Intranasal Insulin Treatment Attenuates Metabolic Distress and Early Brain Injury After Subarachnoid Hemorrhage in Mice

Abstract

Intranasal administration of insulin to the brain bypasses the blood brain barrier (BBB) and can increase cerebral glucose uptake and prevent energy failure. Intranasal insulin treatment has shown neuroprotective effects in multiple central nervous system (CNS) lesions, but the effects of intranasal insulin on the metabolic and pathological process of subarachnoid hemorrhage (SAH) are not clear. This study is designed to explore the effects of intranasal insulin treatment on metabolic distress and early brain injury (EBI) after experimental SAH. SAH model was built by endovascular filament perforation method in adult male C57BL/6J mice, and then, insulin was administrated via intranasal route at 0, 24, and 48h post-SAH. EBI was assessed according to the neurological performance, BBB damage, brain edema, neuroinflammatory reaction, and neuronal apoptosis at each time point. To evaluate metabolic conditions, microdialysis was used to continuously monitor the real-time levels of glucose, pyruvate, and lactate in interstitial fluid (ISF) in living animals. The mRNA and protein expression of glucose transporter-1 and 3 (GLUT-1 and -3) were also tested by RT-PCR and Western blot in brain after SAH. Compared to vehicle, intranasal insulin treatment promoted the relative mRNA and protein levels of GLUT-1 in SAH brain (0.98 ± 0.020 vs 0.33 ± 0.016 at 24h, 0.91 ± 0.25 vs 0.21 ± 0.013 at 48h and 0.94 ± 0.025 vs 0.28 ± 0.015 at 72h in mRNA/0.96 ± 0.023 vs 0.36 ± 0.015 at 24h, 0.91 ± 0.022 vs 0.22 ± 0.011 at 48h and 0.95 ± 0.024 vs 0.27 ± 0.014 at 72h in protein, n = 8/Group, p < 0.001). Similar results were also observed in GLUT-3. Intranasal insulin reduced the lactate/pyruvate ratio (LPR) and increased ISF glucose level. It also improved neurological dysfunction, BBB damage, and brain edema and attenuated the levels of pro-inflammatory cytokines as well as neuronal apoptosis after SAH. The intranasal insulin treatment protects brain from EBI possibly via improving metabolic distress after SAH.