The protective effects and underlying mechanisms of Kaempferol on sepsis associated cognitive impairment in rats
Abstract
Objectives: The neuroprotective effects of Kaempferol (KMF) have been previously reported; however, its possible effects on sepsis-associated encephalopathy are still unclear. This study aimed to investigate the effects and underlying mechanisms of KMF on cognitive impairment in cecal ligation and puncture (CLP)-induced sepsis model.
Methods: Male Wistar rats were submitted to CLP model. The animals were grouped into the sham, sham + KMF, CLP, and CLP + KMF groups and treated with KMF (50 mg/kg, i.p). Twenty-four hours after CLP, the cytokines, NF-kB level, myeloperoxidase (MPO) activity, oxidative damage to lipids and proteins, and antioxidant enzymes activities were evaluated in the hippocampus. 10 days after sepsis induction, behavioral tests were performed to assess the cognitive damage.
Results: KMF reduced the TNF-α and IL-1β levels, MPO activity, protein level of NF-kB, and expression of TLR4 and MYD88 in the hippocampus of septic rats. KMF decreased the levels of oxidative stress parameters (MDA and protein carbonyls groups) and elevated the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). In addition, the expression level of genes involved in the anti-oxidant defense system such as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenease-1 (HO-1) were upregulated following KMF treatment.
Conclusion: These findings indicated that KMF exhibited protective effects on the survival rate and cognitive dysfunction after sepsis by inhibiting the inflammatory responses and oxidative stress.
1. Gu M, Mei X-L, Zhao Y-N. Sepsis and cerebral dysfunction: BBB damage, neuroinflammation, oxidative stress, apoptosis and autophagy as key mediators and the potential therapeutic approaches. Neurotox Res. 2021;39(2):489-503. https://doi.org/10.1007/s12640-020-00270-5
2. Hosokawa K, Gaspard N, Su F, Oddo M, Vincent JL, Taccone FS. Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review. Crit Care. 2014;18(6):674. https://doi.org/10.1186/s13054-014-0674-y
3. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-94. https://doi.org/10.1001/jama.2010.1553
4. Sonneville R, Benghanem S, Jeantin L, de Montmollin E, Doman M, Gaudemer A, et al. The spectrum of sepsis-associated encephalopathy: a clinical perspective. Crit Care. 2023;27(1):386. https://doi.org/10.1186/s13054-023-04655-8
5. Mei B, Li J, Zuo Z. Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central alpha2A adrenoceptor. Brain Behav Immun. 2021;91:296-314. https://doi.org/10.1016/j.bbi.2020.10.008
6. Barichello T, Fortunato JJ, Vitali AM, Feier G, Reinke A, Moreira JC, et al. Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med. 2006;34(3):886-9. https://doi.org/10.1097/01.CCM.0000201880.50116.12
7. Heitman E, Ingram DK. Cognitive and neuroprotective effects of chlorogenic acid. Nutr Neurosci. 2017;20(1):32-9. https://doi.org/10.1179/1476830514Y.0000000146
8. Beg T, Jyoti S, Naz F, Rahul, Ali F, Ali SK, et al. Protective Effect of Kaempferol on the Transgenic Drosophila Model of Alzheimer's Disease. CNS Neurol Disord Drug Targets. 2018;17(6):421-9. https://doi.org/10.2174/1871527317666180508123050
9. Zarei M, Mohammadi S, Jabbari S, Shahidi S. Intracerebroventricular microinjection of kaempferol on memory retention of passive avoidance learning in rats: involvement of cholinergic mechanism(s). Int J Neurosci. 2019;129(12):1203-12. https://doi.org/10.1080/00207454.2019.1653867
10. Kouhestani S, Jafari A, Babaei P. Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia. Neural Regen Res. 2018;13(10):1827-32. https://doi.org/10.4103/1673-5374.238714
