Comparative analysis of the neurovascular injury and functional outcomes in experimental stroke models in diabetic Goto-Kakizaki rats

Abstract

Diabetes worsens functional outcome and is associated with greater hemorrhagic transformation (HT) after ischemic stroke. We have shown that diabetic Goto-Kakizaki (GK) rats develop greater HT and neurological deficit despite smaller infarcts after transient middle cerebral artery occlusion (MCAO) with the suture model. However, the impact of 1) the duration of ischemia/reperfusion (I/R); 2) the method of ischemia; and 3) acute glycemic control on neurovascular injury and functional outcome in diabetic stroke remained unanswered. Wistar and GK rats were subjected to variable MCAO by suture or embolus occlusion. A group of GK rats were treated with insulin or metformin before stroke with suture occlusion. In all groups, infarct size, edema, HT occurrence and severity, and functional outcome were measured. Infarct size at 24 h was smaller in GK rats with both suture and embolic MCAO, but expanded with longer reperfusion period. Edema and HT were increased in GK rats after 90 min and 3 h occlusion with the suture model, but not in the embolic MCAO. Neurological deficit was greater in diabetic rats. These findings suggest that diabetes accelerates the development of HT and amplifies vascular damage in the suture model where blood flow is rapidly reestablished. Acute metformin treatment worsened the infarct size, HT, and behavior outcome, whereas insulin treatment showed a protective effect. These results suggest that the impact of ischemia/reperfusion on neurovascular injury and functional outcome especially in disease models needs to be fully characterized using different models of stroke to model the human condition.

Persistent Cerebrovascular Damage After Stroke in Type Two Diabetic Rats Measured by Magnetic Resonance Imaging

“…With the T2DM model in Goto-Kakizaki rats, infarction volumes were significantly smaller and independent of the 3h/21h of ischemia-reperfusion filament, 9 or 24h embolic MCAo models. 3 Conversely, infarction volumes were significantly increased after stroke in T2DM mice compared to non-diabetic mice. 7,12 Thus, there is a need to delineate the ischemic lesion volume for our animal model, a T2DM model induced by a single intraperitoneal injection of low dose Streptozotocin combined with a HFD, and a 2h suture ischemia-reperfusion model in the young adult Wistar rat.…”

“…2 Diabetes instigates a cascade of events leading to vascular endothelial cell dysfunction, and increased vascular permeability in various vascular beds in humans and animal models. 3 Many pathways are involved in the diabetes-related changes in the blood-brain barrier (BBB). 4,5 In the clinic, the vast majority (90–95%) of diabetic patients have type 2 diabetes mellitus (T2DM), which affects 24 million Americans.…”

MAPK pathway mediates the anti‑oxidative effect of chicoric acid against cerebral ischemia‑reperfusion injury in�vivo

“…However, organizational functions are not recovered in certain patients and the damage is aggravated. Cerebral ischemia-reperfusion (I/R) injury is a complex pathophysiological procedure (4). A previous study have reported that brain cell injuries caused by cerebral blood flow interruption and reperfusion is a rapid cascade reaction that involves a number of steps, including energy barrier, acidosis, increased excitatory amino acid release, the formation of free radicals and the expression of apoptotic genes (4).…”

Blood Brain Barrier Disruption in Diabetic Stroke Related to Unfavorable Outcome

“…This occurs despite a clear increase in neoangiogenesis at baseline in the diabetic animals [30] . There is also evidence that ischemic challenge in diabetic animals is associated with a smaller volume of infarction [31,32] and a greater degree of BBB disruption, which occurs immediately after stroke and persists for a duration exceeding 5 weeks [15] . These BBB changes were found to be associated with greater edema and higher hemorrhagic volumes [15] .…”