Diabetes worsens ischemia-reperfusion brain injury in rats through GSK-3β

Abstract

Background: Diabetes aggravates brain injury after cerebral ischemia/reperfusion (I/R). Objective: To investigate whether limb I/R causes cerebral injury in a rat diabetes model and whether glycogen synthase kinase-3β (GSK-3β) is involved. Methods: Male adult Sprague-Dawley rats were assigned into streptozotocin-induced diabetes (n 30; blood glucose ≥16.7 mmol/L) or control (n 20) groups, further subdivided into diabetes I/R (3-hour femoral artery/vein clamping), diabetes-I/R + TDZD-8 (I/R plus GSK-3β inhibitor), diabetes-sham, control-sham and control-I/R groups (n 10 each). Cortical and hippocampal morphology (hematoxylin/eosin); hippocampal CA1 apoptosis (TUNEL assay); cleaved caspase-3 (apoptosis), and Iba1 (microglial activation) protein expression (immunohistochemistry); phosphorylated/total GSK-3β and nuclear factor-B (NF-B) protein levels (Western blotting); and serum and brain tissue tumor necrosis factor (TNF)-α levels (enzyme-linked immunosorbent assay) were analyzed. Results: The diabetes-I/R group showed greater cortical and hippocampal injury, apoptosis, cleaved caspase-3 expression and Iba1 expression than the control-I/R group; TDZD-8 reduced injury/apoptosis and cleaved caspase-3/Iba1 expressions. The diabetes-I/R group had lower p-GSK-3β and p-NF-Bp65 expression than the control-I/R group (P < 0.05); TDZD-8 increased p-GSK-3β expression but decreased p-NF-Bp65 expression (P < 0.05). The diabetes-I/R group showed higher elevation of serum and brain tissue TNF-α than the control-I/R group (P < 0.05); TDZD-8 reduced TNF-α production. Conclusions: Diabetes exacerbates limb I/R-induced cerebral damage and activates NF-B and GSK-3β.