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Gholami A, Hosseini M, Boskabady M H, Gharib M, Gholamnezhad Z. Memantine, A NMDA Receptor Inhibitor Attenuate Lipopolysaccharide-Induced Lung Inflammation and Oxidative Damage in Mice. rbmb.net 2025; 14 (1) :19-28
URL: http://rbmb.net/article-1-1543-en.html
URL: http://rbmb.net/article-1-1543-en.html
Atlas Gholami 
, Mahmoud Hosseini , Mohammad Hossein Boskabady , Masoumeh Gharib , Zahra Gholamnezhad *
, Mahmoud Hosseini , Mohammad Hossein Boskabady , Masoumeh Gharib , Zahra Gholamnezhad *
Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran & Applied Biomedical Research Center, Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Abstract: (901 Views)
Background: The anti-oxidative and anti-inflammatory effect of memantine (an N-methyl-D-aspartate receptor inhibitor) has been shown. Therefore, the present study aimed to evaluate the preventive effects of memantine against lipopolysaccharide (LPS)-induced sub-acute lung injury in mice.
Methods: Male C57BL/6 mice (n=30) were randomized in five groups as follows: (1) control (saline containing 10% DMSO); (2) LPS (5 mg/kg, intraperitoneally); and (3, 4, and 5) LPS 5 mg/kg + memantine 5, 10, 20 mg/kg, respectively. Memantine (dissolved in 10% DMSO) was administrated orally three days before the LPS injection and continued for three days after injury induction. Finally, the levels of markers of oxidative stress, malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD), interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and nitric oxide (NO), were measured and histopathological changes in the lung tissue were assessed.
Results: Lipopolysaccharide (LPS) administration increased the TNF-α, IL-1β, NO, and MDA, levels, while decreasing the lung tissues activity of CAT (P< 0.05) and SOD (P< 0.001) and caused lung pathological damages. Memantine 20 mg/kg, alleviated LPS-induced injury score, reduced the lung tissue levels of TNF-α, IL-1β, MDA, and NO, and restored CAT activity (P< 0.05, P< 0.01).
Conclusion: LPS-triggered elevation of lung injury markers including histopathological changes, inflammatory cytokines, and oxidative damage. All pathological changes were suppressed by memantine.
Methods: Male C57BL/6 mice (n=30) were randomized in five groups as follows: (1) control (saline containing 10% DMSO); (2) LPS (5 mg/kg, intraperitoneally); and (3, 4, and 5) LPS 5 mg/kg + memantine 5, 10, 20 mg/kg, respectively. Memantine (dissolved in 10% DMSO) was administrated orally three days before the LPS injection and continued for three days after injury induction. Finally, the levels of markers of oxidative stress, malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD), interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and nitric oxide (NO), were measured and histopathological changes in the lung tissue were assessed.
Results: Lipopolysaccharide (LPS) administration increased the TNF-α, IL-1β, NO, and MDA, levels, while decreasing the lung tissues activity of CAT (P< 0.05) and SOD (P< 0.001) and caused lung pathological damages. Memantine 20 mg/kg, alleviated LPS-induced injury score, reduced the lung tissue levels of TNF-α, IL-1β, MDA, and NO, and restored CAT activity (P< 0.05, P< 0.01).
Conclusion: LPS-triggered elevation of lung injury markers including histopathological changes, inflammatory cytokines, and oxidative damage. All pathological changes were suppressed by memantine.
