Impact of aging and comorbidities on ischemic stroke outcomes in preclinical animal models: A translational perspective

Abstract

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.

Keywords: Aging; Comorbidity; Diabetes; Hyperlipidemia; Hypertension; Inflammation; Ischemic stroke; Neuroprotection; Obesity; Stroke models.

Figure 1.

Main causes for the translational failure in ischemic stroke. Deficiencies in both preclinical animal models and clinical trials account for the failure to translate potential neuroprotective strategies into the clinic.

Figure 2.

Aging and Ischemic Stroke. Advanced age is associated with many pathophysiological changes in both the CNS and the periphery. These changes contribute to an altered response to ischemic brain injury, which results in worse functional outcomes in aged compared to young individuals following an ischemic stroke. BBB, blood-brain barrier. MMP-9, matrix metalloproteinase-9. ROS, reactive oxygen species.