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The Effect of Nebivolol on Acute Brain Damage in a Rat Model of Lps-Induced Inflammation

Year 2025, Volume: 32

Abstract

Objective: This research seeks to determine whether nebivolol (NEB) can prevent brain damage caused by lipopolysaccharide (LPS).
Material and method: The thirty-two female Wistar Albino rats were divided into four groups, each containing eight rats: LPS (5mg/kg single dose i.p.), Control, LPS+NEB, and NEB (1 ml of 10 kg mg/kg given by oral gavage every day for three days). In brain tissues, the following parameters were measured: tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor A (VEGFA), caspase-3 (Cas-3), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI).
Results: In the LPS group, there was an increase in the levels of TOS, VEGFA, Cas-3, and TNF-α. NEB therapy markedly reduced TOS, VEGFA, TNF-α, and Cas-3 levels. In both the control and NEB groups, histopathological analysis of the brain, hippocampus, and cerebellum demonstrated normal tissue architecture. In the LPS group, there were mild to moderate hemorrhages and severe hyperemia in the meningeal and parenchymal arteries of the brain and cerebellum. The LPS + NEB group’s histopathology results were significantly ameliorated by NEB treatment.
Conclusion: NEB treatments anti-inflammatory, anti-apoptotic, and antioxidant characteristics helped mitigate the brain damage caused by LPS. NEB may help to reduce the severity of LPS-induced damage.

Project Number

This study was supported by Suleyman Demirel University Scientific Research Projects Coordination Unit (project code TSG-2022-8783).

