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Multifaceted Neuroprotective Role of Punicalagin: A Review

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Abstract

Millions of people worldwide are currently afflicted with neurologic conditions like a seizure, depression, stress, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, the precise etiopathology of these diseases is still unknown. Substantial studies are being conducted to discover more treatments against these disorders because many patients do not experience the therapeutic benefits that would be expected from using existing pharmaceutical strategies. Herbal medicines which have been used in traditional medicine for millennia to treat various neurological problems are also being investigated and scientifically assessed. Punicalagin is a known polyphenol that has significant antioxidant, anti-inflammatory, anti-viral, anti-proliferative, and anti-cancer properties. Around the world, traditional use of herbal drugs is gaining wider acceptance as a part of complementary and alternative medicine. The scientific community should pay attention to these many neuroprotective pharmacodynamic activities of Punicalagin to create effective pharmacotherapeutic plans, as evidenced by mounting data in pre-clinical research investigations. The current review describes the recent studies on the pharmacological effects of Punicalagin in a variety of neurological illnesses and paves the way for further study in this field.

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References

  1. Parvez MK (2018) Natural or plant products for the treatment of neurological disorders: current knowledge. Curr Drug Metab 19(5):424–428

    Article  CAS  PubMed  Google Scholar 

  2. Edwards S, Lawrence MJ, Cable C, Heinrich M (2018) Where do herbal medicines belong? Part 1—an overview of CAM. Lung Cancer 15:05

    Google Scholar 

  3. Patel S, Goyal R (2012) Emblica officinalis geart.: a comprehensive review on phytochemistry, pharmacology, and ethnomedicinal uses. Res J Med Plant 6:6–16

    Article  CAS  Google Scholar 

  4. Morton J (1987) Pomegranate. In: fruits of warm climates 352–355

  5. Medjakovic S, Jungbauer A (2013) Pomegranate: a fruit that ameliorates metabolic syndrome. Food Funct 4:19–39

    Article  CAS  PubMed  Google Scholar 

  6. Masci A, Coccia A, Lendaro E, Mosca L, Paolicelli P, Cesa S (2016) Evaluation of different extraction methods from pomegranate whole fruit or peels and the antioxidant and antiproliferative activity of the polyphenolic fraction. Food Chem 202:59–69

    Article  CAS  PubMed  Google Scholar 

  7. Jalal H, Pal MA, Ahmad SR, Rather M, Andrabi M, Hamdani S (2018) Physico-chemical and functional properties of pomegranate peel and seed powder. J Pharm Innov 7:1127–1131

    Google Scholar 

  8. Khatib M, Innocenti M, Giuliani C, Al-Tamimi A, Romani A, Mulinacci N (2017) Mesocarp and exocarp of Laffan and wonderful pomegranate varieties: by-products as a source of ellagitannins. Int J Food Nutr Sci 4:1–7

    Google Scholar 

  9. Altieri F, Cairone F, Giamogante F, Carradori S, Locatelli M, Chichiarelli S, Cesa S (2019) Influence of ellagitannins extracted by pomegranate fruit on disulfide isomerase PDIA3 activity. Nutrients 11:186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bellone JA, Murray JR, Jorge P, Fogel TG, Kim M, Wallace DR, Hartman RE (2019) Pomegranate supplementation improves cognitive and functional recovery following ischemic stroke: a randomized trial. Nutr Neurosci. https://doi.org/10.1080/1028415X.2018.1436413

    Article  PubMed  Google Scholar 

  11. Tortora K, Femia AP, Romagnoli A, Sineo I, Khatib M, Mulinacci N, Giovannelli L, Caderni G (2018) Pomegranate by-products in colorectal cancer chemoprevention: effects in apc-mutated Pirc rats and mechanistic studies in vitro and ex vivo. Mol Nutr Food Res 62:1700401

    Article  Google Scholar 

  12. Shakeri A, Zirak MR, Sahebkar A (2017) Ellagic acid: a logical lead for drug development? Curr. Pharm Des 23:1–17

    Google Scholar 

  13. Ríos JL, Giner RM, Marín M, Recio MC (2018) A pharmacological update of ellagic acid. Planta Med 84:1068–1093

    Article  PubMed  Google Scholar 

  14. Lee HL, Kang KS (2016) Protection effect of punicalagin isolated from pomegranate on inflammation and ethanol-induced gastric mucosal injury. Bull Korean Chem Soc 37:1778–1782

    Article  CAS  Google Scholar 

  15. Jain V, Pareek A, Bhardwaj Sinha YR, Gupta SK, Singh MM (2021) Punicalagin and ellagic acid containing Punica granatum L. fruit rind extract prevents vincristine-induced neuropathic pain in rats: an in silico and in vivo evidence of GABAergic action and cytokine inhibition. Nutr Neurosci 25(10):2149–2166

