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Updated: Jun 17, 2026
2-Vessel Occlusion/Hypotension: A Rat Model of Global Brain Ischemia
Published on: June 22, 2013
Sildenafil prevents mortality and reduces hippocampal damage after permanent, stepwise, 4-vessel occlusion in rats
Cassia V Romanini1, Angélica P Schiavon, Emilene D Fiuza Ferreira
1Department of Pharmacology, State University of Maringá, CEP 87020-900, Maringá, Paraná, Brazil. cassia_romanini@yahoo.com.br
Insights
Sildenafil treatment significantly reduced mortality and hippocampal damage in a rat model of chronic cerebral hypoperfusion (HCC). This suggests sildenafil
Area of Science:
- Neuroscience
- Pharmacology
- Cerebrovascular Research
Background:
- Chronic cerebral hypoperfusion (HCC) models are crucial for studying neurodegenerative diseases.
- The 4-vessel occlusion (VO)/internal carotid artery (ICA) model is used to induce HCC.
- Previous studies established a safe 7-day interstage interval (ISI) for a three-stage occlusion model.
Purpose of the Study:
- To evaluate the impact of reduced occlusion stages and shorter ISI on survival and hippocampal integrity.
- To assess the efficacy of sildenafil in mitigating adverse outcomes in a modified HCC model.
- To investigate sildenafil's potential therapeutic effects on chronic cerebral hypoperfusion.
Main Methods:
- Modified the 4-VO/ICA model by reducing occlusion stages and shortening ISI.
- Administered sildenafil (0.75-3.0 mg/kg, p.o.) to rats subjected to modified HCC.
- Assessed survival rates, learning and memory capacity, and hippocampal histomorphology.
Main Results:
- Shortening ISI significantly decreased survival rates.
- Sildenafil administration abolished mortality by approximately 95% at the shortest ISIs.
- Sildenafil treatment reduced 4-VO/ICA-induced hippocampal neurodegeneration, despite initial memory performance being unaffected.
Conclusions:
- Sildenafil demonstrates potential therapeutic benefits for chronic cerebral hypoperfusion.
- The modified 4-VO/ICA model requires further investigation to effectively induce cognitive impairment.
- Optimizing the HCC model is essential for robust drug efficacy testing against structural and functional outcomes.
Abstract:
The present study evaluated the effects of sildenafil using the 4-vessel occlusion (VO)/internal carotid artery (ICA) model of chronic cerebral hypoperfusion (HCC). We previously found that permanent, three-stage occlusion of the vertebral arteries (VA) and ICA, four-VO/ICA, with an interstage interval (ISI) of 7 days was innocuous and caused no structural or functional outcomes in rats. Therefore, before testing sildenafil, we evaluated how a reduction in the number of occlusion stages (from three stages to two) and a shortening of the ISI might impact the survival rate, capacity for learning and memory, and histomorphological integrity of the hippocampus. Survival decreased from 100% to 70%, 62%, and 0% as the ISI was shortened from 7 to 5, 4, or 3 days, respectively. Using the two shortest ISIs, sildenafil (0.75-3.0 mg/kg, p.o.) abolished the mortality rate by approximately 95%. Profound neurodegeneration occurred in the CA1, CA2, CA3, and CA4 hippocampal subfields after an ISI of 4 days. Despite this, however, memory performance was unaffected. Subsequently, sildenafil treatment reduced 4-VO/ICA-induced hippocampal damage. The present results suggest that sildenafil may be potentially beneficial in the treatment of chronic cerebral hypoperfusion. Further studies should examine the manner by which the chronic 4-VO/ICA model may effectively cause cognitive impairment, thus improving its applicability in testing the effects of drugs against structural and/or functional outcomes of chronic cerebral hypoperfusion.
