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Berberine attenuates brain aging via stabilizing redox homeostasis and inflammation in an accelerated senescence model of Wistar rats

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Abstract

Aging is a multifaceted and progressive physiological change of the organism categorized by the accumulation of deteriorating processes, which ultimately compromise the biological functions. The objective of this study was to investigate the anti-aging potential of berberine (BBR) in D-galactose (D-Gal) induced aging in rat models. In this study, male Wistar rats were divided into four groups: The control group was given only vehicle, the BBR group was treated with berberine orally, the D-Gal group was treated with D-galactose subcutaneously and the BBR + D-Gal group was treated with D-galactose and berberine simultaneously. D-galactose exposure elevated the pro-oxidants such as malondialdehyde (MDA) level, protein carbonyl and advanced oxidation protein products (AOPP) in the brain. It decreased the anti-oxidants such as reduced glutathione (GSH) and ferric reducing antioxidant potential (FRAP) in the brain. D-galactose treatment also reduced the mitochondrial complexes (I, II, III and IV) activities and elevated the inflammatory markers such as interleukine-6 (IL-6), tumor necrosis factor- α (TNF-α) and C-reactive protein (CRP). The mRNA expressions of IL-6 and TNF-α in the brain were upregulated following D-galactose exposure. Berberine co-treatment in D-galactose induced aging rat model prevented the alteration of pro-oxidant and anti-oxidant in the brain. Berberine treatment restored the mitochondrial complex activities in the brain and also normalized the inflammatory markers. Based on these findings we conclude that berberine treatment has the potential to mitigate brain aging in rats via stabilizing the redox equilibrium and neuroinflammation.

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References

  • Adefegha SA, Oboh G, Okeke BM (2021) Comparative effects of berberine and piperine on the neuroprotective potential of neostigmine. J Complement Integr Med 18:491–497

    Article  CAS  PubMed  Google Scholar 

  • Allameh H, Fatemi I, Malayeri AR, Nesari A, Mehrzadi S, Goudarzi M (2020) Pretreatment with berberine protects against cisplatin-induced renal injury in male Wistar rats. Naunyn-Schmiedeberg’s Archives Pharmacol 393:1825–1833

    Article  CAS  Google Scholar 

  • Bektas A, Schurman SH, Franceschi C, Ferrucci L (2020) A public health perspective of aging: do hyper-inflammatory syndromes such as COVID-19, SARS, ARDS, cytokine storm syndrome, and post-ICU syndrome accelerate short- and long-term inflammaging? Immun Ageing 17:23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benzie IFF, Strain JJ (1996) The Ferric Reducing Ability of Plasma (FRAP) as a measure of antioxidant power: the FRAP Assay. Anal Biochem 239:70–76

    Article  CAS  PubMed  Google Scholar 

  • Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin M-A, Morio B, Vidal H, Rieusset J (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118(2):789–800

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bonomini F, Rodella LF, Rezzani R (2015) Metabolic syndrome, aging and involvement of oxidative stress. Aging Disease 6:109

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen C-C, Hung T-H, Lee CY, Wang L-F, Wu C-H, Ke C-H, Chen S-F (2014) Berberine protects against Neuronal Damage via Suppression of Glia-Mediated Inflammation in traumatic brain Injury. PLoS ONE 9, e115694

    Article  PubMed  PubMed Central  Google Scholar 

  • Dadgostar E, Moghanlou M, Parvaresh M, Mohammadi S, Khandan M, Aschner M, Mirzaei H, Tamtaji OR (2022) Can Berberine Serve as a New Therapy for Parkinson’s Disease? Neurotox Res 40:1096–1102

    Article  PubMed  Google Scholar 

  • El-Horany HE-S, Gaballah HH, Helal DS (2018) Berberine ameliorates renal injury in a rat model of D-galactose-induced aging through a PTEN/Akt-dependent mechanism. Arch Physiol Biochem 126:157–165

    Article  PubMed  Google Scholar 

  • El-Shiekh RA, Ashour RM, El-Haleim A, Ahmed EA, Abdel-Sattar KA, E (2020) Hibiscus sabdariffa L.: a potent natural neuroprotective agent for the prevention of streptozotocin-induced Alzheimer’s disease in mice. Biomed Pharmacother 128:110303

    Article  CAS  PubMed  Google Scholar 

  • Esterbauer H, Cheeseman KH (1990) [42] determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-hydroxynonenal, in: methods in Enzymology. Elsevier, pp 407–421

    Google Scholar 

  • Fang X, Wu H, Wei J, Miao R, Zhang Y, Tian J (2022) Research progress on the pharmacological effects of berberine targeting mitochondria. Front Endocrinol 13:982145

  • Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM (2019) Chronic inflammation in the etiology of disease across the life span. Nat Med 25:1822–1832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garg G, Singh S, Singh AK, Rizvi SI (2017) Antiaging Effect of Metformin on Brain in naturally aged and accelerated Senescence Model of Rat. Rejuven Res 20:173–182

    Article  CAS  Google Scholar 

  • Gendy AM, Soubh A, Elnagar MR, Hamza E, Ahmed KA, Aglan A, El-Haddad AE, Farag MA, El-Sadek HM (2023) New insights into the role of berberine against 3-nitropropionic acid-induced striatal neurotoxicity: possible role of BDNF–TrkB–PI3K/Akt and NF-κB signaling. Food Chem Toxicol 175:113721

    Article  CAS  PubMed  Google Scholar 

  • Glancy B, Balaban RS (2012) Role of mitochondrial Ca2+ in the regulation of Cellular energetics. Biochemistry 51:2959–2973

    Article  CAS  PubMed  Google Scholar 

  • Gupta P, Gupta H, Tripathi S, Poluri KM (2023) Biochemical and metabolomic insights into antifungal mechanism of berberine against Candida Glabrata. Appl Microbiol Biotechnol 107:6085–6102

    Article  CAS  PubMed  Google Scholar 

  • Hadzi-Petrushev N, Stojkovski V, Mitrov D, Mladenov M (2014) d-galactose induced inflammation lipid peroxidation and platelet activation in rats. Cytokine 69:150–153

    Article  CAS  PubMed  Google Scholar 

  • Hussien HM, Abd-Elmegied A, Ghareeb DA, Hafez HS, Ahmed HEA, El-moneam NA (2018) Neuroprotective effect of berberine against environmental heavy metals-induced neurotoxicity and Alzheimer’s-like disease in rats. Food Chem Toxicol 111:432–444

    Article  CAS  PubMed  Google Scholar 

  • Ji Z-H, Liu C, Zhao H, Yu X-Y (2014) Neuroprotective effect of Biatractylenolide against Memory Impairment in d-Galactose-induced aging mice. J Mol Neurosci 55:678–683

    Article  PubMed  Google Scholar 

  • Kulkarni SK, Dhir A (2010) Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 24:317–324

    Article  CAS  PubMed  Google Scholar 

  • Kumar R, Kumar M, Rizvi SI (2021) Chitosan displays a potent caloric restriction Mimetic Effect in senescent rats. Rejuven Res 24:390–396

    Article  CAS  Google Scholar 

  • Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz A-G, Ahn B-W, Shaltiel S, Stadtman ER (1990) [49] determination of carbonyl content in oxidatively modified proteins. Methods in Enzymology. Elsevier, pp 464–478

    Google Scholar 

  • Li PA, Hou X, Hao S (2017) Mitochondrial biogenesis in neurodegeneration. J Neurosci Res 95:2025–2029

    Article  CAS  PubMed  Google Scholar 

  • Li F, Huang H, Wu Y, Lu Z, Zhou X, Tan F, Zhao X (2021) Lactobacillus fermentum HFY06 attenuates d-galactose-induced oxidative stress and inflammation in male Kunming mice. Food Funct 12:12479–12489

    Article  CAS  PubMed  Google Scholar 

  • Liu B, **e Y, Chen J, Xue J, Zhang X, Zhao M, Jia X, Wang Y, Qin S (2021) Protective Effect of Molecular Hydrogen Following Different Routes of Administration on D-Galactose-Induced Aging mice. J Inflamm Res Volume 14:5541–5550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Chen H, Yu T, Fu X, Qian C, Feng X (2023) Berberine mitigates intracerebral hemorrhage-induced neuroinflammation in a gut microbiota-dependent manner in mice. Aging 15:2705–2720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long J, Wang X, Gao H, Liu Z, Liu C, Miao M, Cui X, Packer L, Liu J (2007) d-Galactose toxicity in mice is associated with mitochondrial dysfunction: protecting effects of mitochondrial nutrient R-alpha-lipoic acid. Biogerontology 8:373–381

    Article  CAS  PubMed  Google Scholar 

  • López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) Hallm Aging. Cell 153:1194–1217

    Article  PubMed  PubMed Central  Google Scholar 

  • López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2023) Hallmarks of aging: an expanding universe. Cell 186:243–278

    Article  PubMed  Google Scholar 

  • Lu D-Y, Tang C-H, Chen Y-H, Wei I-H (2010) Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem 110:697–705

    Article  CAS  PubMed  Google Scholar 

  • Luo H, Kou T, Su Y, Shen Y, Yin L (2023) Experimental research on the evaluation of left ventricular systolic function by layered speckle tracking before and after berberine treatment in a cardiac hypertrophy rat model. Cardiovasc Diagnosis Therapy 13:367–383