    Article  PubMed  Google Scholar 

  16. Rojanathammanee L, Floden AM, Manocha GD, Combs CK (2015) Attenuation of microglial activation in a mouse model of Alzheimer’s disease via NFAT inhibition. J Neuroinflamm 42:2015

    Google Scholar 

  17. Giamogante F, Marrocco I, Cervoni L, Eufemi M, Chichiarelli S, Altieri F (2018) Punicalagin, an active pomegranate component, is a new inhibitor of PDIA3 reductase activity. Biochimie 147:122–129

    Article  CAS  PubMed  Google Scholar 

  18. Kim YE, Hwang CJ, Lee HM, Kim CS, Son DJ, Ham YW, Hellström M, Han SB, Kim HS, Park EK, Hong JT (2017) Inhibitory effect of punicalagin on lipopolysaccharide-induced neuroinflammation, oxidative stress and memory impairment via inhibition of nuclear factor-kappab. Neuropharmacology 117:21–32

    Article  CAS  PubMed  Google Scholar 

  19. Seo EJ, Fischer N, Efferth T (2018) Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer’s disease. Pharmacol Res 129:262–273

    Article  CAS  PubMed  Google Scholar 

  20. Chen P, Chen F, Lei F, Zhou B (2023) Pomegranate polyphenol punicalagin improves learning memory deficits, redox homeostasis, and neuroinflammation in aging mice. Phytother Res 37(9):3655–3674

    Article  CAS  PubMed  Google Scholar 

  21. Chu J, Han W (2018) Punicalagin exerts beneficial functions in 6-hydroxydopamine-treated SH-SY5Y cells by attenuating mitochondrial dysfunction and inflammatory responses. Med Sci Monit 24:5905–5913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Elfotuh K, Hamdan AME, Abbas AN, Alahmre ATS, Elewa MAF, Masoud RAE, Ali AA, Othman M, Kamal MM, Hassan FAM, Khalil MG, El-Sisi AM, Hady MMMA, Azazy MAEE, Awny MM, Wahid A (2022) Evaluating the neuroprotective activities of vinpocetine,punicalagin, niacin and vitamin E against behavioural andmotor disabilities of manganese-induced Parkinson’s diseasein sprague dawley rats. Bio & Pharmaco 153:113330

    Google Scholar 

  23. Salem HA, Abu-Elfotuh K, Alzahrani S, Rizk NI, Ali HS, Elsherbiny N, Aljohani A, Hamdan AME, Chellasamy P, Abdou NS, Gowifel AMH, Darwish A, Ibrahim OM, Elmageed ZYA (2023) Punicalagin’s protective effects on Parkinson’s progression in socially isolated and socialized rats: insights into multifaceted pathway. Pharmaceutics 15(10):2420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Clementi ME, Sampaolese B, Lazzarino G, Giardina B (2015) Effect of punicalagin and resveratrol on methionine sulfoxide reductase: a possible protective contribution against Alzheimer’s disease. J Prev Alzheimers Dis 2(1):33–37

    CAS  PubMed  Google Scholar 

  25. Pathakoti K, Goodla L, Manubolu M, Tencomnao T (2016) Metabolic alterations and the protective effect of punicalagin against glutamate-induced oxidative toxicity in HT22 cells. Neurotox Res. https://doi.org/10.1007/s12640-016-9697-2

    Article  Google Scholar 

  26. Cao K, Lv W, Hu S, Gao J, Liu J, Feng Z (2020) Punicalagin activates AMPK/PGC-1α/Nrf2 cascade in mice: the potential protective effect against prenatal stress. Mol Nutr Food Res. https://doi.org/10.1002/mnfr.202000312

    Article  PubMed  Google Scholar 

  27. Mitra S, Das R, Emran TB, Labib RK, Tabassum N, Islam F, Sharma R, Ahmad I, Nainu F, Chidambaram K, Alhumaydhi FA, Chandran D, Capasso R, Wilairatana P (2022) Diallyl disulfide: a bioactive garlic compound with anticancer potential. Front Pharmacol 13:943967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. He X, Pei S, Meng X, Hua Q, Zhang T, Wang Y, Zhang Z, Zhu X, Liu R, Guo Y, Chen L, Li D (2022) Punicalagin attenuates neuronal apoptosis by upregulating 5-Hydroxymethylcytosine in the diabetic mouse brain. J Agric Food Chem 70(16):4995–5004

    Article  CAS  PubMed  Google Scholar 

  29. Yaidikar L, Thakur S (2015) Punicalagin attenuated cerebral ischemia–reperfusion insult via inhibition of proinflammatory cytokines, up-regulation of Bcl-2, down-regulation of bax, and caspase-3. Mol Cell Biochem 402:141–148