Type of Article: Original Article |
Subject:
Immunology
Received: 2024/12/28 | Accepted: 2025/07/12 | Published: 2025/12/9
Received: 2024/12/28 | Accepted: 2025/07/12 | Published: 2025/12/9
References
1. Lee IT, Yang CM. Inflammatory signalings involved in airway and pulmonary diseases. Mediators Inflamm. 2013;2013:791231. [DOI:10.1155/2013/791231] [PMID] []
2. Sul OJ, Ra SW. Quercetin Prevents LPS-Induced Oxidative Stress and Inflammation by Modulating NOX2/ROS/NF-kB in Lung Epithelial Cells. Molecules. 2021;26(22):6949. [DOI:10.3390/molecules26226949] [PMID] []
3. Ware LB. Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med. 2006;27(4):337-49. [DOI:10.1055/s-2006-948288] [PMID]
4. Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5(1):18. [DOI:10.1038/s41572-019-0069-0] [PMID] []
5. Kumar V. Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury. Front Immunol. 2020;11:1722. [DOI:10.3389/fimmu.2020.01722] [PMID] []
6. Domscheit H, Hegeman MA, Carvalho N, Spieth PM. Molecular Dynamics of Lipopolysaccharide-Induced Lung Injury in Rodents. Front Physiol. 2020;11:36. [DOI:10.3389/fphys.2020.00036] [PMID] []
7. Zhang Z, Luo Z, Bi A, Yang W, An W, Dong X, Chen R, Yang S, Tang H, Han X, Luo L. Compound edaravone alleviates lipopolysaccharide (LPS)-induced acute lung injury in mice. Eur J Pharmacol. 2017;811:1-11.
https://doi.org/10.1016/j.ejphar.2017.05.047
https://doi.org/10.1016/j.ejphar.2017.01.008 [DOI:10.1016/j.ejphar.2017.04.006]
8. Ding H, Ci X, Cheng H, Yu Q, Li D. Chicoric acid alleviates lipopolysaccharide-induced acute lung injury in mice through anti-inflammatory and anti-oxidant activities. Int Immunopharmacol. 2019;66:169-176. [DOI:10.1016/j.intimp.2018.10.042] [PMID]
9. Amin Mohedin J, Rezaiemanesh A, Asadi S, Haddadi M, Abdul Ahmed B, Gorgin Karaji A, Salari F. Resolvin D1 (Rvd1) Attenuates In Vitro LPS-Stimulated Inflammation Through Downregulation of miR-155, miR -146, miR -148 and Krupple Like Factor 5. Rep Biochem Mol Biol. 2024;12(4):566-574. [DOI:10.61186/rbmb.12.4.566] [PMID] []
10. Dickman KG, Youssef JG, Mathew SM, Said SI. Ionotropic glutamate receptors in lungs and airways: molecular basis for glutamate toxicity. Am J Respir Cell Mol Biol. 2004;30(2):139-44. [DOI:10.1165/rcmb.2003-0177OC] [PMID]
11. Cheng Q, Fang L, Feng D, Tang S, Yue S, Huang Y, et al. Memantine ameliorates pulmonary inflammation in a mice model of COPD induced by cigarette smoke combined with LPS. Biomed Pharmacother. 2019;109:2005-13. [DOI:10.1016/j.biopha.2018.11.002] [PMID]
12. Kritis AA, Stamoula EG, Paniskaki KA, Vavilis TD. Researching glutamate - induced cytotoxicity in different cell lines: a comparative/collective analysis/study. Front Cell Neurosci. 2015;9:91. [DOI:10.3389/fncel.2015.00091] [PMID] []
13. Ding H, Yang J, Chen L, Li Y, Jiang G, Fan J. Memantine Alleviates Acute Lung Injury Via Inhibiting Macrophage Pyroptosis. Shock. 2021;56(6):1040-1048. [DOI:10.1097/SHK.0000000000001790] [PMID]
14. Hasanagic S, Serdarevic F. Potential role of memantine in the prevention and treatment of COVID-19: its antagonism of nicotinic acetylcholine receptors and beyond. Eur Respir J. 2020;56(2):2001610. [DOI:10.1183/13993003.01610-2020] [PMID] []
15. Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Anti-Inflammatory Effects of Amantadine and Memantine: Possible Therapeutics for the Treatment of Covid-19? J Pers Med. 2020;10(4):217. [DOI:10.3390/jpm10040217] [PMID] []
16. 16.Alomar SY, Gheit REAE, Enan ET, El-Bayoumi KS, Shoaeir MZ, Elkazaz AY, et al. Novel Mechanism for Memantine in Attenuating Diabetic Neuropathic Pain in Mice via Downregulating the Spinal HMGB1/TRL4/NF-kB Inflammatory Axis. Pharmaceuticals (Basel). 2021;14(4):307. [DOI:10.3390/ph14040307] [PMID] []
17. Bardaghi Z, Rajabian A, Beheshti F, Arabi MH, Hosseini M, Salmani H. Memantine, an NMDA receptor antagonist, protected the brain against the long-term consequences of sepsis in mice. Life Sci. 2023;323:121695. [DOI:10.1016/j.lfs.2023.121695] [PMID]
18. .Severgnini M, Takahashi S, Tu P, Perides G, Homer RJ, Jhung JW, Bhavsar D, Cochran BH, Simon AR. Inhibition of the Src and Jak kinases protects against lipopolysaccharide-induced acute lung injury. Am J Respir Crit Care Med. 2005;171(8):858-67. [DOI:10.1164/rccm.200407-981OC] [PMID]
19. Gholamnezhad Z, Rouki V, Rezaee R, Boskabady MH. Medicago sativa ameliorated cyclophosphamide-induced thrombocytopenia and oxidative stress in rats. Toxin Rev. 2023;42(2):527-36. [DOI:10.1080/15569543.2023.2175870]
20. Madesh M, Balasubramanian KA. A microtiter plate assay for superoxide using MTT reduction method. Indian J Biochem Biophys. 1997;34(6):535-9.
