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Dextrorphan reduces infarct volume, vascular injury, and brain edema after ischemic brain injury
1Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
Focal cerebral ischemia confined to the cerebral cortex in the right middle cerebral artery (MCA) territory was induced by temporary ligation of the MCA and both common carotid arteries (CCAs). Reperfusion was initiated by releasing all three arterial occlusions after 90 min of ischemia. Infarct volume was morphometrically measured after triphenyltetrazolium chloride staining 24 h postischemia. Blood-brain barrier breakdown was assessed 4 h postischemia by measuring vascular permeability to fluorescein isothiocyanate-conjugated dextran (FITC-D), a macromolecule tracer. Ischemic brain edema was measured based on percent water content, 24 h postischemia. Dextrorphan (DX) 20-10 mg/kg given ip 15 min before ischemia reduced infarct volume in a dose-dependent manner with an apparent U-shaped dose-response curve; best protection was observed at 30 mg/kg. Posttreatment at 30 min, but not 60 min, was still effective. DX (30 mg/kg, given 15 min before ischemia) also reduced the postischemic increase in vascular permeability and brain edema in the right MCA cortex. Results from this study support the idea that NMDA receptor activation contributes to blood-brain barrier breakdown and brain edema after ischemic insults
Insights
Dextrorphan (DX) reduces brain damage after stroke by protecting the blood-brain barrier and decreasing brain edema. Early post-stroke treatment with DX is effective in mitigating ischemic injury.
Area of Science:
- Neuroscience
- Pharmacology
- Cerebrovascular Research
Background:
- Focal cerebral ischemia can lead to significant brain damage, including infarcts, blood-brain barrier (BBB) breakdown, and edema.
- NMDA receptor activation is implicated in the pathophysiology of ischemic brain injury.
Purpose of the Study:
- To investigate the neuroprotective effects of Dextrorphan (DX) in a rat model of focal cerebral ischemia.
- To determine if DX can mitigate infarct volume, BBB breakdown, and brain edema following ischemic stroke.
Main Methods:
- Focal cerebral ischemia was induced in rats by temporary middle cerebral artery (MCA) and common carotid artery (CCA) ligation.
- Infarct volume, BBB permeability (using FITC-dextran), and brain edema were assessed after 90 minutes of ischemia and reperfusion.
- Dextrorphan (DX) was administered at various doses before or after ischemia.
Main Results:
- DX administration before ischemia dose-dependently reduced infarct volume, with optimal protection at 30 mg/kg (U-shaped dose-response).
- Post-treatment with DX 30 minutes after ischemia was effective, but not at 60 minutes.
- DX (30 mg/kg) significantly reduced post-ischemic BBB breakdown and brain edema in the affected cortical area.
Conclusions:
- NMDA receptor activation plays a role in BBB disruption and brain edema formation after ischemic stroke.
- Dextrorphan (DX) exhibits neuroprotective effects against ischemic brain injury, likely through modulation of NMDA receptor activity.
- DX demonstrates potential as a therapeutic agent for acute ischemic stroke, particularly when administered early.