Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats

Abstract

We investigated the changes and the molecular mechanisms of cerebral vascular damage and tested the therapeutic effects of Niaspan in type-1 streptozotocin induced diabetic (T1DM) rats after stroke. T1DM-rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan. Non-streptozotocin rats (WT) were also subjected to MCAo. Functional outcome, blood–brain-barrier (BBB) leakage, brain hemorrhage, immunostaining, and rat brain microvascular endothelial cell (RBEC) culture were performed. Compared to WT-MCAo-rats, T1DM-MCAo-rats did not show an increase lesion volume, but exhibited significantly increased brain hemorrhage, BBB leakage and vascular damage as well as decreased functional outcome after stroke. Niaspan treatment of stroke in T1DM-MCAo-rats significantly attenuated BBB damage, promoted vascular remodeling and improved functional outcome after stroke. T1DM-MCAo-rats exhibited significantly increased Angiopoietin 2 (Ang2) expression, but decreased Ang1 expression in the ischemic brain compared to WT-MCAo-rats. Niaspan treatment attenuated Ang2, but increased Ang1 expression in the ischemic brain in T1DM-MCAo-rats. In vitro data show that the capillary-like tube formation in the WT-RBECs marginally increased compared to T1DM-RBEC. Niaspan and Ang1 treatment significantly increased tube formation compared to non-treatment control. Inhibition of Ang1 attenuated Niacin-induced tube formation in T1DM-RBECs. Niaspan treatment of stroke in T1DM-rats promotes vascular remodeling and improves functional outcome. The Ang1/Ang2 pathway may contribute to Niaspan induced brain plasticity. Niaspan warrants further investigation as a therapeutic agent for the treatment of stroke in diabetics.

Exendin-4-Loaded PLGA Microspheres Relieve Cerebral Ischemia/Reperfusion Injury and Neurologic Deficits through Long-Lasting Bioactivity-Mediated Phosphorylated Akt/eNOS Signaling in Rats

“…The release of Ex-4 from degradable PEx-4 then activated GLP-1R in the brain, leading to the effects on the brain cerebral blood flow intensity and microcirculation. Under DM and stroke insults, BBB endothelial leakage was enhanced, 32,33 possibly resulting in more PEx-4 microspheres and fragments entry into the brain parenchyma.…”

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

“…An interesting study showed that angiogenesis is impaired in the GK diabetic model after stroke and this is associated with decreased VEGF and increased angiostatin signaling. 112 In other studies where immature vessel formation was observed, 104,105 authors reported increased Ang-2 and decreased Ang-1 expression in the brain sections of diabetic rats. 103,104 V. Clinical Relevance On the basis of experimental evidence, cerebral neovascularization response differs in diabetes, stroke, and diabetic stroke ( Figure 6).…”

“…Other studies also showed that type 1 and type 2 diabetes impair angiogenesis after stroke. 104,105 Vessel density in the ipsilateral hemisphere 14 days after stroke is increased but these vessels are not mature as indicated by reduced diameter, arteriolar density, and SMCs. 104,105 These studies were conducted in stroked animals and there were no sham control animals thus it is not possible to comment on how stroke injury affected the neovascularization response in the nonischemic hemisphere.…”

“…It is also of great interest that in both type 1 and type 2 diabetes models, in which repair and recovery are impaired, there is increased bleeding into the brain after ischemic stroke. [101][102][103][104][105] However, the impact of bleeding on vascular repair has not been fully studied. Evidence from intracranial hemorrhage models suggests that hemoglobin and heme released from red blood cells enter the brain parenchyma and free iron from further degradation of the heme molecule, disrupts cellular integrity and function via increased oxidative stress.…”

Illuminating the Effects of Stroke on the Diabetic Brain: Insights From Imaging Neural and Vascular Networks in Experimental Animal Models

“…This drug selectively kills insulin-producing cells in the pancreas, rendering mice hyperglycemic and leading to sequelae that mimic T1D (7). STZ-treated mice with chronic elevations in blood glucose levels (;2-4 weeks) show greater neurological deficits and are less likely to regain full use and dexterity of the stroke-affected limbs after focal ischemic or embolic stroke (8)(9)(10). One caveat with this finding is that it occurs after persistent hyperglycemia rather than after chronic low-grade dysregulation of glucose levels that would typically be present in human patients with diabetes.…”