Sildenafil prevents mortality and reduces hippocampal damage after permanent, stepwise, 4-vessel occlusion in rats.
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.
Romanini
Cassia V
CV
Department of Pharmacology, State University of Maringá, CEP 87020-900, Maringá, Paraná, Brazil. cassia_romanini@yahoo.com.br
Schiavon
Angélica P
AP
Ferreira
Emilene D Fiuza
ED
de Oliveira
Rúbia M Weffort
RM
Milani
Humberto
H
D000818:Animals; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D014715:Vertebrobasilar Insufficiency / Q000188:drug therapy / Q000401:mortality / Q000473:pathology
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate