Hyperglycemia exacerbates ischemic stroke outcome independent of platelet glucose uptake

Abstract

Objective Hyperglycemia is a common comorbidity for ischemic stroke and is associated with worsened neurological outcomes. Platelets are central mediators of ischemic stroke and hyperglycemia mediates platelet hyperactivity. In this study, we investigated the contribution of platelet glucose metabolism to ischemic stroke. Methods Mice lacking both Glut1 and Glut3 specifically in platelets (DKO) and their littermate controls (WT) were subjected to 1‐hour transient middle cerebral artery occlusion under normoglycemic and streptozotocin‐induced hyperglycemic conditions after which stroke outcomes, platelet activation, and platelet‐neutrophil aggregate (PNA) formation were examined. Results Under normoglycemic conditions, DKO mice were protected from ischemic stroke with smaller brain infarct volumes and improved cerebral blood flow. In addition, DKO mice had reduced platelet activation, PNA, and cerebral neutrophil recruitment after stroke. Hyperglycemia significantly increased infarct size and cerebral Evans blue extravasation and worsened neurological outcomes and cerebral blood flow in both WT and DKO mice, abolishing the protective effect witnessed under normoglycemic conditions. Flow cytometric analysis after stroke demonstrated increased platelet activation and neutrophil trafficking to the brain, independent of platelet glucose metabolism. Finally, platelets from healthy DKO mice were unable to become procoagulant upon dual agonist stimulation. Conversely, hyperglycemia increased platelet mitochondrial reactive oxygen species production which potentiated procoagulant platelet formation in WT mice and restored procoagulant platelet formation in DKO mice. Conclusion Hyperglycemia aggravates ischemic stroke outcome independent of platelet glucose uptake. Furthermore, we demonstrated that hyperglycemia primes procoagulant platelet formation. This underlines the therapeutic potential for strategies targeting procoagulant platelet formation for the treatment of acute ischemic stroke.

Neutrophil extracellular traps regulate ischemic stroke brain injury

“…Neutrophils were resuspended to a concentration of 1 × 10 6 cells/mL in Medium 199. Platelets were purified as described previously ( 66 , 67 ), resuspended to 1 × 10 8 cells/mL in Medium 199, and activated with 50 ng/mL convulxin (sc-202554, Santa Cruz Biotechnology) for 15 minutes. Activated platelets and neutrophils were incubated at a 100:1 ratio to induce NETs for 2.5 hours at 37°C in 5% CO 2 /95% air.…”

“…Transient middle cerebral artery occlusion (tMCAO) was performed as described previously ( 67 , 68 ). Briefly, occlusion of the right MCA was achieved by insertion of a standardized monofilament (Doccol Corp.) via the right internal carotid artery to occlude the origin of the right MCA.…”

“…Diabetes was induced as described previously ( 67 ). In brief, 50 mg/kg streptozotocin (S0130, Sigma-Aldrich) was administered by i.p.…”

Prognostic Significance of Admission Glucose Combined with Hemoglobin A1c in Acute Ischemic Stroke Patients with Reperfusion Therapy

“…Hyperglycemia plays an important role in early reperfusion by increasing blood–brain barrier permeability and extravasation of neutrophils within the infarcted area, leading to worse clinical outcomes [ 32 , 33 ]. Recent studies reported that high blood glucose may be related to a lower cerebral glucose level and contributes to procoagulant platelet formation, which would increase the severity of ischemia [ 34 , 35 ].…”

Alleviation of Neuronal Cell Death and Memory Deficit with Chungkookjang Made with Bacillus amyloliquefaciens and Bacillus subtilis Potentially through Promoting Gut–Brain Axis in Artery-Occluded Gerbils

“…The treatment delay develops neuronal cell death to induce adverse outcomes, such as vision problems, paralysis in the limbs, dizziness, confusion, and coordination loss due to blockage in the brain areas. Furthermore, post-stroke hyperglycemia exacerbates the post-stroke outcomes by aggravating neuronal cell death through promoting procoagulant platelet formation and reducing cerebral blood flow [3,4]. Therefore, hyperglycemia, dyslipidemia, and hypertension need to be controlled to reduce stroke events and alleviate post-stroke consequences.…”