Related Experiment Video
Updated: May 24, 2026
A Mouse Model of Hemorrhagic Transformation Induced by Acute Hyperglycemia Combined with Transient Focal Ischemia
Published on: November 15, 2024
Peroxynitrite decomposition with FeTMPyP improves plasma-induced vascular dysfunction and infarction during mild but
Sara Morales Palomares1, Ira Gardner-Morse, Julie G Sweet
1Departments of Neurology, Obstetrics, Gynecology and Reproductive Sciences, and Pharmacology, University of Vermont College of Medicine, Burlington, VT, USA.
Abstract:
We investigated mechanisms by which circulating factors during hyperglycemic (HG) stroke affect cerebrovascular function and the role of peroxynitrite in stroke outcome. Middle cerebral arteries (MCAs) were isolated from male Wistar rats and perfused with plasma from rats that were hyperglycemic for 5 to 6 days by streptozotocin and underwent either MCA occlusion (HG MCAO) or Sham surgery (HG Sham) compared with MCA perfused with physiologic saline (No plasma). Myogenic responses and endothelial function were compared in untreated MCA (n=8/group) or with inhibitors of NADPH oxidase (apocynin; n=8), peroxynitrite (FeTMPyP; n=8) or endothelin-1 (ET-1)(A) (BQ-123; n=8). Finally, animals were treated in vivo before reperfusion after mild (<68% cerebral blood flow (CBF) decrease) or severe (>68% CBF decrease) MCAO with FeTMPyP (n=12) or vehicle (n=12) and CBF and infarction measured. The HG MCAO plasma increased tone in MCA versus No plasma (P<0.05) that was reversed by FeTMPyP, but not by apocynin or BQ-123. The HG Sham plasma also increased tone in MCA (P<0.05) that was reversed by BQ-123 only. In vivo, FeTMPyP was neuroprotective during mild, but not severe ischemia. These results show that circulating factors in plasma can affect cerebrovascular function through peroxynitrite generation and ET-1. In addition, peroxynitrite decomposition improves stroke outcome acutely during mild, but not severe HG ischemia.
Insights
Hyperglycemic stroke plasma affects brain blood vessels via peroxynitrite and endothelin-1. Peroxynitrite reduction improved outcomes in mild hyperglycemic stroke but not severe cases.
Area of Science:
- Cardiovascular Sciences
- Neuroscience
- Endocrinology
Background:
- Hyperglycemia exacerbates stroke outcomes.
- Circulating factors in hyperglycemic states may impair cerebrovascular function.
- The role of peroxynitrite in hyperglycemic stroke is not fully understood.
Purpose of the Study:
- To investigate how circulating factors during hyperglycemia affect cerebrovascular function.
- To determine the role of peroxynitrite in stroke outcomes.
- To explore potential therapeutic targets for hyperglycemic stroke.
Main Methods:
- Isolated rat middle cerebral arteries (MCAs) were perfused with plasma from hyperglycemic rats.
- Vascular responses were assessed with and without inhibitors of NADPH oxidase, peroxynitrite, and endothelin-1.
- In vivo studies involved treating rats with a peroxynitrite inhibitor before reperfusion after mild or severe middle cerebral artery occlusion (MCAO).
Main Results:
- Plasma from hyperglycemic rats induced increased tone in MCAs.
- This effect was reversed by a peroxynitrite inhibitor but not by NADPH oxidase or endothelin-1 inhibitors.
- A peroxynitrite inhibitor provided neuroprotection during mild hyperglycemic MCAO but not severe MCAO.
Conclusions:
- Circulating factors in hyperglycemic stroke impact cerebrovascular function through peroxynitrite and endothelin-1.
- Peroxynitrite decomposition offers acute neuroprotection in mild hyperglycemic stroke.
- Therapeutic strategies targeting peroxynitrite may be beneficial in specific hyperglycemic stroke contexts.
