Animal models of cerebral ischemia: A review Ma, Rong; Xie, Qian; Li, Yong ...
Biomedicine & pharmacotherapy,
November 2020, 2020-Nov, 2020-11-00, 20201101, 2020-11-01, Letnik:
131
Journal Article
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•Patients with stroke in the left hemisphere was more common than that in right.•Patients with permanent cerebral ischemia was more common than that of reperfusion, the mechanisms of ...the two models were different in different phases.•Left-sided permanent cerebral ischemia animal models should be prioritized in preclinical studies.•The preoperative and postoperative details of cerebral ischemia animal models preparation should not be ignored.
Stroke seriously threatens human health because of its characteristics of high morbidity, disability, recurrence, and mortality, thus representing a heavy financial and mental burden to affected families and society. Many preclinical effective drugs end in clinical-translation failure. Animal models are an important approach for studying diseases and drug effects, and play a central role in biomedical research. Some details about animal models of cerebral ischemia have not been published, such as left-/right-sided lesions or permanent cerebral ischemia/cerebral ischemia–reperfusion. In this review, ischemia in the left- and right-hemisphere in patients with clinical stroke and preclinical studies were compared for the first time, as were the mechanisms of permanent cerebral ischemia and cerebral ischemia–reperfusion in different phases of the disease. The results showed that stroke in the left hemisphere was more common in clinical patients, and that most patients with stroke failed to achieve successful recanalization. Significant differences were detected between permanent cerebral ischemia and cerebral ischemia–reperfusion models in the early, subacute, and recovery phases. Therefore, it is recommended that, with the exception of the determined experimental purpose or drug mechanism, left-sided permanent cerebral ischemia animal models should be prioritized, as they would be more in line with the clinical scenario and would promote clinical translation. In addition, other details regarding the preoperative management, surgical procedures, and postoperative care of these animals are provided, to help establish a precise, effective, and reproducible model of cerebral ischemia model and establish a reference for researchers in this field.
Background Shenma Jingfu Granule, a traditional Chinese medicine formula, has been used clinically for the treatment of cerebral circulation insufficiency. However, the mechanism involved in ...alleviating cerebral ischemia has not yet been fully elucidated. Methods An integrated approach involving network pharmacology and transcriptomics was utilized to clarify the potential mechanisms of SMJF Granule. Molecular docking and surface plasmon resonance (SPR) were employed to identify potential targets and ingredients of SMJF Granule. The anti-CI effect of SMJF Granule was determined on the middle cerebral artery occlusion (MCAO) model by using hematoxylin-eosin (H&E) and Nisslʼs staining, as well as triphenyl tetrazolium chloride (TTC) staining, and the potential targets involved in the mechanisms were validated by RT-qPCR and western blotting. Results Integrated analysis revealed the mechanism of SMJF Granule intervening in CI injury might be related to the HIF-1 signaling pathway and angiogenesis. Molecular docking and SPR assays demonstrated robust binding interactions between key compounds like salvianolic acid A and naringenin with the core target HIF-1alpha protein. The experiment confirmed that SMJF Granule lowered neurological scores, diminished infarct volume, and alleviated histopathological changes in vivo. The possible mechanism of SMJF Granule was due to regulating HIF-1 pathway, which contributed to up-regulating expression of VEGF and vWF in the penumbral region, showing a significant promotion of angiogenesis. Conclusion SMJF Granule promoted angiogenesis through HIF-1alpha pathway, thereby alleviating cerebral ischemia injury. In addition, our findings provide some evidence that SMJF Granule is a candidate compound for further investigation in treating CI in the clinical. Graphical Keywords: Shenma Jingfu granule, Cerebral ischemia, HIF-1 signaling pathway, Angiogenesis
Cerebral ischemia is one of the most common causes of dementia, which develops in more than half of patients after an ischemic episode. The main mechanism is thought to be pathological changes in the ...hippocampus, especially in the CA1 area, underlying episodic memory impairment, which is the earliest and most important clinical symptom of post-ischemic dementia. The 13 chapters of this book present a new picture of ischemic brain disease, synthesizing the latest data on disease mechanisms, care for patients with this disease, and potential therapeutic targets. The authors present the characteristics of cerebral ischemia from pregnancy and childhood through adolescence to adulthood. The first two chapters provide a snapshot of the anatomy of the cerebral cortex and the hippocampus, the most affected brain structures after cerebral ischemia. This is followed by nine chapters that present a comprehensive view of the pathological mechanisms of cerebral ischemia, and how a deep understanding of these pathomechanisms hold the key for the discovery and development of novel therapies to help patients affected by cerebral ischemia. Chapter 12 shares real-life experience and challenges of rehabilitating patients into the community after cerebral ischemia, and chapter 13 analyzes the social risk variations, including gender inequality, in the reintegration of post-ischemic stroke patients. Although primarily aimed at scientists and clinicians, the contents of the book will be of interest to all those who are interested in cerebral ischemia, including patients and their caregivers.