11. Lopez-Sanchez C, Poejo J, Garcia-Lopez V, Salazar J, Garcia-Martinez V, Gutierrez-Merino C. Kaempferol prevents the activation of complement C3 protein and the generation of reactive A1 astrocytes that mediate rat brain degeneration induced by 3-nitropropionic acid. Food Chem Toxicol. 2022;164:113017. https://doi.org/10.1016/j.fct.2022.113017
12. Li WH, Cheng X, Yang YL, Liu M, Zhang SS, Wang YH, et al. Kaempferol attenuates neuroinflammation and blood brain barrier dysfunction to improve neurological deficits in cerebral ischemia/reperfusion rats. Brain Res. 2019;1722:146361. https://doi.org/10.1016/j.brainres.2019.146361
13. Chang S, Li X, Zheng Y, Shi H, Zhang D, Jing B, et al. Kaempferol exerts a neuroprotective effect to reduce neuropathic pain through TLR4/NF‐ĸB signaling pathway. Phytother Res. 2022;36(4):1678-91. https://doi.org/10.1002/ptr.7396
14. Zarbato GF, de Souza Goldim MP, Giustina AD, Danielski LG, Mathias K, Florentino D, et al. Dimethyl Fumarate Limits Neuroinflammation and Oxidative Stress and Improves Cognitive Impairment After Polymicrobial Sepsis. Neurotox Res. 2018;34(3):418-30. https://doi.org/10.1007/s12640-018-9900-8
15. Lee K, Lee JS, Jang HJ, Kim SM, Chang MS, Park SH, et al. Chlorogenic acid ameliorates brain damage and edema by inhibiting matrix metalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur J Pharmacol. 2012;689(1-3):89-95. https://doi.org/10.1016/j.ejphar.2012.05.028
16. De Young L, Kheifets J, Ballaron S, Young J. Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions. 1989;26(3):335-41. https://doi.org/10.1007/bf01967298
17. Zhong J, Guo C, Hou W, Shen N, Miao C. Effects of MFHAS1 on cognitive impairment and dendritic pathology in the hippocampus of septic rats. Life Sci. 2019;235:116822. https://doi.org/10.1016/j.lfs.2019.116822
18. Della Giustina A, Goldim MP, Danielski LG, Florentino D, Garbossa L, Joaquim L, et al. Fish oil-rich lipid emulsion modulates neuroinflammation and prevents long-term cognitive dysfunction after sepsis. Nutrition. 2020;70:110417. https://doi.org/10.1016/j.nut.2018.12.003
19. Xu M, Ge C, Qin Y, Gu T, Lv J, Wang S, et al. Activated TNF-alpha/RIPK3 signaling is involved in prolonged high fat diet-stimulated hepatic inflammation and lipid accumulation: inhibition by dietary fisetin intervention. Food Funct. 2019;10(3):1302-16. https://doi.org/10.1039/c8fo01615a
20. Zamani-Garmsiri F, Emamgholipour S, Rahmani Fard S, Ghasempour G, Jahangard Ahvazi R, Meshkani R. Polyphenols: Potential anti-inflammatory agents for treatment of metabolic disorders. Phytother Res. 2022;36(1):415-32. https://doi.org/10.1002/ptr.7329
21. Liu SF, Malik AB. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol. 2006;290(4):L622-L45. https://doi.org/10.1152/ajplung.00477.2005
22. Rahman MM, Islam MR, Islam MT, Harun-Or-Rashid M, Islam M, Abdullah S, et al. Stem Cell Transplantation Therapy and Neurological Disorders: Current Status and Future Perspectives. Biology (Basel). 2022;11(1):147. https://doi.org/10.3390/biology11010147
23. Rauf A, Badoni H, Abu-Izneid T, Olatunde A, Rahman MM, Painuli S, et al. Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases. Molecules. 2022;27(10). https://doi.org/10.3390/molecules27103194
24. Yamamoto Y, Gaynor RB. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci. 2004;29(2):72-9. https://doi.org/10.1016/j.tibs.2003.12.003
25. Kumar V. Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets. Int Immunopharmacol. 2020;89(Pt B):107087. https://doi.org/10.1016/j.intimp.2020.107087
26. Zhang J, Wang Z, Wang Y, Zhou G, Li H. The effect of dexmedetomidine on inflammatory response of septic rats. BMC Anesthesiol. 2015;15:68. https://doi.org/10.1186/s12871-015-0042-8
