Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Roflumilast Protects against Neuroinflammatory Alterations in Brain Tissues of Lipopolysaccharide-induced Mice Model

Author(s): Nisha Kumari, Shivam Kumar Pandey, Mohammed Zunaid Akhtar, Mangaldeep Dey, Avtar Singh Gautam, Anjuman Nanda, Aman Tiwari and Rakesh Kumar Singh*

Volume 20, Issue 1, 2023

Published on: 19 May, 2023

Page: [38 - 47] Pages: 10

DOI: 10.2174/1567205020666230503141817

Price: $65

Abstract

Background: Microglial overactivation promotes the production of various second messengers and inflammatory markers in brain tissue, resulting in neuroinflammation and neurodegeneration, which may lead to cognitive decline. The cyclic nucleotides are one of the important second messengers involved in the regulation of neurogenesis, synaptic plasticity, and cognition. The levels of these cyclic nucleotides are maintained by phosphodiesterase enzyme isoforms, particularly PDE4B, in the brain. An imbalance between PDE4B levels and cyclic nucleotides may lead to aggravating neuroinflammation.

Methods: Lipopolysaccharides (LPS) were administered intraperitoneally on alternate days for 7 days at a dose of 500 μg/kg in mice, which triggered systemic inflammation. This may lead to the activation of glial cells and may activate oxidative stress and neuroinflammatory markers in brain tissue. Furthermore, oral administration of roflumilast (0.1, 0.2, and 0.4 mg/kg) in this model ameliorated oxidative stress markers, neuroinflammation and improved neurobehavioral parameters in these animals.

Results: The detrimental effect of LPS increased oxidative stress, AChE enzyme levels, and decreased catalase levels in brain tissues, along with memory impairment in animals. Moreover, it also enhanced the activity and expression of the PDE4B enzyme, resulting in a decline in cyclic nucleotide levels. Furthermore, treatment with roflumilast improved the cognitive decline, decreased AChE enzyme level, and increased the catalase enzyme level. Roflumilast also reduced the PDE4B expression in a dose-dependent manner, which LPS up-regulated.

Conclusion: Roflumilast has shown an anti-neuroinflammatory effect and reversed the cognitive decline in LPS-induced mice model.

