Anatomy and Cell Biology

Korean Association of Anatomists (대한해부학회)
권호 표지
DOI QR코드

DOI QR Code

Rubus fruticosus leaf extract inhibits vascular dementia-induced memory impairment and neuronal loss by attenuating neuroinflammation

  • Nak Song Sung (Department of General Surgery, Konyang University Hospital) ;
  • Sun Ho Uhm (Research Institute, Healinols Inc.) ;
  • Hyun Bae Kang (Research Institute, Healinols Inc.) ;
  • Nam Seob Lee (Department of Anatomy, College of Medicine, Konyang University) ;
  • Young-Gil Jeong (Department of Anatomy, College of Medicine, Konyang University) ;
  • Do Kyung Kim (Department of Anatomy, College of Medicine, Konyang University) ;
  • Nak-Yun Sung (Division of Natural Product Research, Korea Prime Pharmacy Co., Ltd.) ;
  • Dong-Sub Kim (Division of Natural Product Research, Korea Prime Pharmacy Co., Ltd.) ;
  • Young Choon Yoo (Department of Microbiology, College of Medicine, Konyang University) ;
  • Seung Yun Han (Department of Anatomy, College of Medicine, Konyang University)
  • Received : 2023.07.16
  • Accepted : 2023.07.25
  • Published : 2023.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Vascular dementia (VaD) is characterized by progressive memory impairment, which is associated with microglia-mediated neuroinflammation. Polyphenol-rich natural plants, which possess anti-inflammatory activities, have attracted scientific interest worldwide. This study investigated whether Rubus fruticosus leaf extract (RFLE) can attenuate VaD. Sprague-Dawley rats were separated into five groups: SO, sham-operated and treated with vehicle; OP, operated and treated with vehicle; RFLE-L, operated and treated with low dose (30 mg/kg) of RFLE; RFLE-M, operated and treated with medium dose (60 mg/kg) of RFLE; and RFLE-H, operated and treated with high dose (90 mg/kg) of RFLE. Bilateral common carotid artery and hypotension were used as a modeling procedure, and the RFLE were intraorally administered for 5 days (preoperative 2 and postoperative 3 days). The rats then underwent memory tests including the novel object recognition, Y-maze, Barnes maze, and passive avoidance tests, and neuronal viability and neuroinflammation were quantified in their hippocampi. The results showed that the OP group exhibited VaD-associated memory deficits, neuronal death, and microglial activation in hippocampi, while the RFLE-treated groups showed significant attenuation in all above parameters. Next, using BV-2 microglial cells challenged with lipopolysaccharide (LPS), we evaluated the effects of RFLE in dynamics of proinflammatory mediators and the upstream signaling pathway. RFLE pretreatment significantly inhibited the LPS-induced release of nitric oxide, TNF-α, and IL-6 and upregulation of the MAPKs/NF-κB/iNOS pathway. Collectively, we suggest that RFLE can attenuate the histologic alterations and memory deficits accompanied by VaD, and these roles are, partly due to the attenuation of microglial activation.

Keywords

Acknowledgement

This work was supported by Konyang University Myunggok Research Fund (2018) and Basic Research Program funded by Ministry of Science and ICT (RS-2023-00251456).