    Article  CAS  PubMed  Google Scholar 

  30. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):270–279

    Article  PubMed  Google Scholar 

  31. Siddiqui N, Ali J, Parvez S, Zameer S, Najmi AK, Akhtar M (2021) Linagliptin, a DPP-4 inhibitor, ameliorates Aβ (1–42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in a rat model of Alzheimer’s disease. Neuropharmacol 195:1–14

    Article  Google Scholar 

  32. Husain I, Akhtar M, Vohora D, Abdin MZ, Islamuddin M, Akhtar MJ, Najmi AK (2017) Rosuvastatin attenuates high-salt and cholesterol diet induced neuroinflammation and cognitive impairment via preventing nuclear factor KappaB pathway. Neurochem Res 42(8):2404–2416

    Article  CAS  PubMed  Google Scholar 

  33. Zameer S, Najmi AK, Vohora D, Akhtar M (2017) A review on therapeutic potentials of Trigonella foenum graecum (fenugreek) and its chemical constituents in neurological disorders: complementary roles to its hypolipidemic, hypoglycemic, and antioxidant potential. Nutr Neurosci 21(8):539–545

    Article  PubMed  Google Scholar 

  34. Hampel H, Mesulam MM, Cuello AC, Khachaturian AS, Farlow MR, Snyder PJ, Giacobini E, Khachaturian ZS, Group CSW (2017) Revisiting the cholinergic hypothesis in Alzheimer’s disease: emerging evidence from translational and clinical research. Alzheimers Dement 1552–5260(17):33719–33716

    Google Scholar 

  35. Morzelle MC, Salgado JM, Massarioli AP, Bachiega P, Rios AO, Alencar SM, Schwember AR, Camargo AC (2019) Potential benefits of phenolics from pomegranate pulp and peel in Alzheimer’s disease: antioxidant activity and inhibition of acetylcholinesterase. J Food Bioact 5:136–141

    Article  Google Scholar 

  36. Mazumder KM, Choudhury S, Borah A (2019) An in silico investigation on the inhibitory potential of the constituents of pomegranate juice on antioxidant defense mechanism: relevance to neurodegenerative diseases. IBRO Rep 6:153–159

    Article  PubMed  PubMed Central  Google Scholar 

  37. El-Missiry MA, ElKomy MA, Othman AI, AbouEl-ezz AM (2018) Punicalagin ameliorates the elevation of plasma homocysteine, amyloid-β, TNF-α and apoptosis by advocating antioxidants and modulating apoptotic mediator proteins in brain. Biomed Pharmacother 102:472–480

    Article  CAS  PubMed  Google Scholar 

  38. Olajide O, Fiebich B (2012) Anti-neuroinflammatory and anti-amyloidogenic properties of punicalagin in LPS-activated rat primary microglia. Proc Br Pharmacol Soc 10(4):137

    Google Scholar 

  39. Miller DB, O’Callaghan JP (2015) Biomarkers of Parkinson’s disease: present and future. Metabolism 64(3 Suppl 1):S40–S46

    Article  CAS  PubMed  Google Scholar 

  40. Gasser T (2009) Molecular pathogenesis of Parkinson disease: insights from genetic studies. Exp Rev Mol Med 11:e22

    Article  Google Scholar 

  41. Olanow CW, Stern MB, Sethi S (2009) The scientific and clinical basis for the treatment of Parkinson disease. Neurology. https://doi.org/10.1212/WNL.0b013e3181a1d44c

    Article  PubMed  Google Scholar 

  42. Navale GR, Chauhan R, Saini S, Roy P, Ghosh K (2023) Effect of cycloastragenol and punicalagin on prp (106–126) and Aβ (25–35) oligomerization and fibrillizaton. Biophys Chem 302:107108

    Article  CAS  PubMed  Google Scholar 

  43. Sannino G, Pasqualini L, Ricciardelli E, Montilla P, Soverchia L, Ruggeri B, Falcinelli S, Renzi A, Ludka C, Kirchner T (2016) Acute stress enhances the expression of neuroprotection- and neurogenesis-associated genes in the hippocampus of a mouse restraint model. Oncotarget 7(8):8455–8465

    Article  PubMed  PubMed Central  Google Scholar 

  44. Prokai D, Berga SL (2016) Neuroprotection via reduction in stress: altered menstrual patterns as a marker for stress and implications for long-term neurologic health in women. Int J Mol Sci 17(12):2147

    Article  PubMed  PubMed Central  Google Scholar 

  45. Suomalainen A, Battersby BJ (2017) Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol 19:77–92

    Article  PubMed  Google Scholar 

  46. Kumar CP (2013) Effect of Emblica officinalis on stress induced biochemical and psychological changes in mice. Global J Med Res Veterinary Sci Veterinary Med 13(2):25–28