References

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  • 2. Wang X, Rousset CI, Hagberg H, et al. Lipopolysaccharide-induced inflammation and perinatal brain injury. Seminars in Fetal & Neonatal Medicine 2006;11:343-353.
  • 3. Lehnardt S, Lachance C, Patrizi S, et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 2002;22:2478-86.
  • 4. Pang Y, Cai Z, Rhodes PG. Disturbance of oligodendrocyte development, hypomyelination, and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res 2003;140:205-14.
  • 5. Meneses G, Cárdenas G, Espinosa A, et al. Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury. Ann N Y Acad Sci 2019;1437(1):43-56.
  • 6. Yeh CH, Shih HC, Hong HM, et al. Protective effect of wogonin on proinflammatory cytokine generation via Jak1/3-STAT1/3 pathway in lipopolysaccharide-stimulated BV2 microglial cells. Toxicol Ind Health 2015;31(10):960-6.
  • 7. Shah SA, Khan M, Jo MH, et al. Melatonin stimulates the SIRT1/Nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. CNS Neurosci Ther 2017;23(1):33-44.
  • 8. Cao Y, Chen J, Ren G, et al. Punicalagin prevents inflammation in LPS-induced RAW264.7 macrophages by inhibiting FoxO3a/autophagy signaling pathway. Nutrients 2019;11:2794.
  • 9. Kim WG, Mohney RP, Wilson B, et al. Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: Role of microglia. J Neurosci 2000;20(16):6309-16.
  • 10. Zhang JN, Ma Y, Wei XY, et al. Remifentanil protects against lipopolysaccharide-induced inflammation through PARP-1/NF-κB signaling pathway. Mediators Inflamm 2019; Article ID 3013716.
  • 11. Geiseler SJ, Morland C. The Janus face of VEGF in stroke. Int J Mol Sci 2018;19:1362.
  • 12. Braile M, Marcella S, Cristinziano L, et al. VEGF-A in cardiomyocytes and heart diseases. Int J Mol Sci 2020;21(15):5294.
  • 13. Braile M, Cristinziano L, Marcella S, et al. LPS-mediated neutrophil VEGF-A release is modulated by cannabinoid receptor activation. J Leukoc Biol 2021;109(3):621-31.
  • 14. Tenopoulou M, Doulias PT. Endothelial nitric oxide synthase-derived nitric oxide in the regulation of metabolism. F1000Res 2020;9:1190.
  • 15. Valko M, Leibfritz D, Moncola J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.
  • 16. Baysal SS, Koc S. Oxidant-antioxidant balance in patients with coronary slow flow. Pak J Med Sci 2019;35(3):786-92.
  • 17. Xiang M, Feng J, et al. Sera total oxidant/antioxidant status in lung cancer patients. Medicine 2019;98:37.
  • 18. Huang Q, Feng J, Wu R, et al. Total oxidant/antioxidant status in sera of patients with esophageal cancer. Med Sci Monit 2017;23:3789-94.
  • 19. Priyadarshni S, Curry BH. Nebivolol. StatPearls Publishing; 2021.
  • 20. Gao J, Xie Q, Wei T, et al. Nebivolol improves obesity-induced vascular remodeling by suppressing NLRP3 activation. J Cardiovasc Pharmacol 2019;73(5):326-33.
  • 21. Morsy MA, Heeba GH. Nebivolol ameliorates cisplatin-induced nephrotoxicity in rats. Basic Clin Pharmacol Toxicol 2016;118(6):449-55.
  • 22. El-Sheikh AAK, Morsy MA, Abdel-Latif RG. Modulation of eNOS/iNOS by nebivolol protects against cyclosporine A-mediated nephrotoxicity through targeting inflammatory and apoptotic pathways. Environ Toxicol Pharmacol 2019;69:26-35.
  • 23. Samuvel DJ, Shunmugavel A, Singh AK, et al. S-nitrosoglutathione ameliorates acute renal dysfunction in a rat model of lipopolysaccharide-induced sepsis. J Pharm Pharmacol 2016;68(10):1310-19.
  • 24. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37(4):277-85.
  • 25. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38(12):1103-11.
  • 26. Brown GC. The endotoxin hypothesis of neurodegeneration. J Neuroinflammation 2019;16(1):180.
  • 27. Colak S, Gurlek B, Topcu A, et al. Protective effects of nebivolol on ovarian ischemia-reperfusion injury in rats. J Obstet Gynaecol Res 2020;46(11):2407-16.
  • 28. Kumar S, Gupta E, Kaushik S, et al. Evaluation of oxidative stress and antioxidant status: correlation with the severity of sepsis. Scand J Immunol 2018;87.
  • 29. You M, Miao Z, Pan Y, et al. Trans-10-hydroxy-2-decenoic acid alleviates LPS-induced blood-brain barrier dysfunction by activating the AMPK/PI3K/AKT pathway. Eur J Pharmacol 2019;865:172736.
  • 30. Yang L, Zhou R, Tong Y, et al. Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation. Neurobiol Dis 2020;140:104814.
  • 31. Han Q, Yuan Q, Meng X, et al. 6-shogaol attenuates LPS-induced inflammation in BV2 microglia cells by activating PPAR-γ. Oncotarget 2017;8(26):42001-6.
  • 32. Chen L, Liu P, Feng X, et al. Salidroside suppresses LPS-induced myocardial injury by inhibiting ROS-mediated PI3K/Akt/mTOR pathway in vitro and in vivo. J Cell Mol Med 2017;21(12):3178-89.
  • 33. Park J, Min JS, Kim B, et al. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neurosci Lett 2015;584:191-6.
  • 34. Ju S, Xu C, Wang G, et al. VEGF-C induces alternative activation of microglia to promote recovery from traumatic brain injury. J Alzheimers Dis 2019;1-11.
  • 35. Zhang W, Wang L, Wang R, et al. A blockade of microRNA-155 signal pathway has a beneficial effect on neural injury after intracerebral hemorrhage via reduction in neuroinflammation and oxidative stress. Arch Physiol Biochem 2020;May:1-7.
  • 36. Li X, Shan C, Wu Z, et al. Emodin alleviated pulmonary inflammation in rats with LPS-induced acute lung injury through inhibiting the mTOR/HIF-1α/VEGF signaling pathway. Inflamm Res 2020;69(4):365-73.
  • 37. Xu WT, Shen GN, Li TZ, et al. Isoorientin induces the apoptosis and cell cycle arrest of A549 human lung cancer cells via the ROS regulated MAPK, STAT3 and NF-κB signaling pathways. Int J Oncol 2020;57(2):550-61.
  • 38. Khalilzadeh B, Shadjou N, Kanberoglu GS, et al. Advances in nanomaterial-based optical biosensing and bioimaging of apoptosis via caspase-3 activity: a review. Mikrochim Acta 2018;185(9):434.
  • 39. Ramirez MLG, Salvesen GS. A primer on caspase mechanisms. Semin Cell Dev Biol 2018;82:79-85.
  • 40. Mohamed EA, Kassem HH. Protective effect of nebivolol on doxorubicin-induced cardiotoxicity in rats. Arch Med Sci 2018;14(6):1450-58.
Year 2025, Volume: 32

Abstract

Project Number

This study was supported by Suleyman Demirel University Scientific Research Projects Coordination Unit (project code TSG-2022-8783).