References

  1. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, Willis RJ, Wallace RB. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 2007;29:125-32. 
  2. Bastos-Leite AJ, van der Flier WM, van Straaten EC, Staekenborg SS, Scheltens P, Barkhof F. The contribution of medial temporal lobe atrophy and vascular pathology to cognitive impairment in vascular dementia. Stroke 2007;38:3182-5. 
  3. Sun M, Shen X, Ma Y. Rehmannioside A attenuates cognitive deficits in rats with vascular dementia (VD) through suppressing oxidative stress, inflammation and apoptosis. Biomed Pharmacother 2019;120:109492. 
  4. Luo XQ, Li A, Yang X, Xiao X, Hu R, Wang TW, Dou XY, Yang DJ, Dong Z. Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2. Chin Med 2018;13:14. 
  5. Stanimirovic D, Satoh K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol 2000;10:113-26.
  6. Ueno M. [Elucidation of mechanism of blood-brain barrier damage for prevention and treatment of vascular dementia]. Rinsho Shinkeigaku 2017;57:95-109. Japanese. 
  7. Cechetti F, Pagnussat AS, Worm PV, Elsner VR, Ben J, da Costa MS, Mestriner R, Weis SN, Netto CA. Chronic brain hypoperfusion causes early glial activation and neuronal death, and subsequent long-term memory impairment. Brain Res Bull 2012;87:109-16.
  8. Sinha K, Sun C, Kamari R, Bettermann K. Current status and future prospects of pathophysiology-based neuroprotective drugs for the treatment of vascular dementia. Drug Discov Today 2020;25:793-9.
  9. Daglia M. Polyphenols as antimicrobial agents. Curr Opin Biotechnol 2012;23:174-81. 
  10. Xie Y, Chen J, Xiao A, Liu L. Antibacterial activity of polyphenols: structure-activity relationship and influence of hyperglycemic condition. Molecules 2017;22:1913. 
  11. Mhatre S, Srivastava T, Naik S, Patravale V. Antiviral activity of green tea and black tea polyphenols in prophylaxis and treatment of COVID-19: a review. Phytomedicine 2021;85:153286. 
  12. Luo J, Si H, Jia Z, Liu D. Dietary anti-aging polyphenols and potential mechanisms. Antioxidants (Basel) 2021;10:283. 
  13. Korkina LG, De Luca C, Kostyuk VA, Pastore S. Plant polyphenols and tumors: from mechanisms to therapies, prevention, and protection against toxicity of anti-cancer treatments. Curr Med Chem 2009;16:3943-65. 
  14. Yang CS, Lambert JD, Sang S. Antioxidative and anti-carcinogenic activities of tea polyphenols. Arch Toxicol 2009;83:11-21. 
  15. Yahfoufi N, Alsadi N, Jambi M, Matar C. The immunomodulatory and anti-inflammatory role of polyphenols. Nutrients 2018;10:1618. 
  16. Zia-Ul-Haq M, Riaz M, De Feo V, Jaafar HZ, Moga M. Rubus fruticosus L.: constituents, biological activities and health related uses. Molecules 2014;19:10998-1029. 
  17. Zafra-Rojas QY, Gonzalez-Martinez BE, Cruz-Cansino NDS, Lopez-Cabanillas M, Suarez-Jacobo A, Cervantes-Elizarraras A, Ramirez-Moreno E. Effect of ultrasound on in vitro bioaccessibility of phenolic compounds and antioxidant capacity of blackberry (Rubus fruticosus) residues cv. Tupy. Plant Foods Hum Nutr 2020;75:608-13. 
  18. Verma R, Gangrade T, Punasiya R, Ghulaxe C. Rubus fruticosus (blackberry) use as an herbal medicine. Pharmacogn Rev 2014;8:101-4. 
  19. Weli AM, Al-Saadi HS, Al-Fudhaili RS, Hossain A, Putit ZB, Jasim MK. Cytotoxic and antimicrobial potential of different leaves extracts of R. fruticosus used traditionally to treat diabetes. Toxicol Rep 2020;7:183-7. 
  20. Dou ZM, Chen C, Huang Q, Fu X. The structure, conformation, and hypoglycemic activity of a novel heteropolysaccharide from the blackberry fruit. Food Funct 2021;12:5451-64. 
  21. Gudej J, Tomczyk M. Determination of flavonoids, tannins and ellagic acid in leaves from Rubus L. species. Arch Pharm Res 2004;27:1114-9. 
  22. Riaz M, Zia-Ul-Haq M, Ur-Rahman N, Ahmadi M. Neuropharmacological effects of methanolic extracts of Rubusfruticosus L. Turk J Med Sci 2014;44:454-60. 
  23. Carbone L. Pain management standards in the eighth edition of the Guide for the Care and Use of Laboratory Animals. J Am Assoc Lab Anim Sci 2012;51:322-8. 
  24. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016;7:27-31.
  25. Sanderson TH, Wider JM. 2-vessel occlusion/hypotension: a rat model of global brain ischemia. J Vis Exp 2013;76:50173. 
