Background and purpose Pre-existing diabetes worsens brain functionality in ischemic stroke. We have previously shown that type-2-diabetic rats exhibit enhanced dysfunctional cerebral neovascularization and when these rats are subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation (HT) and greater neurological deficits. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that vascular repair is impaired in the post-stroke period in diabetes, and this is associated with poor sensorimotor and cognitive function. We further hypothesized that glycemic control prevents impaired vascularization and improves functional outcome in diabetes. Methods Vascularization was assessed in the ipsilateral and contralateral hemispheres in control, diabetes and diabetes plus metformin groups 14 days after ischemic reperfusion injury as well as in respective sham controls. 3-dimensional reconstruction of the FITC stained vasculature was achieved by confocal microscopy and stereological parameters including vascular volume and surface area were measured. Astrogliosis was determined by GFAP staining. The relative rates of sensorimotor recovery, cognitive decline and spontaneous activity were assessed. Results Vascular density in the peri-infarct area was significantly reduced in diabetes whereas there was reparative neovascularization in control rats. Astroglial swelling and reactivity was more pronounced in diabetic stroke compared to control stroke. Diabetes blunted sensorimotor recovery and also exacerbated anxiety-like symptoms and cognitive deficits. Glycemic control started after stroke partially prevented these changes. Conclusion Diabetes impairs post-stroke reparative neovascularization and impedes the recovery. Glycemic control after stroke can improve neurovascular repair and improve functional outcome.

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.

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Treatment with interferon beta-1b partially restores defective T suppressor cell function in patients with MS. This potentially beneficial action is synergistically potentiated by RA. Interferon beta-1b increases the number of interferon gamma-secreting cells in the circulation when treatment is initiated. A similar increment in interferon gamma-secreting cells is observed when interferon beta-1b is added to cultural peripheral blood mononuclear cells in vitro. This potentially deleterious action of interferon beta-1b is reversed by RA. Interferon beta-1b inhibits lymphocyte proliferation modestly but reproducibly. This action of interferon beta-1b is unaltered by RA. These data provide a rationale for a trial of combination treatment with interferon beta-1b and RA in patients with MS.