A clinically relevant model of focal embolic cerebral ischemia by thrombus and thrombolysis in rhesus monkeys

Stroke remains the second leading cause of death worldwide and the third cause of disability-adjusted life-years. Most strokes are ischemic in nature, meaning they are caused by the disruption of cerebral blood flow resulting from obstructed blood vessels. Reperfusion therapies such as thrombolysis with tissue plasminogen activator and endovascular mechanical thrombectomy are very effective and are becoming game changers for eligible patients. Despite these advances, the achieved effects are insufficient from the perspective of the entire population of stroke patients. Therefore, there is an urgent need to expand eligibility for reperfusion therapies and implement adjuvant therapeutic measures. Animal stroke models are at the forefront of these efforts, helping to untangle complex pathophysiology and providing valuable preclinical data to guide further clinical trials. Various stroke models are available, including direct blocking of cerebral arteries or using other means to recapitulate stroke pathophysiology. International advisory boards recommend initial in vivo experiments be performed in smaller animals, such as rodents. However, second testing would be more desirable in larger animals such as cats, pigs, dogs, and non-human primates. Due to larger cerebral volume, gyrencephalization, and higher white/gray matter ratio, large animals are crucial in translational stroke research. Animal stroke models differ in the time and complexity of the stroke induction procedure, the reproducibility rate, the level of similarity to the human condition, and the possibilities for analysis, imaging, and follow-up studies. The choice of the most appropriate stroke model may translate to better bench-to-bedside translation of preclinical stroke research; ideally, this choice should be based solely on scientific merit.

/pdf/animal-models-of-focal-ischemic-stroke-brain-size-matters-3sn54ps9.pdf

Animal models of focal ischemic stroke: brain size matters

One of the most frequent reasons of mortality and disability today is acute ischemic stroke, which occurs by an abrupt disruption of cerebral circulation. The intricate damage mechanism involves several factors, such as inflammatory response, disturbance of ion balance, loss of energy production, excessive reactive oxygen species and glutamate release, and finally, neuronal death. Stroke research is now carried out using several experimental models and potential therapeutics. Furthermore, studies are being conducted to address the shortcomings of clinical care. A great deal of research is being done on novel pharmacological drugs, mitochondria targeting compounds, and different approaches including brain cooling and new technologies. Still, there are many unanswered questions about disease modeling and treatment strategies. Before these new approaches may be used in therapeutic settings, they must first be tested on large animals, as most of them have been done on rodents. However, there are several limitations to large animal stroke models used for research. In this review, the damage mechanisms in acute ischemic stroke and experimental acute ischemic stroke models are addressed. The current treatment approaches and promising experimental methods such as mitochondrial transplantation, hydrogel-based interventions, and strategies like mitochondria encapsulation and chemical modification, are also examined in this work. 

Stroke Studies in Large Animals: Prospects of Mitochondrial Transplantation and Enhancing Efficiency using Hydrogels and Nanoparticle-assisted Delivery

A major challenge in human stroke research is interpatient variability in the extent of sensorimotor deficits and determining the time course of recovery following stroke. Although the relationship between the extent of the lesion and the degree of sensorimotor deficits is well established, the factors determining the speed of recovery remain uncertain. To test these experimentally, we created a cortical lesion over the motor cortex using a reproducible approach in four common marmosets, and characterized the time course of recovery by systematically applying several behavioral tests before and up to 8 weeks after creation of the lesion. Evaluation of in-cage behavior and reach-to-grasp movement revealed consistent motor impairments across the animals. In particular, performance in reaching and grasping movements continued to deteriorate until 4 weeks after creation of the lesion. We also found consistent time courses of recovery across animals for in-cage and grasping movements. For example, in all animals, the score for in-cage behaviors showed full recovery at 3 weeks after creation of the lesion, and the performance of grasping movement partially recovered from 4 to 8 weeks. In addition, we observed longer time courses of recovery for reaching movement, which may rely more on cortically initiated control in this species. These results suggest that different recovery speeds for each movement could be influenced by what extent the cortical control is required to properly execute each movement.

/pdf/time-course-of-recovery-of-different-motor-functions-1vnhrfj1.pdf

Time course of recovery of different motor functions following a reproducible cortical infarction in non-human primates

Background Recently, the common marmoset (Callithrix jacchus) has attracted significant interest as a non-human primate stroke model. Functional impairment in non-human primate stroke models should be evaluated quantitatively and successively after stroke, but conventional observational assessments of behavior cannot fully fit this purpose. In this paper, we report a behavioral analysis using MarmoDetector, a three-dimensional motion analysis, in an ischemic stroke model using photosensitive dye, along with an observational behavioral assessment and imaging examination. Methods Ischemic stroke was induced in the left hemisphere of three marmosets. Cerebral infarction was induced by intravenous injection of rose bengal and irradiation with green light. The following day, the success of the procedure was confirmed by magnetic resonance imaging (MRI). The distance traveled, speed, activity time, and jumps/climbs were observed for 28 days after stroke using MarmoDetector. We also assessed the marmosets’ specific movements and postural abnormalities using conventional neurological scores. Results Magnetic resonance imaging diffusion-weighted and T2-weighted images showed hyperintense signals, indicating cerebral infarction in all three marmosets. MarmoDetector data showed that the both indices immediately after stroke onset and gradually improved over weeks. Neurological scores were the worst immediately after stroke and did not recover to pre-infarction levels during the observation period (28 days). A significant correlation was observed between MarmoDetector data and conventional neurological scores. Conclusion In this study, we showed that MarmoDetector can quantitatively evaluate behavioral changes in the acute to subacute phases stroke models. This technique can be practical for research on the pathophysiology of ischemic stroke and for the development of new therapeutic methods.

https://www.frontiersin.org/articles/10.3389/fnins.2022.964928/pdf

Quantitative behavioral evaluation of a non-human primate stroke model using a new monitoring system

A pilot behavioural and neuroimaging investigation on photothrombotic stroke models in rhesus monkeys.

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A pilot behavioural and neuroimaging investigation on photothrombotic stroke models in rhesus monkeys.