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Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion.
Neuropharmacology. 2018 08; 138:360-370.N

Abstract

Chronic cerebral hypoperfusion (CCH) has been associated with aging-related vascular dementia, including Alzheimer's disease. It can be induced by the four-vessel occlusion/internal carotid artery (4VO/ICA) model in aged rats, resulting in persistent memory deficits, white matter injury, and significant neuronal loss in the hippocampus and cerebral cortex. The phosphodiesterase type 4 inhibitor (PDE4-I) roflumilast has been reported to have pro-cognitive effects in several behavioral paradigms. The present study evaluated the effects of repeated roflumilast treatment in aged rats that were subjected to CCH. After surgery, roflumilast (0.003 and 0.01 mg/kg) was administered intraperitoneally once per day for 29 days. Memory performance was assessed in the aversive radial maze (AvRM) 7, 14, and 21 days after CCH. The effects of roflumilast on hippocampal neurodegeneration and white matter injury were investigated using Nissl and Kluver-Barrera staining, respectively. Western blot and RT-qPCR were used to explore microglial polarization using M1 (Iba-1 and iNOS) and M2 (Arginase-1) markers. Chronic cerebral hypoperfusion caused persistent memory deficits, hippocampal neurodegeneration, and vacuolization and fiber disarrangement in white matter. Repeated roflumilast treatment restored CCH-induced cognitive impairments in aged rats but in the absence of the rescue of hippocampal neurons. Attenuation of white matter injury was detected in the optic tract in aged CCH rats that were treated with roflumilast. In vitro, roflumilast increased Arg-1 gene expression in myelin-laden primary microglia. The present data suggest that roflumilast might be useful for the treatment of cognitive sequelae associated with CCH.

Authors+Show Affiliations

Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900, Maringá, Paraná, Brazil.Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900, Maringá, Paraná, Brazil.Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Department of Immunology and Biochemistry, Biomedical Research Institute, Hasselt University, Hasselt, Belgium.Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900, Maringá, Paraná, Brazil.Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Department of Immunology and Biochemistry, Biomedical Research Institute, Hasselt University, Hasselt, Belgium.Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, CEP 87020-900, Maringá, Paraná, Brazil. Electronic address: rmmwoliveira@uem.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29933009

Citation

Santiago, Amanda, et al. "Roflumilast Promotes Memory Recovery and Attenuates White Matter Injury in Aged Rats Subjected to Chronic Cerebral Hypoperfusion." Neuropharmacology, vol. 138, 2018, pp. 360-370.
Santiago A, Soares LM, Schepers M, et al. Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion. Neuropharmacology. 2018;138:360-370.
Santiago, A., Soares, L. M., Schepers, M., Milani, H., Vanmierlo, T., Prickaerts, J., & Weffort de Oliveira, R. M. (2018). Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion. Neuropharmacology, 138, 360-370. https://doi.org/10.1016/j.neuropharm.2018.06.019
Santiago A, et al. Roflumilast Promotes Memory Recovery and Attenuates White Matter Injury in Aged Rats Subjected to Chronic Cerebral Hypoperfusion. Neuropharmacology. 2018;138:360-370. PubMed PMID: 29933009.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion. AU - Santiago,Amanda, AU - Soares,Lígia Mendes, AU - Schepers,Melissa, AU - Milani,Humberto, AU - Vanmierlo,Tim, AU - Prickaerts,Jos, AU - Weffort de Oliveira,Rúbia M, Y1 - 2018/06/19/ PY - 2017/08/21/received PY - 2018/04/24/revised PY - 2018/06/14/accepted PY - 2018/6/23/pubmed PY - 2019/2/14/medline PY - 2018/6/23/entrez KW - Chronic cerebral hypoperfusion KW - Memory KW - Phosphodiesterase inhibitor KW - Roflumilast SP - 360 EP - 370 JF - Neuropharmacology JO - Neuropharmacology VL - 138 N2 - Chronic cerebral hypoperfusion (CCH) has been associated with aging-related vascular dementia, including Alzheimer's disease. It can be induced by the four-vessel occlusion/internal carotid artery (4VO/ICA) model in aged rats, resulting in persistent memory deficits, white matter injury, and significant neuronal loss in the hippocampus and cerebral cortex. The phosphodiesterase type 4 inhibitor (PDE4-I) roflumilast has been reported to have pro-cognitive effects in several behavioral paradigms. The present study evaluated the effects of repeated roflumilast treatment in aged rats that were subjected to CCH. After surgery, roflumilast (0.003 and 0.01 mg/kg) was administered intraperitoneally once per day for 29 days. Memory performance was assessed in the aversive radial maze (AvRM) 7, 14, and 21 days after CCH. The effects of roflumilast on hippocampal neurodegeneration and white matter injury were investigated using Nissl and Kluver-Barrera staining, respectively. Western blot and RT-qPCR were used to explore microglial polarization using M1 (Iba-1 and iNOS) and M2 (Arginase-1) markers. Chronic cerebral hypoperfusion caused persistent memory deficits, hippocampal neurodegeneration, and vacuolization and fiber disarrangement in white matter. Repeated roflumilast treatment restored CCH-induced cognitive impairments in aged rats but in the absence of the rescue of hippocampal neurons. Attenuation of white matter injury was detected in the optic tract in aged CCH rats that were treated with roflumilast. In vitro, roflumilast increased Arg-1 gene expression in myelin-laden primary microglia. The present data suggest that roflumilast might be useful for the treatment of cognitive sequelae associated with CCH. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/29933009/Roflumilast_promotes_memory_recovery_and_attenuates_white_matter_injury_in_aged_rats_subjected_to_chronic_cerebral_hypoperfusion_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(18)30300-9 DB - PRIME DP - Unbound Medicine ER -