Abstract

Introduction: Latest findings show that the proline-rich polypeptide complex (PRP), known as Colostrinin, and its component peptides may have beneficial effects on cellular response to oxidative stress, which is the main aspect of aging and an essential feature in neurodegenerative disorders. Recently isolated and described nonapeptide NP-POL (RPKHPIKHQ) was shown to have potential protective properties in neuronal cells, including the regulation of cell survival, neurite protection and intracellular ROS release. Based on those findings, further studies were performed covering the possible effects of NP-POL on molecular and enzymatic mechanisms of response to oxidative stress. Materials/Methods: To evaluate the regulatory effects of NP-POL on oxidative stress, 6-hydroxydopamine-treated rat pheochromocytoma (PC12) cells were used as an experimental model and a series of assays were performed, including H2O2 release, glutathione turnover and the expression and activity of superoxide dismutases (Mn-SOD and Cu-Zn-SOD). Results: NP-POL was shown to modify the cellular antioxidative response to reverse the toxic effects of 6-hydroxydopamine. The direct effects of NP-POL include a significant reduction of the total amount of released H2O2 and enhanced glutathione activation. Moreover, NP-POL enhanced the expression of superoxide dismutase in untreated cells, which confirms its contribution in secondary enzymatic response. Discussion: The newly discovered peptide NP-POL, isolated from the colostrum-derived polypeptide complex Colostrinin, was shown to have potential antioxidant and neuroprotective properties, which makes it very promising as a natural therapeutic in neurodegenerative diseases.

References

• 1. Alekseenko A.V., Kolos V.A., Vasim T.V., Fedorovich S.V.: Glutamateinduces the formation of free radicals in rat brain synaptosomes.Biofizika, 2009; 54: 876–880
  Google Scholar
• 2. Allen R.G., Tresini M.: Oxidative stress and gene regulation. FreeRadic. Biol. Med., 2000; 28: 463–499
  Google Scholar
• 3. Bacsi A., Stanton G.J., Hughes T.K., Kruze M., Boldogh I.: Colostrinin-driven neurite outgrowth requires p53 activation in PC12cells. Cell Mol. Neurobiol., 2005; 25: 1123–1139
  Google Scholar
• 4. Bacsi A., Woodberry M., Kruzel M.L., Boldogh I.: Colostrinindelays the onset of proliferative senescence of diploid murine fibroblastcells. Neuropeptides, 2007; 41: 93–101
  Google Scholar
• 5. Bilikiewicz A., Gaus W.: Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer’sdisease. J. Alzheimers Dis., 2004; 6: 17–26
  Google Scholar
• 6. Blum D., Torch S., Lambeng N., Nissou M., Benabid A.L., SadoulR., Verna J.M.: Molecular pathways involved in the neurotoxicityof 6-OHDA, dopamine and MPTP: Contribution to the apoptotictheory in Parkinson’s disease. Prog. Neurobiol., 2001; 65: 135–172
  Google Scholar
• 7. Boldogh I., Aguilera-Aguirre L., Bacsi A., Choudhury B.K., Saavedra-Molina A., Kruzel M.: Colostrinin decreases hypersensitivityand allergic responses to common allergens. Int. Arch. AllergyImmunol., 2008; 146: 298–306
  Google Scholar
• 8. Boldogh I., Kruzel M.L.: Colostrinin: An oxidative stress modulatorfor prevention and treatment of age-related disorders. J.Alzheimers Dis., 2008; 13: 303–321
  Google Scholar
• 9. Boldogh I., Liebenthal D., Hughes T.K., Juelich T.L., GeorgiadesJ.A., Kruzel M.L., Stanton G.J.: Modulation of 4HNE-mediatedsignaling by proline-rich peptides from ovine colostrum. J. Mol.Neurosci., 2003; 20: 125–134
  Google Scholar
• 10. Buettner G.R.: Superoxide dismutase in redox biology: Theroles of superoxide and hydrogen peroxide. Anti-Cancer AgentsMed. Chem., 2011; 11: 341–346
  Google Scholar
• 11. Douraghi-Zadeh D., Matharu B., Razvi A., Austen B.: The protectiveeffects of the nutraceutical, colostrinin, against Alzheimer’sdisease, is mediated via prevention of apoptosis in humanneurons induced by aggregated β-amyloid. J. Nutr. Health Aging,2009; 13: 522–527
  Google Scholar
• 12. Forman H.J., Maiorino M., Ursini F.: Signalling functions of reactiveoxygen species. Biochemistry, 2010; 49: 835–842
  Google Scholar