27. Yang YL, Cheng X, Li WH, Liu M, Wang YH, Du GH. Kaempferol Attenuates LPS-Induced Striatum Injury in Mice Involving Anti-Neuroinflammation, Maintaining BBB Integrity, and Down-Regulating the HMGB1/TLR4 Pathway. Int J Mol Sci. 2019;20(3):491. https://doi.org/10.3390/ijms20030491
28. Hopkins RO. Sepsis, oxidative stress, and brain injury. Crit Care Med. 2007;35(9):2233-4. https://doi.org/10.1097/01.CCM.0000281456.13311.0B
29. Ritter C, Andrades ME, Reinke A, Menna-Barreto S, Moreira JC, Dal-Pizzol F. Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis. Crit Care Med. 2004;32(2):342-9. https://doi.org/10.1097/01.CCM.0000109454.13145.CA
2. Hosokawa K, Gaspard N, Su F, Oddo M, Vincent JL, Taccone FS. Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review. Crit Care. 2014;18(6):674. https://doi.org/10.1186/s13054-014-0674-y
3. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-94. https://doi.org/10.1001/jama.2010.1553
4. Sonneville R, Benghanem S, Jeantin L, de Montmollin E, Doman M, Gaudemer A, et al. The spectrum of sepsis-associated encephalopathy: a clinical perspective. Crit Care. 2023;27(1):386. https://doi.org/10.1186/s13054-023-04655-8
5. Mei B, Li J, Zuo Z. Dexmedetomidine attenuates sepsis-associated inflammation and encephalopathy via central alpha2A adrenoceptor. Brain Behav Immun. 2021;91:296-314. https://doi.org/10.1016/j.bbi.2020.10.008
6. Barichello T, Fortunato JJ, Vitali AM, Feier G, Reinke A, Moreira JC, et al. Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med. 2006;34(3):886-9. https://doi.org/10.1097/01.CCM.0000201880.50116.12
7. Heitman E, Ingram DK. Cognitive and neuroprotective effects of chlorogenic acid. Nutr Neurosci. 2017;20(1):32-9. https://doi.org/10.1179/1476830514Y.0000000146
8. Beg T, Jyoti S, Naz F, Rahul, Ali F, Ali SK, et al. Protective Effect of Kaempferol on the Transgenic Drosophila Model of Alzheimer's Disease. CNS Neurol Disord Drug Targets. 2018;17(6):421-9. https://doi.org/10.2174/1871527317666180508123050
9. Zarei M, Mohammadi S, Jabbari S, Shahidi S. Intracerebroventricular microinjection of kaempferol on memory retention of passive avoidance learning in rats: involvement of cholinergic mechanism(s). Int J Neurosci. 2019;129(12):1203-12. https://doi.org/10.1080/00207454.2019.1653867
10. Kouhestani S, Jafari A, Babaei P. Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia. Neural Regen Res. 2018;13(10):1827-32. https://doi.org/10.4103/1673-5374.238714
11. Lopez-Sanchez C, Poejo J, Garcia-Lopez V, Salazar J, Garcia-Martinez V, Gutierrez-Merino C. Kaempferol prevents the activation of complement C3 protein and the generation of reactive A1 astrocytes that mediate rat brain degeneration induced by 3-nitropropionic acid. Food Chem Toxicol. 2022;164:113017. https://doi.org/10.1016/j.fct.2022.113017
12. Li WH, Cheng X, Yang YL, Liu M, Zhang SS, Wang YH, et al. Kaempferol attenuates neuroinflammation and blood brain barrier dysfunction to improve neurological deficits in cerebral ischemia/reperfusion rats. Brain Res. 2019;1722:146361. https://doi.org/10.1016/j.brainres.2019.146361
13. Chang S, Li X, Zheng Y, Shi H, Zhang D, Jing B, et al. Kaempferol exerts a neuroprotective effect to reduce neuropathic pain through TLR4/NF‐ĸB signaling pathway. Phytother Res. 2022;36(4):1678-91. https://doi.org/10.1002/ptr.7396
14. Zarbato GF, de Souza Goldim MP, Giustina AD, Danielski LG, Mathias K, Florentino D, et al. Dimethyl Fumarate Limits Neuroinflammation and Oxidative Stress and Improves Cognitive Impairment After Polymicrobial Sepsis. Neurotox Res. 2018;34(3):418-30. https://doi.org/10.1007/s12640-018-9900-8
