Ischemic Stroke, Lessons from the Past towards Effective Preclinical Models

Abstract

Ischemic stroke is a leading cause of death worldwide, mainly in western countries. So far, approved therapies rely on reperfusion of the affected brain area, by intravenous thrombolysis or mechanical thrombectomy. The last approach constitutes a breakthrough in the field, by extending the therapeutic window to 16–24 h after stroke onset and reducing stroke mortality. The combination of pharmacological brain-protective strategies with reperfusion is the future of stroke therapy, aiming to reduce brain cell death and decrease patients’ disabilities. Recently, a brain-protective drug—nerinetide—reduced brain infarct and stroke mortality, and improved patients’ functional outcomes in clinical trials. The success of new therapies relies on bringing preclinical studies and clinical practice close together, by including a functional outcome assessment similar to clinical reality. In this review, we focused on recent upgrades of in vitro and in vivo stroke models for more accurate and effective evaluation of therapeutic strategies: from spheroids to organoids, in vitro models that include all brain cell types and allow high throughput drug screening, to advancements in in vivo preclinical mouse stroke models to mimic the clinical reality in surgical procedures, postsurgical care, and functional assessment.

Are Ischemic Stroke and Alzheimer’s Disease Genetically Consecutive Pathologies?

“…tMCAO rats are considered suitable for preclinical stroke research [189,190], while the APP/PS1 mice model is used for AD research [191]. Although the suitability of IS [192] and AD [193] models is still being debated, we still need to refer to them to obtain most of the transcriptomics data. It is important to consider all limitations when translating these results to humans.…”

Organoids Modeling Stroke in a Petri Dish

“…During an ischemic stroke, a lack of oxygen and nutrients causes an impairment in cell metabolism, leading to a dysfunction in energy-dependent processes [14]. The resulting loss of energy causes an ionic imbalance and neuronal depolarization with a consequent inhibition of neurotransmitter reuptake and neurotransmitter release [15,16].…”

“…Its excessive release activates the ionotropic N-methyl-D-aspartic acid (NMDA) and 1-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, causing an excessive calcium influx [15,18]. This intracellular calcium influx triggers signaling cascades that result in mitochondrial disruption, caused by mitochondrial permeability transition pore (mtPTP) opening and cytochrome c release, and the activation of free radicals, phospholipases, and proteases that degrade structural proteins, cell membranes and nucleic acids, ending with cellular death [14,15,18]. Free radicals are responsible for the Phosphatidylinositol 3-kinase (PI3-kinase)/serine/threonine kinase(Akt) pathway activation and nuclear factor kappa B(NF-kB) activation, which can both cause recovery improvement or impediment [16].…”

Avanços científicos relacionados às doenças do Sistema Nervoso: a neurociência foi a área onde aconteceram os maiores avanços científicos nas últimas décadas

“…Esta doença também faz parte daquelas denominadas de neurodegenerativas, pois a Assim, as nanopartículas têm sido usadas no tratamento de ambos os tipos de AVC, transportando, dependendo do caso, agentes coagulantes ou anticoagulantes até o local da lesão vascular [5]. Hoje compreende-se melhor as questões sociais e psicológicas ligadas à epilepsia e à própria forma de viver dessas pessoas e há muitas iniciativas para melhorar a sua qualidade de vida [6].…”