  26. Kang HB, Kim SH, Uhm SH, Kim DK, Lee NS, Jeong YG, Sung NY, Kim DS, Han IJ, Yoo YC, Han SY. Perilla frutescens leaf extract attenuates vascular dementia-associated memory deficits, neuronal damages, and microglial activation. Curr Issues Mol Biol 2022;44:257-72. 
  27. Olsson B, Hertze J, Lautner R, Zetterberg H, Nagga K, Hoglund K, Basun H, Annas P, Lannfelt L, Andreasen N, Minthon L, Blennow K, Hansson O. Microglial markers are elevated in the prodromal phase of Alzheimer's disease and vascular dementia. J Alzheimers Dis 2013;33:45-53. 
  28. Fitzpatrick AL, Kuller LH, Lopez OL, Kawas CH, Jagust W. Survival following dementia onset: Alzheimer's disease and vascular dementia. J Neurol Sci 2005;229-30:43-9. 
  29. Wang J, Zhang HY, Tang XC. Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment. Acta Pharmacol Sin 2009;30:879-88. 
  30. Lyman M, Lloyd DG, Ji X, Vizcaychipi MP, Ma D. Neuroinflammation: the role and consequences. Neurosci Res 2014;79:1-12. 
  31. Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases (Review). Mol Med Rep 2016;13:3391-6. 
  32. Riazi K, Galic MA, Kentner AC, Reid AY, Sharkey KA, Pittman QJ. Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. J Neurosci 2015;35:4942-52. 
  33. Damodaran T, Muller CP, Hassan Z. Chronic cerebral hypoperfusion-induced memory impairment and hippocampal long-term potentiation deficits are improved by cholinergic stimulation in rats. Pharmacol Rep 2019;71:443-8. 
  34. Muldoon LL, Alvarez JI, Begley DJ, Boado RJ, Del Zoppo GJ, Doolittle ND, Engelhardt B, Hallenbeck JM, Lonser RR, Ohlfest JR, Prat A, Scarpa M, Smeyne RJ, Drewes LR, Neuwelt EA. Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab 2013;33:13-21. 
  35. Solanki I, Parihar P, Parihar MS. Neurodegenerative diseases: from available treatments to prospective herbal therapy. Neurochem Int 2016;95:100-8. 
  36. Bhullar KS, Rupasinghe HP. Polyphenols: multipotent therapeutic agents in neurodegenerative diseases. Oxid Med Cell Longev 2013;2013:891748. 
  37. Ahmed T, Setzer WN, Nabavi SF, Orhan IE, Braidy N, Sobarzo-Sanchez E, Nabavi SM. Insights into effects of ellagic acid on the nervous system: a mini review. Curr Pharm Des 2016;22:1350-60. 
  38. Wei YZ, Zhu GF, Zheng CQ, Li JJ, Sheng S, Li DD, Wang GQ, Zhang F. Ellagic acid protects dopamine neurons from rotenone-induced neurotoxicity via activation of Nrf2 signalling. J Cell Mol Med 2020;24:9446-56. 
  39. Chen P, Chen F, Zhou B. Antioxidative, anti-inflammatory and anti-apoptotic effects of ellagic acid in liver and brain of rats treated by D-galactose. Sci Rep 2018;8:1465. Erratum in: Sci Rep 2019;9:19129. 
  40. Jha AB, Panchal SS, Shah A. Ellagic acid: insights into its neuroprotective and cognitive enhancement effects in sporadic Alzheimer's disease. Pharmacol Biochem Behav 2018;175:33-46. 
  41. Macrae IM. Preclinical stroke research--advantages and disadvantages of the most common rodent models of focal ischaemia. Br J Pharmacol 2011;164:1062-78. 
  42. Leon-Moreno LC, Castaneda-Arellano R, Rivas-Carrillo JD, Duenas-Jimenez SH. Challenges and improvements of developing an ischemia mouse model through bilateral common carotid artery occlusion. J Stroke Cerebrovasc Dis 2020;29:104773. 
  43. Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 2014;81:229-48. 
  44. Zhang JH, Badaut J, Tang J, Obenaus A, Hartman R, Pearce WJ. The vascular neural network--a new paradigm in stroke pathophysiology. Nat Rev Neurol 2012;8:711-6. 
  45. Zhang LM, Jiang CX, Liu DW. Hydrogen sulfide attenuates neuronal injury induced by vascular dementia via inhibiting apoptosis in rats. Neurochem Res 2009;34:1984-92. 
  46. Kwon KJ, Kim MK, Lee EJ, Kim JN, Choi BR, Kim SY, Cho KS, Han JS, Kim HY, Shin CY, Han SH. Effects of donepezil, an acetylcholinesterase inhibitor, on neurogenesis in a rat model of vascular dementia. J Neurol Sci 2014;347:66-77. 
  47. Bhatia P, Singh N. Tadalafil ameliorates memory deficits, oxidative stress, endothelial dysfunction and neuropathological changes in rat model of hyperhomocysteinemia induced vascular dementia. Int J Neurosci 2022;132:384-96. 
  48. Venkat P, Chopp M, Zacharek A, Cui C, Zhang L, Li Q, Lu M, Zhang T, Liu A, Chen J. White matter damage and glymphatic dysfunction in a model of vascular dementia in rats with no prior vascular pathologies. Neurobiol Aging 2017;50:96-106.