« Previous Next »
[1]
Kaur N, Chugh H, Sakharkar MK, Dhawan U, Chidambaram SB, Chandra R. Neuroinflammation mechanisms and phytotherapeutic intervention: A systematic review. ACS Chem Neurosci 2020; 11(22): 3707-31.
[http://dx.doi.org/10.1021/acschemneuro.0c00427] [PMID: 33146995]
[2]
Ransohoff RM, Perry VH. Microglial physiology: Unique stimuli, specialized responses. Annu Rev Immunol 2009; 27(1): 119-45.
[http://dx.doi.org/10.1146/annurev.immunol.021908.132528] [PMID: 19302036]
[3]
Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: A general review. Int J Neurosci 2017; 127(7): 624-33.
[http://dx.doi.org/10.1080/00207454.2016.1212854] [PMID: 27412492]
[4]
Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: The role and consequences. Neurosci Res 2014; 79: 1-12.
[http://dx.doi.org/10.1016/j.neures.2013.10.004] [PMID: 24144733]
[5]
Swaroop S, Sengupta N, Suryawanshi AR, Adlakha YK, Basu A. HSP60 plays a regulatory role in IL-1β-induced microglial inflammation via TLR4-p38 MAPK axis. J Neuroinflammation 2016; 13(1): 27.
[http://dx.doi.org/10.1186/s12974-016-0486-x] [PMID: 26838598]
[6]
Jaeger LB, Dohgu S, Sultana R, et al. Lipopolysaccharide alters the blood–brain barrier transport of amyloid β protein: A mechanism for inflammation in the progression of Alzheimer’s disease. Brain Behav Immun 2009; 23(4): 507-17.
[http://dx.doi.org/10.1016/j.bbi.2009.01.017] [PMID: 19486646]
[7]
Zakaria R, Wan Yaacob WMH, Othman Z, Long I, Ahmad AH, Al-Rahbi B. Lipopolysaccharide-induced memory impairment in rats: A model of Alzheimer’s disease. Physiol Res 2017; 66(4): 553-65.
[http://dx.doi.org/10.33549/physiolres.933480] [PMID: 28406691]
[8]
Miklossy J. Chronic inflammation and amyloidogenesis in Alzheimer’s disease -- role of Spirochetes. J Alzheimers Dis 2008; 13(4): 381-91.
[http://dx.doi.org/10.3233/JAD-2008-13404] [PMID: 18487847]
[9]
Nabavi SM, Talarek S, Listos J, Nabavi SF, Devi KP, Roberto de Oliveira M, et al. Phosphodiesterase inhibitors say NO to Alzheimer’s disease. Food Chem Toxicol 2019; 134: 110822.
[http://dx.doi.org/10.1016/j.fct.2019.110822]
[10]
Kelly MP. Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain. Cell Signal 2018; 42: 281-91.
[http://dx.doi.org/10.1016/j.cellsig.2017.11.004] [PMID: 29175000]
[11]
Bhat A, Ray B, Mahalakshmi AM, et al. Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders. Pharmacol Res 2020; 160: 105078.
[http://dx.doi.org/10.1016/j.phrs.2020.105078] [PMID: 32673703]
[12]
Wu Y, Li Z, Huang YY, Wu D, Luo HB. Novel phosphodiesterase inhibitors for cognitive improvement in Alzheimer’s Disease. J Med Chem 2018; 61(13): 5467-83.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01370] [PMID: 29363967]
[13]
Prickaerts J, Heckman PRA, Blokland A. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease. Expert Opin Investig Drugs 2017; 26(9): 1033-48.
[http://dx.doi.org/10.1080/13543784.2017.1364360] [PMID: 28772081]
[14]
Wallace DA, Johnston LA, Huston E, et al. Identification and characterization of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cAMP phosphodiesterase gene. Mol Pharmacol 2005; 67(6): 1920-34.
[http://dx.doi.org/10.1124/mol.104.009423] [PMID: 15738310]
[15]
Wang ZZ, Zhang Y, Zhang HT, Li YF. Phosphodiesterase: An interface connecting cognitive deficits to neuropsychiatric and neurodegenerative diseases. Curr Pharm Des 2014; 21(3): 303-16.
[http://dx.doi.org/10.2174/1381612820666140826115559] [PMID: 25159069]
[16]
Ahmad F, Murata T, Shimizu K, Degerman E, Maurice D, Manganiello V. Cyclic Nucleotide Phosphodiesterases: Important signaling modulators and therapeutic targets. Oral Dis 2015; 21(1): e25-50.
[http://dx.doi.org/10.1111/odi.12275] [PMID: 25056711]
[17]
