Ischemic stroke is a highly complex and devastating neurological disease. The sudden loss of blood flow to a brain region due to an ischemic insult leads to severe damage to that area resulting in the formation of an infarcted tissue, also known as the ischemic core. This is surrounded by the peri-
infarct region or penumbra that denotes the functionally impaired but potentially salvageable tissue. Thus, the penumbral tissue is the main target for the development of neuroprotective strategies to minimize the extent of ischemic brain damage by timely therapeutic intervention. Given the limitations of reperfusion
therapies with recombinant
tissue plasminogen activator or mechanical
thrombectomy, there is high enthusiasm to combine reperfusion
therapy with neuroprotective strategies to further reduce the progression of ischemic
brain injury. Till date, a large number of candidate
neuroprotective drugs have been identified as potential
therapies based on highly promising results from studies in rodent
ischemic stroke models. However, none of these interventions have shown therapeutic benefits in
stroke patients in clinical trials. In this review article, we discussed the urgent need to utilize preclinical models of
ischemic stroke that more accurately mimic the clinical conditions in
stroke patients by incorporating aged animals and animal
stroke models with comorbidities. We also outlined the recent findings that highlight the significant differences in
stroke outcome between young and aged animals, and how major comorbid conditions such as
hypertension, diabetes,
obesity and
hyperlipidemia dramatically increase the vulnerability of the brain to ischemic damage that eventually results in worse functional outcomes. It is evident from these earlier studies that including animal models of aging and comorbidities during the early stages of drug development could facilitate the identification of neuroprotective strategies with high likelihood of success in
stroke clinical trials.