• 13. Forman H.J., Zhang H., Rinna A.: Glutathione: Overview of itsprotective roles, measurement, and biosynthesis. Mol. AspectsMed., 2009; 30: 1–12
  Google Scholar
• 14. Froud K.E., Wardhaugh T., Banks D., Saffrey M.J., Stewart M.G.:Colostrinin™ alleviates amyloid-β induced toxicity in rat primaryhippocampal cultures. J. Alzheimers Dis., 2010; 20: 423–426
  Google Scholar
• 15. Gawryluk J.W., Wang J.F., Andreazza A.C., Shao L., Young L.T.:Decreased levels of glutathione, the major brain antioxidant, inpost-mortem prefrontal cortex from patients with psychiatric disorders.Int. J. Neuropsychopharmacol., 2011; 14: 123–130
  Google Scholar
• 16. Hermida-Ameijeiras A., Méndez-Alvarez E., Sánchez-IglesiasS., Sanmartín-Suárez C., Soto-Otero R.: Autoxidation and MAOmediatedmetabolism of dopamine as a potential cause of oxidativestress: Role of ferrous and ferric ions. Neurochem. Int, 2004;45: 103–116
  Google Scholar
• 17. Janusz M., Lisowski J.: Proline-rich polypeptide (PRP) – an immunomodulatorypeptide from ovine colostrum. Arch. Immunol.Ther. Exp., 1993; 41: 275–279
  Google Scholar
• 18. Janusz M., Zabłocka A.: Colostral proline-rich polypeptides– immunoregulatory properties and prospects of therapeutic usein Alzheimer’s disease. Curr. Alzheimer Res. 2010; 7: 323–333
  Google Scholar
• 19. Kim G.H., Kim J.E., Rhie S.J., Yoon S.: The role of oxidative stressin neurodegenerative diseases. Exp. Neurobiol., 2015; 24: 325–340
  Google Scholar
• 20. Lamichhane A., Chaudhary V., Sah N.K., Singh M., Pandey R.:Low molecular weight antioxidants (LMWA) and their orchestration.Nepal J. Med. Sci., 2013; 2: 171–180
  Google Scholar
• 21. Lebovitz R.M., Zhang H., Vogel H., Cartwright J.Jr., Dionne L.,Lu N., Huang S., Matzuk M.M.: Neurodegeneration, myocardial injury,and perinatal death in mitochondrial superoxide dismutasedeficientmice. Proc. Natl. Acad. Sci. USA, 1996; 93: 9782–9787
  Google Scholar
• 22. Lemieszewska M., Polanowski A., Wilusz T., SokołowskaA., Zambrowicz A., Mikołajewicz K., Macała J., Rymaszewska J.,Zabłocka A.: Isolation and characterization of NP-POL nonapeptidefor possible therapeutic use in Parkinson’s disease. Oxid. Med. Cell.Longev., 2018; 2018: 3760124
  Google Scholar
• 23. Leszek J., Inglot A.D., Janusz M., Byczkiewicz F., Kiejna A., GeorgiadesJ., Lisowski J.: Colostrinin proline-rich polypeptide complexfrom ovine colostrum – a long-term study of its efficacy in Alzheimer’sdisease. Med. Sci Monit, 2002; 8: PI93–PI96
  Google Scholar
• 24. Magalingam K.B., Radhakrishnan A., Haleagrahara N.: Protectiveeffects of flavonol isoquercitrin, against 6-hydroxy dopamine(6-OHDA)-induced toxicity in PC12 cells. BMC Res. Notes, 2014; 7: 49
  Google Scholar
• 25. Magalingam K.B., Radhakrishnan A., Haleagrahara N.: Rutin, abioflavonoid antioxidant protects rat pheochromocytoma (PC-12)cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity.Int. J. Mol. Med., 2013; 32: 235–240
  Google Scholar
• 26. Meiser J., Weindl D., Hiller K.: Complexity of dopamine metabolism.Cell Commun. Signal., 2013; 11: 34
  Google Scholar
• 27. Meng J., Lv Z., Qiao X., Li X., Li Y., Zhang Y., Chen C.: The decayof redox-stress response capacity is a substantive characteristicof aging: Revising the redox theory of aging. Redox Biol., 2017;11: 365–374
  Google Scholar
• 28. Morgan M.J., Liu Z.G.: Crosstalk of reactive oxygen species andNF-κB signalling. Cell Res., 2011; 21: 103–115
  Google Scholar
• 29. Patel R., Rinker L., Peng J., Chilian W.M.: Reactive oxygen species:The good and the bad. In: Reactive Oxygen Species (ROS) inLiving Cells, ed.: C. Filip, E. Albu, IntechOpen Ltd., London 2018
  Google Scholar
• 30. Pick E., Keisari Y.: A simple colorimetric method for the measurementof hydrogen peroxide produced by cells in culture. J. Immunol.Methods, 1980; 38: 161–170
  Google Scholar
• 31. Popik P., Bobula B., Janusz M., Lisowski J., Vetulani J.: Colostrinin,a polypeptide isolated from early milk, facilitates learningand memory in rats. Pharmacol. Biochem. Behav., 1999; 64: 183–189
  Google Scholar