    Article  PubMed  PubMed Central  Google Scholar 

  • Ma X, Jiang Y, Wu A, Chen X, Pi R, Liu M, Liu Y (2010) Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice. PLoS ONE 5:13489

    Article  PubMed  PubMed Central  Google Scholar 

  • Munkhzul C, Yi SS, Kim J, Lee S, Kim H, Moon J-S, Lee M (2023) The microRNA-mediated gene regulatory network in the hippocampus and hypothalamus of the aging mouse. PLoS ONE 18, 0291943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Navarro A, Gómez C, Sánchez-Pino M-J, González H, Bández MJ, Boveris AD, Boveris A (2005) Vitamin E at high doses improves survival, neurological performance, and brain mitochondrial function in aging male mice. Am J Physiol-Regul Integr Comp Physiol 289:R1392–R1399

    Article  CAS  PubMed  Google Scholar 

  • Okoro NO, Odiba AS, Osadebe PO, Omeje EO, Liao G, Fang W, ** C, Wang B (2021) Bioactive phytochemicals with anti-aging and Lifespan extending potentials in Caenorhabditis elegans. Molecules 26:7323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pantiya P, Thonusin C, Ongnok B, Chunchai T, Kongkaew A, Nawara W, Arunsak B, Chattipakorn N, Chattipakorn SC (2023) Chronic D-galactose administration induces natural aging characteristics, in rat’s brain and heart. Toxicology 492:153553

    Article  CAS  PubMed  Google Scholar 

  • Paradies G, Petrosillo G, Paradies V, Ruggiero FM (2011) Mitochondrial dysfunction in brain aging: role of oxidative stress and cardiolipin. Neurochem Int 58:447–457

    Article  CAS  PubMed  Google Scholar 

  • Qin X, Jiang M, Zhao Y, Gong J, Su H, Yuan F, Fang K, Yuan X, Yu X, Dong H, Lu F (2020) Berberine protects against diabetic kidney disease via promoting PGC-1α‐regulated mitochondrial energy homeostasis. Br J Pharmacol 177:3646–3661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sadigh-Eteghad S, Majdi A, McCann SK, Mahmoudi J, Vafaee MS, Macleod MR (2017) Correction: D-galactose-induced brain ageing model: a systematic review and meta-analysis on cognitive outcomes and oxidative stress indices. PLoS ONE 12, e0190328

    Article  PubMed  PubMed Central  Google Scholar 

  • Samadi P, Sarvarian P, Gholipour E, Asenjan KS, Aghebati-Maleki L, Motavalli R, Hojjat‐Farsangi M, Yousefi M (2020) Berberine: a novel therapeutic strategy for cancer. IUBMB Life 72:2065–2079

    Article  CAS  PubMed  Google Scholar 

  • Seth E, Ahsan AU, Kaushal S, Mehra S, Chopra M (2021) Berberine affords protection against oxidative stress and apoptotic damage in F1 generation of Wistar rats following lactational exposure to chlorpyrifos. Pestic Biochem Physiol 179:104977

    Article  CAS  PubMed  Google Scholar 

  • Shwe T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC (2018) Role of D-galactose-induced brain aging and its potential used for therapeutic interventions. Exp Gerontol 101:13–36

    Article  CAS  PubMed  Google Scholar 

  • Singh SP, Sashidhara KV (2017) Lipid lowering agents of natural origin: an account of some promising chemotypes. Eur J Med Chem 140:331–348

    Article  CAS  PubMed  Google Scholar 

  • Singh AK, Singh S, Garg G, Rizvi SI (2017) Rapamycin mitigates erythrocyte membrane transport functions and oxidative stress during aging in rats. Arch Physiol Biochem 124:45–53

    Article  PubMed  Google Scholar 

  • Singh AK, Singh SK, Nandi MK, Mishra G, Maurya A, Rai A, Rai GK, Awasthi R, Sharma B, Kulkarni GT (2019) Berberine: a plant-derived alkaloid with therapeutic potential to Combat Alzheimer’s disease. Cent Nerv Syst Agents Med Chem 19:154–170

    Article  CAS  PubMed  Google Scholar 

  • Song B, Tang X, Wang X, Huang X, Ye Y, Lu X, Wei X, Zeng Y (2012) Bererine induces peripheral lymphocytes immune regulations to realize its neuroprotective effects in the cerebral ischemia/reperfusion mice. Cell Immunol 276:91–100

    Article  CAS  PubMed  Google Scholar 

  • Srividhya R, Zarkovic K, Stroser M, Waeg G, Zarkovic N, Kalaiselvi P (2009) Mitochondrial alterations in aging rat brain: effective role of (–)-epigallo catechin gallate. Int J Dev Neurosci 27:223–231

