title: Cilostazol but not sildenafil prevents memory impairment after chronic cerebral hypoperfusion in middle-aged rats.
abstract: We previously reported that the phosphodiesterase-5 (PDE5) inhibitor sildenafil prevented neurodegeneration but not learning deficits in middle-aged rats that were subjected to the permanent, three-stage, four-vessel occlusion/internal carotid artery (4-VO/ICA) model of chronic cerebral hypoperfusion (CCH). In the present study, we examined whether the PDE3 inhibitor cilostazol alleviates the loss of long-term memory (i.e., retrograde amnesia) caused by CCH. The effect of sildenafil was then compared to cilostazol. Naive rats (12-15 months old) were trained in a non-food-rewarded eight-arm radial maze and subjected to CCH. One week later, retrograde memory was assessed for 5 weeks. Cilostazol (50mg/kg, p.o.) was administered for 42 days or 15 days, beginning approximately 45 min after the first occlusion stage. Sildenafil (3mg/kg, p.o.) was similarly administered for 15 days only. Histological examination was performed after behavioral testing. Chronic cerebral hypoperfusion caused persistent retrograde amnesia, which was reversed by cilostazol after both short-term and long-term treatment. This antiamnesic effect of cilostazol was sustained throughout the experiment, even after discontinuing treatment (15-day treatment group). This effect occurred in the absence of neuronal rescue. Sildenafil failed to prevent CCH-induced retrograde amnesia, but it reduced hippocampal cell death. Extending previous findings from this laboratory, we conclude that sildenafil does not afford memory recovery after CCH, despite its neuroprotective effect. In contrast, cilostazol abolished CCH-induced retrograde amnesia, an effect that may not depend on histological neuroprotection. The present data suggest that cilostazol but not sildenafil represents a potential strategy for the treatment of cognitive sequelae associated with CCH.
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Maringá, Paraná 87020-900, Brazil.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Godinho
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Maringá, Paraná 87020-900, Brazil.
authors.forename: Janaina Nicolau
authors.initials: JN
authors.lastname: de Oliveira
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Maringá, Paraná 87020-900, Brazil.
authors.forename: Emilene Dias Fiuza
authors.initials: ED
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Maringá, Paraná 87020-900, Brazil.
authors.forename: Gislene Gonçalves D
authors.initials: GG
authors.lastname: Zaghi
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Maringá, Paraná 87020-900, Brazil.
authors.forename: Cristiano Correia
authors.initials: CC
authors.lastname: Bacarin
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Maringá, Paraná 87020-900, Brazil.
authors.forename: Rúbia Maria Weffort
authors.initials: RM
authors.lastname: de Oliveira
authors.affiliation: Department of Pharmacology and Therapeutics, Health Science Center, State University of Maringá, Maringá, Paraná 87020-900, Brazil. Electronic address: hmilani@uem.br.
authors.forename: Humberto
authors.initials: H
authors.lastname: Milani
mesh_terms: D000375:Aging; D000648:Amnesia, Retrograde / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002340:Carotid Artery Diseases; D002343:Carotid Artery, Internal; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D000077407:Cilostazol; D004195:Disease Models, Animal; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D057567:Memory, Long-Term / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017208:Rats, Wistar; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D018697:Nootropic Agents; D013777:Tetrazoles; D000068677:Sildenafil Citrate; D000077407:Cilostazol
keywords: Chronic cerebral hypoperfusion; Cilostazol; Memory loss; Memory recovery; Middle-aged rat; Sildenafil