• 32. Qian Y., Guan T., Huang M., Cao L., Li Y., Cheng H., Jin H., Yu D.:Neuroprotection by the soy isoflavone, genistein, via inhibition ofmitochondria-dependent apoptosis pathways and reactive oxygeninduced-NF-κB activation in a cerebral ischemia mouse model.Neurochem. Int., 2012; 60: 759–767
  Google Scholar
• 33. Rahman I., Kode A., Biswas S.K.: Assay for quantitative determinationof glutathione and glutathione disulfide levels usingenzymatic recycling method. Nat. Protoc., 2006; 1: 3159–3165
  Google Scholar
• 34. Ray P.D., Huang B.W., Tsuji Y.: Reactive oxygen species (ROS)homeostasis and redox regulation in cellular signaling. Cell Signal.,2012; 24: 981–990
  Google Scholar
• 35. Rio D.C., Ares M. Jr., Hannon G.J., Nilsen T.W.: Purification ofRNA using TRIzol (TRI reagent). Cold Spring Harb. Protoc., 2010;2010: pdb.prot5439
  Google Scholar
• 36. Saso L., Firuzi O.: Pharmacological applications of antioxidants:Lights and shadows. Curr. Drug Targets, 2014; 15: 1177–1199
  Google Scholar
• 37. Schulz J.B., Lindenau J., Seyfried J., Dichgans J.: Glutathione,oxidative stress and neurodegeneration. Eur. J. Biochem., 2000;267: 4904–4911
  Google Scholar
• 38. Schuster D., Rajendran A., Hui S.W., Nicotera T., SrikrishnanT., Kruzel M.L.: Protective effect of colostrinin on neuroblastomacell survival is due to reduced aggregation of β-amyloid. Neuropeptides,2005; 39: 419–426
  Google Scholar
• 39. Shimizu E., Hashimoto K., Komatsu N., Iyo M.: Roles of endogenousglutathione levels on 6-hydroxydopamine-induced apoptoticneuronal cell death in human neuroblastoma SK-N-SH cells.Neuropharmacology, 2002; 43: 434–443
  Google Scholar
• 40. Szaniszlo P., German P., Hajas G., Saenz D.N., Kruzel M., BoldoghI: New insights into clinical trial for colostrinin™ in Alzheimer’sdisease. J. Nutr. Health. Aging, 2009; 13: 235–241
  Google Scholar
• 41. Tabassum N., Rasool S., Malik Z.A., Ahmad F.: Natural cognitiveenhancers. J. Pharm. Res., 2012; 5: 153–160
  Google Scholar
• 42. Wang X., Michaelis E.K.: Selective neuronal vulnerability tooxidative stress in the brain. Front. Aging Neurosci., 2010; 2: 12
  Google Scholar
• 43. Wang Y., Branicky R., Noë A., Hekimi S.: Superoxide dismutases:Dual roles in controlling ROS damage and regulating ROS signaling.J. Cell Biol., 2018; 217: 1915–1928
  Google Scholar
• 44. Wu G., Fang Y.Z., Yang S., Lupton J.R., Turner N.D.: Glutathionemetabolism and its implications for health. J. Nutr., 2004; 134:489–492
  Google Scholar
• 45. Zabłocka A., Janusz M..: Effect of the proline-rich polypeptidecomplex/colostrinin™ on the enzymatic antioxidant system. Arch.Immun. Ther. Exp., 2012; 60: 383–390
  Google Scholar
• 46. Zabłocka A., Janusz M., Macała J., Lisowski J.: A proline-richpolypeptide complex and its nonapeptide fragment inhibit nitricoxide production induced in mice. Regul. Pept., 2005; 125: 35–39
  Google Scholar
• 47. Zabłocka A., Janusz M., Macała J., Lisowski J.: A proline-richpolypeptide complex (PRP) isolated from ovine colostrum. Modulationof H2O2 and cytokine induction in human leukocytes. Int.Immunopharmacol., 2007; 7: 981–988
  Google Scholar
• 48. Zabłocka A., Janusz M., Rybka K., Wirkus-Romanowska I.,Kupryszewski G., Lisowski J.: Cytokine-inducing activity of a proline-rich polypeptide complex (PRP) from ovine colostrum and itsactive nonapeptide fragment analogs. Eur. Cytokine Netw., 2001;12: 462-467
  Google Scholar
• 49. Zabłocka A., Siednienko J., Mitkiewicz M., Gorczyca W.A.,Lisowski J., Janusz M.: Proline-rich polypeptide complex (PRP)regulates secretion of inflammatory mediators by its effect on NF–κB activity. Biomed. Pharmacother., 2010; 64: 16–20
  Google Scholar
• 50. Zabłocka A., Sokołowska A., Macała J., Bartoszewska M., MitkiewiczM., Janusz M., Wilusz T., Polanowski A.: Colostral prolinerichpolypeptide complexes. Comparative study of the antioxidantproperties, cytokine-inducing activity, and nitric oxide release ofpreparations produced by a laboratory and a large-scale method.Int. J. Pept. Res. Ther., 2020; 26: 685–694
  Google Scholar
• 51. Zhang J., Hu J., Ding J.H., Yao H.H., Hu G.: 6-Hydroxydopamineinducedglutathione alteration occurs via glutathione enzymesystem in primary cultured astrocytes. Acta Pharmacol. Sin., 2005;26: 799–805
  Google Scholar

Full text