21. .Thomas RC, Bath MF, Stover CM, Lambert DG, Thompson JP. Exploring LPS-induced sepsis in rats and mice as a model to study potential protective effects of the nociceptin/orphanin FQ system. Peptides. 2014;61:56-60. [DOI:10.1016/j.peptides.2014.08.009] [PMID]
22. Anderson ST, Commins S, Moynagh PN, Coogan AN. Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse. Brain Behav Immun. 2015;43:98-109. [DOI:10.1016/j.bbi.2014.07.007] [PMID]
23. Gholamnezhad Z, Fatehi Hassanabad Z. Effects of lipopolysaccharide-induced septic shock on rat isolated kidney, possible role of nitric oxide and protein kinase C pathways. Iran J Basic Med Sci. 2018;21(10):1073-1078.
24. Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med. 2012;40(3):754-61. [DOI:10.1097/CCM.0b013e318232db65] [PMID]
25. Rezaei Moghaddam H, Sahranavard T, Rezaee R, Boskabady MH, Gholamnezhad Z. Moderate-intensity Exercise Alleviates Rat's Systemic Inflammation Induced by Repeated Exposure to Lipopolysaccharide. Iran J Allergy Asthma Immunol. 2024;23(3):311-320. [DOI:10.18502/ijaai.v23i3.15640] [PMID]
26. Kutumova EO, Akberdin IR, Egorova VS, Kolesova EP, Parodi A, Pokrovsky VS, et al. Physiologically based pharmacokinetic model for predicting the biodistribution of albumin nanoparticles after induction and recovery from acute lung injury. Heliyon. 2024;10(10):e30962. [DOI:10.1016/j.heliyon.2024.e30962] [PMID] []
27. Gong H, Chen Y, Chen M, Li J, Zhang H, Yan S, Lv C. Advanced development and mechanism of sepsis-related acute respiratory distress syndrome. Front Med (Lausanne). 2022;9:1043859. [DOI:10.3389/fmed.2022.1043859] [PMID] []
28. Aldhalmi AK, Al-Athari AJH, Makki Al-Hindy HA. Association of Tumor Necrosis Factor-α and Myeloperoxidase enzyme with Severe Asthma: A comparative study. Rep Biochem Mol Biol. 2022;11(2):238-245. [DOI:10.61186/rbmb.11.2.238] [PMID] []
29. Chang YC, Tsai MH, Sheu WH, Hsieh SC, Chiang AN. The therapeutic potential and mechanisms of action of quercetin in relation to lipopolysaccharide-induced sepsis in vitro and in vivo. PLoS One. 2013;8(11):e80744. [DOI:10.1371/journal.pone.0080744] [PMID] []
30. Okazaki S, Tachibana Y, Koga-Ogawa Y, Takeshita K. Redox evaluation in sepsis model mice by the in vivo ESR technique using acyl-protected hydroxylamine. Free Radic Biol Med. 2014;68:72-9. [DOI:10.1016/j.freeradbiomed.2013.11.011] [PMID]
31. da Cunha AA, Nunes FB, Lunardelli A, Pauli V, Amaral RH, de Oliveira LM, et al. Treatment with N-methyl-D-aspartate receptor antagonist (MK-801) protects against oxidative stress in lipopolysaccharide-induced acute lung injury in the rat. Int Immunopharmacol. 2011;11(6):706-11. [DOI:10.1016/j.intimp.2011.01.016] [PMID]
32. Strapkova A, Antosova M. Glutamate receptors and the airways hyperreactivity. Gen Physiol Biophys. 2012;31(1):93-100. [DOI:10.4149/gpb_2012_012] [PMID]
