title: Sildenafil provides sustained neuroprotection in the absence of learning recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats.
abstract: In this study, we tested whether the phosphodiesterase-5 inhibitor sildenafil protects against neurodegeneration and facilitates recovery from learning deficits examined long after chronic cerebral hypoperfusion (CCH) induced by the 4-vessel occlusion/internal carotid artery (4-VO/ICA) model in middle-aged rats. Male Wistar rats (12-15 months of age) were subjected to permanent 3-stage 4-VO/ICA with an interstage interval of 4 days. Sildenafil (3 mg/kg, p.o.) was administered at one dose per day for 10 days, beginning soon after the first occlusion stage. Three months later, learning in a non-food-rewarded, eight-arm radial maze task was tested. Learning performance is expressed as the latency to find a goal box and the number of reference or working memory errors. Histological examination was performed 1-3 days after behavioral testing. In the vehicle-treated group, permanent 4-VO/ICA markedly disrupted learning performance and caused moderate-to-severe neurodegeneration in the CA1-CA4 subfields of the hippocampus (56.2%), dentate gyrus (DG; 19.2%), retrosplenial cortex (RS cortex; 47.4%), and parietal association cortex (PtA cortex; 38.2%). Sildenafil treatment did not prevent 4-VO/ICA-induced learning deficits, whereas neurodegeneration was significantly reduced in the CA1-CA4 subfields (30.5%), DG (7.2%), RS cortex (11.8%), and PtA cortex (6.5%). Advancing previous findings from our laboratory, this study suggests that while sildenafil can provide important neuroprotection in different brain regions of middle-aged rats subjected to CCH, such histological effect does not translate into cognitive recovery.
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Av. Colombo, 5790, CEP 87020-900 Maringá, Paraná, Brazil. Electronic address: emilenedias2@hotmail.com.
authors.forename: Emilene
authors.initials: E
authors.lastname: Dias Fiuza Ferreira
authors.forename: Cássia
authors.initials: C
authors.lastname: Valério Romanini
authors.forename: Paulo Eduardo
authors.initials: PE
authors.lastname: Cypriano
authors.forename: Rúbia Maria
authors.initials: RM
authors.lastname: Weffort de Oliveira
authors.forename: Humberto
authors.initials: H
authors.lastname: Milani
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications / Q000401:mortality / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002343:Carotid Artery, Internal / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D007859:Learning Disabilities / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate