Modeling Ischemic Stroke In Vitro: Status Quo and Future Perspectives

Stroke is a devastating disease accounting for 5.5 million deaths annually worldwide.1 Despite significant preclinical and clinical investigations, with >1026 candidate neuroprotective stroke drugs investigated and ≈200 clinical trials, no effective therapy other than tissue-type plasminogen activator has been approved.2 The reasons for these failures are numerous. Recent Stroke Treatment and Academic Roundtable guidelines focusing on the appropriate use of animal models and clinical trial design will undoubtedly improve the odds of identifying effective therapeutics. However, improvements will need to be made across all levels of the drug discovery pipeline if new therapies are to be effectively identified and developed. This review will cover current methods used for modeling ischemic stroke in vitro, along with some of the insights that have been gained and the technological developments that may allow for the production of more effective and relevant models for research in stroke. In vivo models have enabled a great insight into the pathophysiology of human disease and have been critical in our understanding of stroke. Rodents are often the chosen species, because of availability of genetically altered strains. However, ≈70 million years of evolution, separate humans from rodents and just a 10% difference in genome implies that ≈3000 genes differ.3 Aside from macrostructural discrepancies, many cellular and molecular differences exist. For example, the expression levels of transporters and pumps that contribute to the blood–brain barrier (BBB), and the functional diversity and abundance of astrocytes distinguish the human BBB from the rodent.4 Duration of excitotoxicity has also been demonstrated to differ significantly between humans and mice.5 Considering the large inflammatory component of stroke pathology, it is also important to note differences in immune biology between species. Many important immune signaling molecules (interleukin-8, chemokine (C-X-C motif) ligand 7, chemokine (C-C motif) ligand [CCL] 18, monocyte chemoattractant …

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