Opportunities and Limitations of Vascular Risk Factor Models in Studying Plasticity-Promoting and Restorative Ischemic Stroke Therapies

Table 3

Animal models of diabetes and obesity used in ischemic stroke studies.

Animal model	Model origin/characteristics	Systemic vascular pathology	Cerebrovascular features
Streptozotocin-induced type-1 and type-2 diabetic rat or mouse	Type-1 diabetes induced by repeated streptozotocin injections, resulting in near-complete β-cell loss [42–45]. Type-2 diabetes by single streptozotocin injection in middle-aged rats [46] or rats receiving high-cholesterol diet [47] exhibits partial β-cell loss	Fatty streaks in aortic wall and coronary arteries. Rats exhibiting more atherosclerosis than mice, BALB/c mice exhibiting more atherosclerosis than C57BL6 mice. Microvascular thrombosis and blood-brain barrier leakage noted in middle-aged rats with streptozotocin-induced type-2 diabetes [46]	Infarct volume, brain edema, and hemorrhagic transformation increased after cerebral thromboembolism, permanent or transient proximal MCAO in streptozotocin-induced type-1 diabetic rats [42–44]. Infarct volume only modestly reduced by tissue-plasminogen activator thrombolysis [43]. Insulin restored the efficacy of tissue-plasminogen activator thrombolysis, reducing infarct volume, brain edema, and hemorrhagic transformation [45]. Increased sensorimotor deficits, reduced neurogenesis/oligodendrogenesis, impaired dendritic/synaptic plasticity, but unchanged infarct volume after thromboembolism in middle-aged type-2 diabetic rats [46]. Mesenchymal stem cell delivery enhanced neurological recovery, angiogenesis, and white matter remodeling after transient proximal MCAO in type-2 diabetic rats [47], but induced poor neurological recovery associated with aberrant angiogenesis, brain hemorrhages, and massive M1-macrophage infiltrates in type-1 diabetic rats [44, 48]
Lep^ob/ob mouse/Lepr^db/db mouse	Homozygous mice with spontaneous mutations of leptin (Lep^ob/ob) or leptin receptor (Lepr^db/db) genes conferring hyperphagia, obesity, hyperinsulinemia, and type-2 diabetes [49–53]	Fatty streaks in aortic wall and coronary arteries	Infarct volume and brain edema after transient proximal MCAO or unilateral hypoxia-ischemia (Vannucci model) increased in Lep^ob/ob and Lepr^db/db mice due to excessive extracellular matrix breakdown with brain neutrophil and macrophage infiltration [49–52]. Rosuvastatin decreased infarct volume in Lep^ob/ob, but not wild-type mice via mechanisms involving intercellular adhesion molecule-1 downregulation and prevention of brain leukocyte entry [51]. Peroxisome proliferator-activated receptor-γ agonist darglitazone reduced infarct volume in Lep^ob/ob, but not control mice [52]. Oligodendrocyte precursor cell proliferation, white matter myelination, and neurological recovery compromised after transient distal MCAO in Lepr^db/db compared to control mice [53]. Microglia/macrophage polarization shifted towards M1-phenotype [53]
KK-A^Y mouse	Heterozygous mouse with spontaneously mutated yellow obese A^Y agouti gene [54]. KK mouse without mutation exhibits glucose intolerance and insulin resistance [54]. Homozygous mutation lethal	Vascular changes modest when exposed to regular diet	Infarct volume, neurological deficits, and brain concentrations of tumor necrosis factor-α decreased by low-dose telmisartan in KK-A^Y mice exposed to permanent proximal MCAO via mechanisms involving peroxisome proliferator-activated receptor-γ activation [54]. At the doses administered, telmisartan did not influence blood pressure
Zucker diabetic fatty rat (ZDF)	Inbred rat with spontaneous leptin receptor mutation conferring hyperphagia, obesity, and diabetes in Zucker rat strain that without this mutation is insulin-resistant [55]	Vascular changes modest when exposed to regular diet. In comparison to Zucker lean controls, significantly elevated CD11b on blood neutrophils and elevated soluble intercellular adhesion molecule-1 levels [55]	Infarct volume, brain edema, neurological deficits, and endothelial neutrophil adhesion increased in ZDF compared to Zucker lean controls exposed to transient proximal MCAO [55]. Cerebral inflammatory response, evaluated by interleukin-1β, CXC-motif ligand-1, and E-selectin levels, increased [55]
Goto-Kakizaki rat	Inbred nonobese type-2 diabetic Wistar rat obtained by mating high blood glucose rats [56]	If at all very subtle vascular changes	Hemorrhagic transformation, but not infarct volume, increased in Goto-Kakizaki rats compared to nondiabetic Wistar controls exposed to transient proximal MCAO [56]. Cerebrovascular tortuosity index increased, suggestive of vascular architecture disturbances [56]

Modified from Reference [6].