    Article  CAS  PubMed  Google Scholar 

  • Stadtman ER, Berlett BS (2008) Reactive oxygen-mediated protein oxidation in aging and disease. Drug Metab Rev 30:225–243

    Article  Google Scholar 

  • Tatullo M (2023) Entropy meets physiology: should we translate Ageing as Disorder? Stem cells. https://doi.org/10.1093/stmcls/sxad084

  • Tong T, Guo J, Wu Y, Sharma D, Sangar M, Sangpreecha N, Song D, Unno T, Ham K, Kang S (2023) Dietary supplementation of ark clams protects gut health and modifies gut microbiota in D-galactose‐induced aging rats. J Sci Food Agric 104(2):675–685

    Article  PubMed  Google Scholar 

  • Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84

    Article  CAS  PubMed  Google Scholar 

  • Wang P, Wang X, Wang Q, Jiao Y, Wang X, Chen C, Chen H, Song T (2023) Cognitive improvement via a modulated rhythmic pulsed magnetic field in D-galactose-induced accelerated aging mice. Brain Res 1810:148372

    Article  CAS  PubMed  Google Scholar 

  • Witko-Sarsat V, Friedlander M, Capeillère-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49:1304–1313

    Article  CAS  PubMed  Google Scholar 

  • Witko-Sarsat V, Friedlander M, Khoa TN, Capeillère-Blandin C, Nguyen AT, Canteloup S, Dayer J-M, Jungers P, Drüeke T, Descamps-Latscha B (1998) Advanced oxidation protein products as Novel mediators of inflammation and monocyte activation in chronic renal Failure1, 2. J Immunol 161:2524–2532

    Article  CAS  PubMed  Google Scholar 

  • Yadawa AK, Srivastava P, Singh A, Kesherwani R, Bhoumik S, Kumar R, Arya JK, Rizvi SI (2023) Berberine may provide redox homeostasis during aging in rats. Z für Naturforschung C 78:307–315

    Article  CAS  Google Scholar 

  • Yanar K, Aydın S, Çakatay U, Mengi M, Buyukpınarbaşılı N, Atukeren P, Sitar ME, Sönmez A, Uslu E (2011) Protein and DNA oxidation in different anatomic regions of rat brain in a mimetic ageing model. Basic Clin Pharmacol Toxicol 109:423–433

    Article  CAS  PubMed  Google Scholar 

  • Yang M, Liu Y, Luo S, Liu C, Jiang N, Li C, Zhao H, Han Y, Chen W, Li L, Sun L (2024) DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis. Acta Pharmacol Sin. https://doi.org/10.1038/s41401-023-01216-1

  • Zhao H, Halicka HD, Li J, Darzynkiewicz Z (2013) Berberine suppresses gero-conversion from cell cycle arrest to senescence. Aging 5:623–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhuang J, Chen X, Cai G, Wu D, Tu C, Zhu S, Huang Y, Xu P, Zhong Z (2021) Age-related accumulation of advanced oxidation protein products promotes osteoclastogenesis through disruption of redox homeostasis. Cell Death Dis 12:1160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zych M, Wojnar W, Kielanowska M, Folwarczna J, Kaczmarczyk-Sedlak I (2020) Effect of Berberine on Glycation, Aldose reductase activity, and oxidative stress in the lenses of Streptozotocin-Induced Diabetic rats in Vivo—A preliminary study. Int J Mol Sci 21:4278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Dr. Arun Kumar Yadawa is grateful to University Grant Commission, India for providing Dr. DS Kothari Postdoctoral Fellowship. Authors also acknowledge the Department of Biotechnology, Government of India for providing support under the “Research Resources, Service Facilities, and Platforms” program.

Funding

This experimental work was financially supported by University Grant Commission, India in the form of Dr. DS Kothari fellowship (No.F.4 − 2/2006 (BSR)/BL/19–20/0240; dated 23.06.2020) to Dr. Arun Kumar Yadawa.

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SIR designed the experiments, interpreted the results and critically reviewed the manuscript. AKY designed and performed the experiments, analysed the data, interpreted the results and wrote the manuscript. AS, PS, RK and JKA performed the experiments.

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Correspondence to Syed Ibrahim Rizvi.

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All animal care and experimental procedures were carried out with the approval of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) and the Institutional Animal Ethics Committee (IAEC/AU/2019(1)/08), University of Allahabad, India.

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Yadawa, A.K., Srivastava, P., Singh, A. et al. Berberine attenuates brain aging via stabilizing redox homeostasis and inflammation in an accelerated senescence model of Wistar rats. Metab Brain Dis 39, 649–659 (2024). https://doi.org/10.1007/s11011-024-01350-7

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