title: Rolipram improves cognition, reduces anxiety- and despair-like behaviors and impacts hippocampal neuroplasticity after transient global cerebral ischemia.
abstract: Cognitive impairment, anxiety- and depressive-like symptoms are well recognized outcome of cerebral ischemia in clinical and preclinical settings. Rolipram, a phosphodiesterase-4 (PDE-4) inhibitor, improves cognition and produces anxiolytic- and antidepressant-like effects in rodents. Rolipram also exerts anti-inflammatory effects and enhances survival of newborn hippocampal neurons in mice subjected to transient global cerebral ischemia. Here, we evaluated the effects of chronic rolipram treatment in mice subjected to transient global brain ischemia. C56B6/7 mice were subjected to bilateral common carotid artery occlusion (BCCAO) and were then tested in a multi-tiered behavioral battery including the elevated zero maze (EZM), open field (OF), object location test (OLT), and forced swim test (FST). We also investigated the effects of rolipram on hippocampal neurodegeneration and the expression of the neuronal plasticity markers doublecortin (DCX) and microtubule-associated protein (MAP-2). Ischemic mice exhibited memory deficits OLT, higher levels of anxiety EZM and behavioral despair FST. BCCAO caused neuronal loss in the CA3 hippocampal subfield and basolateral amygdala (BLA). In the hippocampus of BCCAO mice, a disrupted neuronal plasticity was evidenced by decreased DCX expression. Chronic treatment with rolipram attenuated the behavioral effects of BCCAO. Rolipram also decreased neurodegeneration in the CA3 while it increased dendritic arborization of DCX-immunoreactive (DCX-IR) neurons and microtubule associate MAP-2 expression in the hippocampus of BCCAO mice. These data suggest that chronic inhibition of PDE-4 can be a useful therapeutic strategy to improve the emotional and cognitive outcomes of transient global cerebral ischemia.
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900 Maringá,, Paraná, Brazil.
authors.forename: Lígia Mendes
authors.initials: LM
authors.lastname: Soares
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Jochen
authors.initials: J
authors.lastname: De Vry
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Harry W M
authors.initials: HWM
authors.lastname: Steinbusch
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900 Maringá,, Paraná, Brazil.
authors.forename: Humberto
authors.initials: H
authors.lastname: Milani
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Prickaerts
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900 Maringá,, Paraná, Brazil. Electronic address: rubiaweffort@gmail.com.
authors.forename: Rúbia M
authors.initials: RM
authors.lastname: Weffort de Oliveira
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000517:prevention & control*; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000209:etiology / Q000517:prevention & control*; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage*; D020889:Rolipram / Q000008:administration & dosage*; D065852:Spatial Memory / Q000187:drug effects
chemical_list: C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D058988:Phosphodiesterase 4 Inhibitors; D020889:Rolipram
keywords: bilateral common carotid artery occlusion; neuroprotection; rolipram