Research ReportsPositive effects of roflumilast on behavior, neuroinflammation, and white matter injury in mice with global cerebral ischemiaVilhena, Emanuella R.a; Bonato, Jéssica M.a; Schepers, Melissab,,c; Kunieda, Juliana K.C.a; Milani, Humbertoa; Vanmierlo, Timb,,c; Prickaerts, Josc; de Oliveira, Rúbia M.W.a Author Information aDepartment of Pharmacology and Therapeutics, State University of Maringá, Paraná, Brazil bNeuroimmune Connect and Repair Lab., Biomedical Research Institute, Hasselt University, Hasselt, Belgium cDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Received 12 November 2020 Accepted as revised 22 April 2021 Correspondence to Rúbia M.W. Oliveira, PhD, State University of Maringá, Av. Colombo, 5790, CEP 87020-900, Maringá, Paraná, Brazil, E-mail: [email protected] Behavioural Pharmacology: September 2021 - Volume 32 - Issue 6 - p 459-471 doi: 10.1097/FBP.0000000000000640 Buy Metrics Abstract Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro. Balb/c mice were subjected to bilateral common carotid artery occlusion (BCCAO) and tested during 21 days in multiple behavioral tasks to investigate the long-term effects of roflumilast on functional recovery. The effects of roflumilast were also investigated on hippocampal cell loss, white matter injury, and expression of neuroinflammatory markers. Roflumilast prevented cognitive and emotional deficits induced by BCCAO in mice. Roflumilast also prevented neurodegeneration and reduced the white matter damage in the brain of ischemic animals. Besides, roflumilast decreased Iba-1 (microglia marker) levels and increased Arginase-1 (Arg-1; microglia M2 phenotype marker) levels in the hippocampus of these mice. Likewise, roflumilast suppressed inducible nitric oxide synthase (microglia M1 phenotype marker) expression and increased Arg-1 levels in a primary mouse microglia culture. These findings support evidence that PDE4 inhibition by roflumilast might be beneficial in cerebral ischemic conditions. The neuroprotective effects of roflumilast appear to be mediated by a decrease in neuroinflammation. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.