There is a growing interest in using natural medicines to treat stroke as the leading cause of disability worldwide. Especially plant-derived natural medicines have multiple beneficial effects, ...including antioxidative, anti-inflammatory, antiapoptotic, suggesting their potential for stroke treatment. However, failure in clinical translation has created a substantial challenge for their use as stroke treatment. This review summarises the status of using natural medicinal formulations in stroke treatment, as well as the challenges. Although natural medicines have excellent prospects for ischaemic stroke treatment, several concerns need to be addressed for translating the success in animal research to humans. Specifically, there should be more considerations for investigating the precise mechanisms of natural medicines mediating the neuroprotective effects on stroke. Moreover, to further improve the prospects of clinical translation, further studies should be performed in aged animals rather than young adult animals.
We previously showed that stroke alters circular RNA (circRNA) expression profiles. Many circRNAs undergo epitranscriptomic modifications, particularly methylation of adenosine to form ...N6-methyladenosine (m6A). This modification significantly influences the circRNA metabolism and functionality. Hence, we currently evaluated if transient focal ischemia in adult C57BL/6J mice alters the m6A methylation of circRNAs. Changes in m6A were profiled in the peri-infarct cortex following immunoprecipitation coupled with microarrays. Correlation and gene ontology analyses were performed to understand the association of m6A changes with circRNA regulation and functional implications after stroke. Many circRNAs showed differential regulation (up or down) after stroke, and this change was highest at 24h of reperfusion. Notably, most circRNAs differentially regulated after stroke also exhibited temporal changes in m6A modification patterns. The majority of circRNAs that showed post-stroke differential m6A modifications were derived from protein-coding genes. Hyper-than hypomethylation of circRNAs was most prevalent after stroke. Gene ontology analysis of the host genes suggested that m6A-modified circRNAs might regulate functions such as synapse-related processes, indicating that m6A epitranscriptomic modification in circRNAs could potentially influence post-stroke synaptic pathophysiology.
•Stroke induces differential regulation of cerebral circRNAs.•Most circRNAs with altered regulation exhibit temporal changes in m6A modification.•m6A modified circRNAs primarily originate from protein-coding genes and display higher hypermethylation compared to hypomethylation.•CircRNA m6A modification might be crucial in regulating synapse-related processes after stroke.
Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely ...evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using 18FDPA-714 and 18FBR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats. The assessment of brain oedema, blood brain barrier (BBB) disruption and neurofunctional progression after treatment was evaluated with T2 weighted and dynamic contrast-enhanced magnetic resonance imaging (T2 W and DCE-MRI) and neurological evaluation. The activation of α7 nAChRs resulted in a decrease of ischemic lesion, midline displacement and cell neurodegeneration from days 3 to 7 after ischemia. Besides, the treatment with PHA 568487 improved the neurofunctional outcome. Treated ischemic rats showed a significant 18FDPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of α7 receptors displayed an increase of 18FBR-351-PET signal in ischemic cortical regions, which resulted from the overactivation of MMP-2. Finally, the treatment with PHA 568487 showed a protective effect on BBB disruption and blood brain vessel integrity after cerebral ischemia.
Stroke is a group of diseases resulting from cerebral vascular rupture or obstruction and subsequent brain blood circulation disorder, leading to rapid neurological deficits. Ischemic stroke accounts ...for the majority of all stroke cases. The current treatments for ischemic stroke mainly include t-PA thrombolytic therapy and surgical thrombectomy. However, these interventions aimed at recanalizing cerebral vessels can paradoxically lead to ischemia-reperfusion injury, which exacerbates the severity of brain damage. Minocycline, a semi-synthetic tetracycline antibiotic, has been shown to possess a wide range of neuroprotective effects independent of its antibacterial activity. Here we summarize the mechanisms underlying the protective effects of minocycline against cerebral ischemia-reperfusion injury based on the pathogenesis of cerebral ischemia-reperfusion injury, including its modulation of oxidative stress, inflammatory response, excitotoxicity, programmed cell death and blood-brain barrier injury, and also introduce the role of minocycline in alleviating stroke-related complications, in order to provide a theoretical basis for the clinical application of minocycline in cerebral ischemia-reperfusion injury.
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