Pigs are a robust translational animal model for biomedical research, especially gut and brain research, due to the myriad of similarities to humans in physiology, anatomy, pathology, and eating behavior ( Watanabe et al, 2001 ; Lind et al, 2007 ; Swindle et al, 2012 ; Kaiser and West, 2020 ). They are omnivorous and have similar intestinal size and length in proportion to humans, contributing comparable transit time to humans ( Clouard et al, 2012 ; Heinritz et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Dynamic Changes in the Gut Microbiome at the Acute Stage of Ischemic Stroke in a Pig Model

et al. 2020

View full text Add to dashboard Cite

Stroke is a major cause of death and long-term disability affecting seven million adults in the United States each year. Recently, it has been demonstrated that neurological diseases, associated pathology, and susceptibility changes correlated with changes in the gut microbiota. However, changes in the microbial community in stroke has not been well characterized. The acute stage of stroke is a critical period for assessing injury severity, therapeutic intervention, and clinical prognosis. We investigated the changes in the gut microbiota composition and diversity using a middle cerebral artery (MCA) occlusion ischemic stroke pig model. Ischemic stroke was induced by cauterization of the MCA in pigs. Blood samples were collected prestroke and 4 h, 12 h, 1 day, and 5 days poststroke to evaluate circulating proinflammatory cytokines. Fecal samples were collected prestroke and 1, 3, and 5 days poststroke to assess gut microbiome changes. Results showed elevated systemic inflammation with increased plasma levels of tumor necrosis factor alpha at 4 h and interleukin-6 at 12 h poststroke, relative to prestroke. Microbial diversity and evenness were reduced at 1 day poststroke compared to prestroke. Microbial diversity at 3 days poststroke was negatively correlated with lesion volume. Moreover, beta-diversity analysis revealed trending overall differences over time, with the most significant changes in microbial patterns observed between prestroke and 3 days poststroke. Abundance of the Proteobacteria was significantly increased, while Firmicutes decreased at 3 days poststroke, compared to prestroke populations. Abundance of the lactic acid bacteria Lactobacillus was reduced at 3 days poststroke. By day 5, the microbial pattern returned to similar values as prestroke, suggesting the plasticity of gut microbiome in an acute period of stroke in a pig model. These findings provide a basis for characterizing gut microbial changes during the acute stage of stroke, which can be used to assess stroke pathology and the potential development of therapeutic targets.

show abstract

Large animal ischemic stroke models: replicating human stroke pathophysiology

Cited by 56 publications

References 131 publications

Magnetic Resonance Imaging and Gait Analysis Indicate Similar Outcomes Between Yucatan and Landrace Porcine Ischemic Stroke Models

Magnetic Resonance Imaging and Gait Analysis Indicate Similar Outcomes Between Yucatan and Landrace Porcine Ischemic Stroke Models

Cerebral autoregulation and neurovascular coupling are progressively impaired during septic shock: an experimental study

Dynamic Changes in the Gut Microbiome at the Acute Stage of Ischemic Stroke in a Pig Model

Contact Info

Product

Resources

About