15. Lee K, Lee JS, Jang HJ, Kim SM, Chang MS, Park SH, et al. Chlorogenic acid ameliorates brain damage and edema by inhibiting matrix metalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur J Pharmacol. 2012;689(1-3):89-95. https://doi.org/10.1016/j.ejphar.2012.05.028
16. De Young L, Kheifets J, Ballaron S, Young J. Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions. 1989;26(3):335-41. https://doi.org/10.1007/bf01967298
17. Zhong J, Guo C, Hou W, Shen N, Miao C. Effects of MFHAS1 on cognitive impairment and dendritic pathology in the hippocampus of septic rats. Life Sci. 2019;235:116822. https://doi.org/10.1016/j.lfs.2019.116822
18. Della Giustina A, Goldim MP, Danielski LG, Florentino D, Garbossa L, Joaquim L, et al. Fish oil-rich lipid emulsion modulates neuroinflammation and prevents long-term cognitive dysfunction after sepsis. Nutrition. 2020;70:110417. https://doi.org/10.1016/j.nut.2018.12.003
19. Xu M, Ge C, Qin Y, Gu T, Lv J, Wang S, et al. Activated TNF-alpha/RIPK3 signaling is involved in prolonged high fat diet-stimulated hepatic inflammation and lipid accumulation: inhibition by dietary fisetin intervention. Food Funct. 2019;10(3):1302-16. https://doi.org/10.1039/c8fo01615a
20. Zamani-Garmsiri F, Emamgholipour S, Rahmani Fard S, Ghasempour G, Jahangard Ahvazi R, Meshkani R. Polyphenols: Potential anti-inflammatory agents for treatment of metabolic disorders. Phytother Res. 2022;36(1):415-32. https://doi.org/10.1002/ptr.7329
21. Liu SF, Malik AB. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol. 2006;290(4):L622-L45. https://doi.org/10.1152/ajplung.00477.2005
22. Rahman MM, Islam MR, Islam MT, Harun-Or-Rashid M, Islam M, Abdullah S, et al. Stem Cell Transplantation Therapy and Neurological Disorders: Current Status and Future Perspectives. Biology (Basel). 2022;11(1):147. https://doi.org/10.3390/biology11010147
23. Rauf A, Badoni H, Abu-Izneid T, Olatunde A, Rahman MM, Painuli S, et al. Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases. Molecules. 2022;27(10). https://doi.org/10.3390/molecules27103194
24. Yamamoto Y, Gaynor RB. IkappaB kinases: key regulators of the NF-kappaB pathway. Trends Biochem Sci. 2004;29(2):72-9. https://doi.org/10.1016/j.tibs.2003.12.003
25. Kumar V. Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets. Int Immunopharmacol. 2020;89(Pt B):107087. https://doi.org/10.1016/j.intimp.2020.107087
26. Zhang J, Wang Z, Wang Y, Zhou G, Li H. The effect of dexmedetomidine on inflammatory response of septic rats. BMC Anesthesiol. 2015;15:68. https://doi.org/10.1186/s12871-015-0042-8
27. Yang YL, Cheng X, Li WH, Liu M, Wang YH, Du GH. Kaempferol Attenuates LPS-Induced Striatum Injury in Mice Involving Anti-Neuroinflammation, Maintaining BBB Integrity, and Down-Regulating the HMGB1/TLR4 Pathway. Int J Mol Sci. 2019;20(3):491. https://doi.org/10.3390/ijms20030491
28. Hopkins RO. Sepsis, oxidative stress, and brain injury. Crit Care Med. 2007;35(9):2233-4. https://doi.org/10.1097/01.CCM.0000281456.13311.0B
29. Ritter C, Andrades ME, Reinke A, Menna-Barreto S, Moreira JC, Dal-Pizzol F. Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis. Crit Care Med. 2004;32(2):342-9. https://doi.org/10.1097/01.CCM.0000109454.13145.CA
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| Issue | Vol 2 No 4 (2024) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/abi.v2i4.19109 | |
| Keywords | ||
| Kaempferol cecal ligation and puncture sepsis Inflammation cognitive impairment oxidative stress | ||
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How to Cite
1.
Shi B, Chen M, Xu H. The protective effects and underlying mechanisms of Kaempferol on sepsis associated cognitive impairment in rats. ABI. 2024;2(4):213-220.