References

  • 1. Zhao J, Bi W, Xiao S, et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Scientific Reports 2019;9:5790(1-12).
  • 2. Wang X, Rousset CI, Hagberg H, et al. Lipopolysaccharide-induced inflammation and perinatal brain injury. Seminars in Fetal & Neonatal Medicine 2006;11:343-353.
  • 3. Lehnardt S, Lachance C, Patrizi S, et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 2002;22:2478-86.
  • 4. Pang Y, Cai Z, Rhodes PG. Disturbance of oligodendrocyte development, hypomyelination, and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res Dev Brain Res 2003;140:205-14.
  • 5. Meneses G, Cárdenas G, Espinosa A, et al. Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury. Ann N Y Acad Sci 2019;1437(1):43-56.
  • 6. Yeh CH, Shih HC, Hong HM, et al. Protective effect of wogonin on proinflammatory cytokine generation via Jak1/3-STAT1/3 pathway in lipopolysaccharide-stimulated BV2 microglial cells. Toxicol Ind Health 2015;31(10):960-6.
  • 7. Shah SA, Khan M, Jo MH, et al. Melatonin stimulates the SIRT1/Nrf2 signaling pathway counteracting lipopolysaccharide (LPS)-induced oxidative stress to rescue postnatal rat brain. CNS Neurosci Ther 2017;23(1):33-44.
  • 8. Cao Y, Chen J, Ren G, et al. Punicalagin prevents inflammation in LPS-induced RAW264.7 macrophages by inhibiting FoxO3a/autophagy signaling pathway. Nutrients 2019;11:2794.
  • 9. Kim WG, Mohney RP, Wilson B, et al. Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: Role of microglia. J Neurosci 2000;20(16):6309-16.
  • 10. Zhang JN, Ma Y, Wei XY, et al. Remifentanil protects against lipopolysaccharide-induced inflammation through PARP-1/NF-κB signaling pathway. Mediators Inflamm 2019; Article ID 3013716.
  • 11. Geiseler SJ, Morland C. The Janus face of VEGF in stroke. Int J Mol Sci 2018;19:1362.
  • 12. Braile M, Marcella S, Cristinziano L, et al. VEGF-A in cardiomyocytes and heart diseases. Int J Mol Sci 2020;21(15):5294.
  • 13. Braile M, Cristinziano L, Marcella S, et al. LPS-mediated neutrophil VEGF-A release is modulated by cannabinoid receptor activation. J Leukoc Biol 2021;109(3):621-31.
  • 14. Tenopoulou M, Doulias PT. Endothelial nitric oxide synthase-derived nitric oxide in the regulation of metabolism. F1000Res 2020;9:1190.
  • 15. Valko M, Leibfritz D, Moncola J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.
  • 16. Baysal SS, Koc S. Oxidant-antioxidant balance in patients with coronary slow flow. Pak J Med Sci 2019;35(3):786-92.
  • 17. Xiang M, Feng J, et al. Sera total oxidant/antioxidant status in lung cancer patients. Medicine 2019;98:37.
  • 18. Huang Q, Feng J, Wu R, et al. Total oxidant/antioxidant status in sera of patients with esophageal cancer. Med Sci Monit 2017;23:3789-94.
  • 19. Priyadarshni S, Curry BH. Nebivolol. StatPearls Publishing; 2021.
  • 20. Gao J, Xie Q, Wei T, et al. Nebivolol improves obesity-induced vascular remodeling by suppressing NLRP3 activation. J Cardiovasc Pharmacol 2019;73(5):326-33.
  • 21. Morsy MA, Heeba GH. Nebivolol ameliorates cisplatin-induced nephrotoxicity in rats. Basic Clin Pharmacol Toxicol 2016;118(6):449-55.
  • 22. El-Sheikh AAK, Morsy MA, Abdel-Latif RG. Modulation of eNOS/iNOS by nebivolol protects against cyclosporine A-mediated nephrotoxicity through targeting inflammatory and apoptotic pathways. Environ Toxicol Pharmacol 2019;69:26-35.
  • 23. Samuvel DJ, Shunmugavel A, Singh AK, et al. S-nitrosoglutathione ameliorates acute renal dysfunction in a rat model of lipopolysaccharide-induced sepsis. J Pharm Pharmacol 2016;68(10):1310-19.