33. Kobayashi S, Kuwata K, Sugimoto T, Igarashi K, Osaki M, Okada F, et al. Enhanced expression of cystine/glutamate transporter in the lung caused by the oxidative-stress-inducing agent paraquat. Free Radic Biol Med. 2012;53(12):2197-203. [DOI:10.1016/j.freeradbiomed.2012.09.040] [PMID]
34. Piani D, Fontana A. Involvement of the cystine transport system xc- in the macrophage-induced glutamate-dependent cytotoxicity to neurons. J Immunol. 1994;152(7):3578-85. [DOI:10.4049/jimmunol.152.7.3578] [PMID]
35. Vandenberg RJ, Ryan RM. Mechanisms of glutamate transport. Physiol Rev. 2013;93(4):1621-57. [DOI:10.1152/physrev.00007.2013] [PMID]
36. Li Y, Liu Y, Peng X, Liu W, Zhao F, Feng D, Han J, et al. NMDA Receptor Antagonist Attenuates Bleomycin-Induced Acute Lung Injury. PLoS One. 2015;10(5):e0125873. [DOI:10.1371/journal.pone.0125873] [PMID] []
37. Shang LH, Luo ZQ, Deng XD, Wang MJ, Huang FR, Feng DD, Yue SJ. Expression of N-methyl-D-aspartate receptor and its effect on nitric oxide production of rat alveolar macrophages. Nitric Oxide. 2010;23(4):327-31. [DOI:10.1016/j.niox.2010.09.004] [PMID]
38. Bakaeva Z, Lizunova N, Tarzhanov I, Boyarkin D, Petrichuk S, Pinelis V, et al. Lipopolysaccharide From E. coli Increases Glutamate-Induced Disturbances of Calcium Homeostasis, the Functional State of Mitochondria, and the Death of Cultured Cortical Neurons. Front Mol Neurosci. 2022;14:811171. [DOI:10.3389/fnmol.2021.811171] [PMID] []
39. Bai W, Zhu WL, Ning YL, Li P, Zhao Y, Yang N, et al. Dramatic increases in blood glutamate concentrations are closely related to traumatic brain injury-induced acute lung injury. Sci Rep. 2017;7(1):5380. [DOI:10.1038/s41598-017-05574-9] [PMID] []
40. Costa BM. NMDA receptor modulation and severe acute respiratory syndrome treatment. F1000Res. 2021 Oct 18;10:Chem Inf Sci-1060. [DOI:10.12688/f1000research.73897.1] [PMID] []
41. Hu H, Jiang H, Zhang K, Zhang Z, Wang Y, Yi P, et al. Memantine nitrate MN-08 suppresses NLRP3 inflammasome activation to protect against sepsis-induced acute lung injury in mice. Biomed Pharmacother. 2022;156:113804. [DOI:10.1016/j.biopha.2022.113804] [PMID]
42. Mashkina AP, Cizkova D, Vanicky I, Boldyrev AA. NMDA receptors are expressed in lymphocytes activated both in vitro and in vivo. Cell Mol Neurobiol. 2010;30(6):901-7. [DOI:10.1007/s10571-010-9519-7] [PMID] []
43. Hamasato EK, Ligeiro de Oliveira AP, Lino-dos-Santos-Franco A, Ribeiro A, Ferraz de Paula V, Peron JP, et al. Effects of MK-801 and amphetamine treatments on allergic lung inflammatory response in mice. Int Immunopharmacol. 2013;16(4):436-43 [DOI:10.1016/j.intimp.2013.04.019] [PMID]
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