    Google Scholar 

  47. Wankhar D, Devi RS, Ashok I (2014) Emblica officinalis outcome on noise stress induced behavioral changes in wistar albino rats. Biomed Prev Nutr 4(2):219–224

    Article  Google Scholar 

  48. Yaidikar L, Byna B, Thakur SR (2014) Neuroprotective effect of punicalagin against cerebral ischemia reperfusion-induced oxidative brain Injury in rats. J Stroke Cerebrovasc Dis 23(10):2869–2878

    Article  PubMed  Google Scholar 

  49. Fernández J, Silvan B, Entrialgo-Cadierno R, Villar CJ, Capasso R, Uranga JA, Lombo F, Abalo R (2021) Antiproliferative and palliative activity of flavonoids in colorectal cancer. Biomed Pharmacother 143:112241

    Article  PubMed  Google Scholar 

  50. Rocha F, Viana C, Filho LCPA, Almeida TS, Neto JJL, Neto VV, Tabosa PMS, Nunes-Pinheiro DCS, Girão-Carmona VCC, Carvalho AFU, Mota EF (2023) In vitro anti-inflammatory activity and ameliorative effects on gastric ulcers of licania rigida Benth seed extract. Inflammopharmacology 31(5):2631–2640

    Article  Google Scholar 

  51. Agagunduz D, Icer MA, Yesildemir O, Kocak T, Kocyigit E, Capasso R (2023) The roles of dietary lipids and lipidomics in gut-brain axis in type 2 diabetes mellitus. J Translational Med 21:240

    Article  CAS  Google Scholar 

  52. Agagunduz D, Cocozza E, Cemali O, Bayazıt AD, Nanì MF, Cerqua I, Morgillo F, Saygılı SK, Canani RB, Amero P, Capasso R (2023) Understanding the role of the gut microbiome in gastrointestinal cancer: a review. Front Pharmacol 14:1130562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Agagunduz D, Kocaadam-Bozkurt B, Bozkurt O, Sharma H, Esposito R, ozogul F, Capasso R (2022) Microbiota alteration and modulation in Alzheimer’s disease by gerobiotics: the gut-health axis for a good mind. Biomed Pharmacother 153:113430

    Article  CAS  PubMed  Google Scholar 

  54. Jurenka JS (2008) Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern. Med Rev A J Clin 13:128–144

    Google Scholar 

  55. Syed DN, Chamcheu JC, Adhami VM, Mukhtar H (2013) Pomegranate extracts and cancer prevention: molecular and cellular activities. Anti-Cancer Agents Med Chem 13:1149–1161

    Article  CAS  Google Scholar 

  56. Paller CJ, Pantuck A, Carducci MA (2017) A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis 20:265–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Singh B, Singh JP, Kaur A, Singh N (2018) Phenolic compounds as beneficial phytochemicals in pomegranate (Punica granatum L.) peel: a review. Food Chem 261:75–86

    Article  CAS  PubMed  Google Scholar 

  58. Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D (2005) In vitro antiproliferative, apoptotic and antioxi-dant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem 16:360–367

    Article  CAS  PubMed  Google Scholar 

  59. Kraszni M, Marosi A, Larive CK (2013) NMR assignments and the acid–base characterization of the pomegranate ellagitannin punicalagin in the acidic pH-range. Anal Bioanal Chem 405:5807–5816

    Article  CAS  PubMed  Google Scholar 

  60. Oudane B, Boudemagh D, Bounekhel M, Sobhi W, Vidal M, Broussy S (2018) Isolation, characterization, antioxidant activity, and protein-precipitating capacity of the hydrolyzable tannin punicalagin from pomegranate yellow peel (Punica granatum). J Mol Struct 1156:390–396

    Article  CAS  Google Scholar 

  61. Tang J, Li B, Hong S, Liu C, Min J, Hu M, Li Y, Liu Y, Hong L (2017) Punicalagin suppresses the proliferation and invasion of cervical cancer cells through inhibition of the β-catenin pathway. Mol Med Rep 16:1439–1444

    Article  CAS  PubMed  Google Scholar 

  62. Bialonska D, Ramnani P, Kasimsetty SG, Muntha KR, Gibson GR, Ferreira D (2010) The influence of pomegranate by-product and punicalagins on selected groups of human intestinal microbiota. Int J Food Microbiol 140:175–182

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors of this research express their gratitude to Meerut Institute of Engineering and Technology, Meerut for extending his hel** hands required to write this review work.

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  1. Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, 250005, India

    Nazia Siddiqui, Alimuddin Saifi, Anurag Chaudhary, Prabhash Nath Tripathi, Ankit Chaudhary & Alok Sharma

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Siddiqui, N., Saifi, A., Chaudhary, A. et al. Multifaceted Neuroprotective Role of Punicalagin: A Review. Neurochem Res 49, 1427–1436 (2024). https://doi.org/10.1007/s11064-023-04081-w

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