Huang H, Hong Q, Tan H, Xiao C, Gao Y. Ferulic acid prevents LPS-induced up-regulation of PDE4B and stimulates the cAMP/CREB signaling pathway in PC12 cells. Acta Pharmacol Sin 2016; 37(12): 1543-54.
[http://dx.doi.org/10.1038/aps.2016.88] [PMID: 27665850]
[18]
Tibbo AJ, Baillie GS. Phosphodiesterase 4B: Master regulator of brain signaling. Cells 2020; 9(5): 1254.
[http://dx.doi.org/10.3390/cells9051254] [PMID: 32438615]
[19]
Zhang X, Chen Y, Fan L, et al. Pharmacological mechanism of roflumilast in the treatment of asthma–COPD overlap. Drug Des Devel Ther 2018; 12: 2371-9.
[http://dx.doi.org/10.2147/DDDT.S165161] [PMID: 30122895]
[20]
Lueptow LM. Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp 2017; 2017(126): 55718.
[21]
Antunes M, Biala G. The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn Process 2012; 13(2): 93-110.
[http://dx.doi.org/10.1007/s10339-011-0430-z] [PMID: 22160349]
[22]
Silvers JM, Harrod SB, Mactutus CF, Booze RM. Automation of the novel object recognition task for use in adolescent rats. J Neurosci Methods 2007; 166(1): 99-103.
[http://dx.doi.org/10.1016/j.jneumeth.2007.06.032] [PMID: 17719091]
[23]
Feng H, Wang C, He W, et al. Roflumilast ameliorates cognitive impairment in APP/PS1 mice via cAMP/CREB/BDNF signaling and anti-neuroinflammatory effects. Metab Brain Dis 2019; 34(2): 583-91.
[http://dx.doi.org/10.1007/s11011-018-0374-4] [PMID: 30610438]
[24]
Vorhees CV, Williams MT. Morris water maze: Procedures for assessing spatial and related forms of learning and memory. Nat Protoc 2006; 1(2): 848-58.
[http://dx.doi.org/10.1038/nprot.2006.116] [PMID: 17406317]
[25]
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95(2): 351-8.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[26]
Giustarini D, Rossi R, Milzani A, Dalle-Donne I. Nitrite and nitrate measurement by Griess reagent in human plasma: Evaluation of interferences and standardization. Methods Enzymol 2008; 440: 361-80.
[http://dx.doi.org/10.1016/S0076-6879(07)00823-3] [PMID: 18423230]
[27]
Ellman GL, Courtney KD, Andres V Jr, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7(2): 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[28]
Góth L. A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 1991; 196(2-3): 143-51.
[http://dx.doi.org/10.1016/0009-8981(91)90067-M]
[29]
Tyagi E, Agrawal R, Nath C, Shukla R. Effect of anti-dementia drugs on LPS induced neuroinflammation in mice. Life Sci 2007; 80(21): 1977-83.
[http://dx.doi.org/10.1016/j.lfs.2007.02.039] [PMID: 17395211]
[30]
Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21(3): 383-421.
[http://dx.doi.org/10.1016/S0197-4580(00)00124-X] [PMID: 10858586]
[31]
O’Shea JJ, Ma A, Lipsky P. Cytokines and autoimmunity. Nat Rev Immunol 2002; 2(1): 37-45.
[http://dx.doi.org/10.1038/nri702] [PMID: 11905836]
[32]
Blokland A, Heckman P, Vanmierlo T, Schreiber R, Paes D, Prickaerts J. Phosphodiesterase type 4 inhibition in CNS diseases. Trends Pharmacol Sci 2019; 40(12): 971-85.
[http://dx.doi.org/10.1016/j.tips.2019.10.006] [PMID: 31704172]
[33]
Tyagi E, Agrawal R, Nath C, Shukla R. Influence of LPS-induced neuroinflammation on acetylcholinesterase activity in rat brain. J Neuroimmunol 2008; 205(1-2): 51-6.
[http://dx.doi.org/10.1016/j.jneuroim.2008.08.015] [PMID: 18838174]
[34]
Bhat A, Tan V, Heng B, et al. Roflumilast, a cAMP-specific phosphodiesterase-4 inhibitor, reduces oxidative stress and improves synapse functions in human cortical neurons exposed to the excitotoxin quinolinic acid. ACS Chem Neurosci 2020; 11(24): 4405-15.
[http://dx.doi.org/10.1021/acschemneuro.0c00636] [PMID: 33261317]
[35]
Waltereit R, Weller M. Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 2003; 27(1): 99-106.