  • 24. Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37(4):277-85.
  • 25. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38(12):1103-11.
  • 26. Brown GC. The endotoxin hypothesis of neurodegeneration. J Neuroinflammation 2019;16(1):180.
  • 27. Colak S, Gurlek B, Topcu A, et al. Protective effects of nebivolol on ovarian ischemia-reperfusion injury in rats. J Obstet Gynaecol Res 2020;46(11):2407-16.
  • 28. Kumar S, Gupta E, Kaushik S, et al. Evaluation of oxidative stress and antioxidant status: correlation with the severity of sepsis. Scand J Immunol 2018;87.
  • 29. You M, Miao Z, Pan Y, et al. Trans-10-hydroxy-2-decenoic acid alleviates LPS-induced blood-brain barrier dysfunction by activating the AMPK/PI3K/AKT pathway. Eur J Pharmacol 2019;865:172736.
  • 30. Yang L, Zhou R, Tong Y, et al. Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation. Neurobiol Dis 2020;140:104814.
  • 31. Han Q, Yuan Q, Meng X, et al. 6-shogaol attenuates LPS-induced inflammation in BV2 microglia cells by activating PPAR-γ. Oncotarget 2017;8(26):42001-6.
  • 32. Chen L, Liu P, Feng X, et al. Salidroside suppresses LPS-induced myocardial injury by inhibiting ROS-mediated PI3K/Akt/mTOR pathway in vitro and in vivo. J Cell Mol Med 2017;21(12):3178-89.
  • 33. Park J, Min JS, Kim B, et al. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neurosci Lett 2015;584:191-6.
  • 34. Ju S, Xu C, Wang G, et al. VEGF-C induces alternative activation of microglia to promote recovery from traumatic brain injury. J Alzheimers Dis 2019;1-11.
  • 35. Zhang W, Wang L, Wang R, et al. A blockade of microRNA-155 signal pathway has a beneficial effect on neural injury after intracerebral hemorrhage via reduction in neuroinflammation and oxidative stress. Arch Physiol Biochem 2020;May:1-7.
  • 36. Li X, Shan C, Wu Z, et al. Emodin alleviated pulmonary inflammation in rats with LPS-induced acute lung injury through inhibiting the mTOR/HIF-1α/VEGF signaling pathway. Inflamm Res 2020;69(4):365-73.
  • 37. Xu WT, Shen GN, Li TZ, et al. Isoorientin induces the apoptosis and cell cycle arrest of A549 human lung cancer cells via the ROS regulated MAPK, STAT3 and NF-κB signaling pathways. Int J Oncol 2020;57(2):550-61.
  • 38. Khalilzadeh B, Shadjou N, Kanberoglu GS, et al. Advances in nanomaterial-based optical biosensing and bioimaging of apoptosis via caspase-3 activity: a review. Mikrochim Acta 2018;185(9):434.
  • 39. Ramirez MLG, Salvesen GS. A primer on caspase mechanisms. Semin Cell Dev Biol 2018;82:79-85.
  • 40. Mohamed EA, Kassem HH. Protective effect of nebivolol on doxorubicin-induced cardiotoxicity in rats. Arch Med Sci 2018;14(6):1450-58.
There are 40 citations in total.

Details

Primary Language English
Subjects Brain and Nerve Surgery (Neurosurgery)
Journal Section Research Articles
Authors

Ali Serdar Oğuzoğlu 0000-0002-1735-4062

Nilgün Şenol 0000-0002-1714-3150

Duygu Doguc 0000-0002-3879-9917

Şerife Taşan 0000-0002-1469-3464

Yalçın Erzurumlu 0000-0001-6835-4436

Halil Aşcı 0000-0002-1545-035X

Project Number This study was supported by Suleyman Demirel University Scientific Research Projects Coordination Unit (project code TSG-2022-8783).
Early Pub Date February 18, 2025
Publication Date
Submission Date September 4, 2024
Acceptance Date November 25, 2024
Published in Issue Year 2025 Volume: 32

Cite

Vancouver Oğuzoğlu AS, Şenol N, Doguc D, Taşan Ş, Erzurumlu Y, Aşcı H. The Effect of Nebivolol on Acute Brain Damage in a Rat Model of Lps-Induced Inflammation. Med J SDU. 2025;32.

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