[http://dx.doi.org/10.1385/MN:27:1:99] [PMID: 12668903]
[36]
Pearse DD, Hughes ZA. PDE4B as a microglia target to reduce neuroinflammation. Glia 2016; 64(10): 1698-709.
[http://dx.doi.org/10.1002/glia.22986] [PMID: 27038323]
[37]
Mosenden R, Taskén K. Cyclic AMP-mediated immune regulation — Overview of mechanisms of action in T cells. Cell Signal 2011; 23(6): 1009-16.
[http://dx.doi.org/10.1016/j.cellsig.2010.11.018] [PMID: 21130867]
[38]
Jin SLC, Conti M. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-α responses. Proc Natl Acad Sci USA 2002; 99(11): 7628-33.
[http://dx.doi.org/10.1073/pnas.122041599] [PMID: 12032334]
[39]
Teixeira MM, Gristwood RW, Cooper N, Hellewell PG. Phosphodiesterase (PDE)4 inhibitors: Anti-inflammatory drugs of the future? Trends Pharmacol Sci 1997; 18(5): 164-70.
[http://dx.doi.org/10.1016/S0165-6147(97)01049-3] [PMID: 9184477]
[40]
Witwicka H, Kobiałka M, Siednienko J, Mitkiewicz M, Gorczyca WA. Expression and activity of cGMP-dependent phosphodiesterases is up-regulated by lipopolysaccharide (LPS) in rat peritoneal macrophages. Biochim Biophys Acta Mol Cell Res 2007; 1773(2): 209-18.
[http://dx.doi.org/10.1016/j.bbamcr.2006.10.008] [PMID: 17141339]
[41]
Francis SH, Turko IV, Corbin JD. Cyclic nucleotide phosphodiesterases: Relating structure and function. Prog Nucleic Acid Res Mol Biol 2001; 65: 1-52.
[PMID: 11008484]
[42]
Houslay MD. PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol Biol 2001; 69: 249-315.
[http://dx.doi.org/10.1016/S0079-6603(01)69049-4] [PMID: 11550796]
[43]
Zhao J, Bi W, Xiao S, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 2019; 9(1): 5790.
[http://dx.doi.org/10.1038/s41598-019-42286-8] [PMID: 30962497]
[44]
Batista CRA, Gomes GF, Candelario-Jalil E, Fiebich BL, de Oliveira ACP. Lipopolysaccharide-induced neuroinflammation as a bridge to understand neurodegeneration. Int J Mol Sci 2019; 20(9): 2293.
[http://dx.doi.org/10.3390/ijms20092293] [PMID: 31075861]
[45]
Lopez-Rodriguez AB, Hennessy E, Murray CL, et al. Acute systemic inflammation exacerbates neuroinflammation in Alzheimer’s disease: IL‐1β drives amplified responses in primed astrocytes and neuronal network dysfunction. Alzheimers Dement 2021; 17(10): 1735-55.
[http://dx.doi.org/10.1002/alz.12341] [PMID: 34080771]
[46]
Qin L, Wu X, Block ML, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 2007; 55(5): 453-62.
[http://dx.doi.org/10.1002/glia.20467] [PMID: 17203472]
[47]
Jabaris SGSL, Sumathy H, Kumar RS, Narayanan S, Thanikachalam S, Babu CS. Effects of rolipram and roflumilast, phosphodiesterase-4 inhibitors, on hypertension-induced defects in memory function in rats. Eur J Pharmacol 2015; 746: 138-47.
[http://dx.doi.org/10.1016/j.ejphar.2014.10.039] [PMID: 25446433]
[48]
Bhat A, Bishir M, Pandi-Perumal SR, Chang SL, Chidambaram SB. Roflumilast, a phosphodiesterase-4 inhibitor, ameliorates sleep deprivation-induced cognitive dysfunction in C57BL/6J Mice. ACS Chem Neurosci 2022; 13(13): 1938-47.
[http://dx.doi.org/10.1021/acschemneuro.2c00127] [PMID: 35736514]
[49]
Kwak HJ, Song JS, Heo JY, Yang SD, Nam JY, Cheon HG. Roflumilast inhibits lipopolysaccharide-induced inflammatory mediators via suppression of nuclear factor-kappaB, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase activation. J Pharmacol Exp Ther 2005; 315(3): 1188-95.
[http://dx.doi.org/10.1124/jpet.105.092056] [PMID: 16126838]
[50]
Al-Harbi NO, Imam F, Al-Harbi MM, et al. Protective effect of apremilast against LPS-induced acute lung injury via modulation of oxidative stress and inflammation. Saudi J Biol Sci 2022; 29(5): 3414-24.
[http://dx.doi.org/10.1016/j.sjbs.2022.02.023] [PMID: 35844406]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy