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Bacosides Encapsulated in Lactoferrin Conjugated PEG-PLA-PCL-OH Based Polymersomes Act as Epigenetic Modulator in Chemically Induced Amnesia

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Abstract

The present study demonstrates the epigenetic mechanisms underlying the effect of Bacoside rich extract of Bacopa monniera—a nootropic herb, on scopolamine treated amnesic mice conferred via chromatin modifying enzymes. The focus of the work was to elucidate the modulation of the chromatin modifying enzymes: DNMT1, DNMT3a, DNMT3b, HDAC2, HDAC5 and CPB in scopolamine induced amnesic mice after treatment with bacoside rich extract of Bacopa monniera (BA) and BA encapsulated in lactoferrin conjugated PEG-PLA-PCL-OH based polymersomes (BAN). We observed remarkable difference between the results obtained after the treatment with BA and BAN. Interestingly BAN was found to be more efficient in downregulating DNA methylation and histone chain deacetylation. Scopolamine treatment showed up-regulation of DNMT1 expression in qRT-PCR by 3.14-fold as compared to the control, which was considerably decreased by 1.5-fold after treatment with BA and remarkably decreased 0.11-fold by BAN treatment. Scopolamine treatment up-regulated the expression of DNMT3a by 1.6-fold while for DNMT3b by 3.13-fold. In DNMT3a and DNMT3b the fold change decreased to 0.64 and 0.76 after BA treatment, whereas the BAN treatment further down-regulated to 0.32- and 0.63-fold, respectively. Similarly scopolamine up-regulated HDAC2 and HDAC5 by 3.12 fold and 3.64-fold, respectively. BA treatment reversed the changes by reducing HDAC2 mRNA to 0.89-fold and HDAC5 mRNA 0.83-fold. BAN further reduced expression of HDAC2 further to 0.39-fold and HDAC5 to 0.31-fold. On the other hand scopolamine down-regulated CBP mRNA expression by 0.28-fold and increased by 1.09 after BA treatment. BAN significantly increased the CPB expression by 1.65-fold as compared to BA treatment. These findings were consolidated by DNMT and HDAC enzyme activity assay, methylation in the promoter region of the memory related genes: ARC and BDNF and Dot blot assay for DNA methylation. The percent activity increase of DNMT and HDAC after scopolamine administration was 375.74 and 240.90 respectively. After treatment with BA the downfall in percent activity was observed as 167.99 in DMNT and 130.57 in HDAC. BAN treatment further decreased the percent enzyme activity of DNMT and HDAC significantly by 30.0 and 61.81 respectively. The potency of BAN in reversing the epigenetic changes of scopolamine induced amnesic mouse brain, can be attributed to the brain specific delivery of BA through polymersomes which are able to cross the blood brain barrier (BBB) via receptor mediated endocytosis.

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Fig. 1

(Reproduced from Goyal et al. [7] with permission from the Royal Society of Chemistry)

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Abbreviations

DMNT:

DNA methyl transferase

HDAC:

Histone deacetylase

5mC:

5-Methyl cytosine

BDNF:

Brain derived neurotrophic factor

CBP:

CREB binding protein

References

  1. McGaugh JL (2015) Consolidating memories. Annu Rev Psychol 66:1–24

    Article  PubMed  Google Scholar 

  2. Hosseini-Sharifabad A, Rabbani M, Sharifzadeh M, Bagheri N (2016) Acute and chronic tramadol administration impair spatial memory in rat. Res Pharm Sci 11:49

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ghumatkar PJ, Patil SP, Jain PD, Tambe RM, Sathaye S (2015) Nootropic, neuroprotective and neurotrophic effects of phloretin in scopolamine induced amnesia in mice. Pharmacol Biochem Behav 135:182–191

    Article  CAS  PubMed  Google Scholar 

  4. Kumar N, Abichandani L, Thawani V, Gharpure K, Naidu M, Venkat Ramana G (2016) Efficacy of standardized extract of Bacopa monnieri (Bacognize®) on cognitive functions of medical students: a six-week, randomized placebo-controlled trial. Evid-Based Complement Altern Med 2016:4103423

    Article  Google Scholar 

  5. Kamkaew N, Paracha TU, Ingkaninan K, Waranuch N, Chootip K (2019) Vasodilatory effects and mechanisms of action of Bacopa monnieri active compounds on rat mesenteric arteries. Molecules 24:2243

    Article  CAS  PubMed Central  Google Scholar 

  6. Krishna G, Hosamani R (2019) Bacopa monnieri supplements offset paraquat-induced behavioral phenotype and brain oxidative pathways in mice. Cent Nerv Syst Agents Med Chem 19:57–66

    Article  CAS  PubMed  Google Scholar 

  7. Goyal K, Konar A, Kumar BH, Koul V (2018) Lactoferrin-conjugated pH and redox-sensitive polymersomes based on PEG-SS-PLA-PCL-OH boost delivery of bacosides to the brain. Nanoscale 10:17781–17798

    Article  CAS  PubMed  Google Scholar 

  8. Abdul Manap AS, Vijayabalan S, Madhavan P, Chia YY, Arya A, Wong EH, Rizwan F, Bindal U, Koshy S (2019) Bacopa monnieri, a neuroprotective lead in Alzheimer Disease: a review on its properties, mechanisms of action, and preclinical and clinical studies. Drug Target Insights 13:1177392819866412

    Article  PubMed  PubMed Central  Google Scholar 

  9. Das DN, Naik PP, Nayak A, Panda PK, Mukhopadhyay S, Sinha N, Bhutia SK (2016) Bacopa monnieri-induced protective autophagy inhibits Benzo [a] pyrene-mediated apoptosis. Phytother Res 30:1794–1801

    Article  CAS  PubMed  Google Scholar 

  10. Smith E, Palethorpe H, Tomita Y, Pei J, Townsend A, Price T, Young J, Yool A, Hardingham J (2018) The purified extract from the medicinal plant Bacopa monnieri, bacopaside II, inhibits growth of colon cancer cells in vitro by inducing cell cycle arrest and apoptosis. Cells 7:81

    Article  PubMed Central  CAS  Google Scholar 

  11. Singh P, Konar A, Kumar A, Srivas S, Thakur MK (2015) Hippocampal chromatin-modifying enzymes are pivotal for scopolamine-induced synaptic plasticity gene expression changes and memory impairment. J Neurochem 134:642–651

    Article  CAS  PubMed  Google Scholar 

  12. Kumar A, Lale SV, Mahajan S, Choudhary V, Koul V (2015) ROP and ATRP fabricated dual targeted redox sensitive polymersomes based on pPEGMA-PCL-ss-PCL-pPEGMA triblock copolymers for breast cancer therapeutics. ACS Appl Mater Interfaces 7:9211–9227

    Article  CAS  PubMed  Google Scholar 

  13. Sharath R, Harish B, Krishna V, Sathyanarayana B, Swamy H (2010) Wound healing and protease inhibition activity of Bacoside-A, isolated from Bacopa monnieri wettest. Phytother Res 24:1217–1222

    Article  CAS  PubMed  Google Scholar 

  14. Jose S, Sowmya S, Cinu T, Aleykutty N, Thomas S, Souto E (2014) Surface modified PLGA nanoparticles for brain targeting of Bacoside-A. Eur J Pharm Sci 63:29–35

    Article  CAS  PubMed  Google Scholar 

  15. Shilpi S, Vimal VD, Soni V (2015) Assessment of lactoferrin-conjugated solid lipid nanoparticles for efficient targeting to the lung. Progr Biomater 4:55–63

    Article  CAS  Google Scholar 

  16. Gao X, Cui Y, Levenson RM, Chung LW, Nie S (2004) In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 22:969

    Article  CAS  PubMed  Google Scholar 

  17. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  18. Kumar D, Thakur MK (2017) Effect of perinatal exposure to Bisphenol-A on DNA methylation and histone acetylation in cerebral cortex and hippocampus of postnatal male mice. J Toxicol Sci 42:281–289

    Article  CAS  PubMed  Google Scholar 

  19. Jacinto FV, Ballestar E, Esteller M (2008) Methyl-DNA immunoprecipitation (MeDIP): hunting down the DNA methylome. Biotechniques 44:35–43

    Article  CAS  PubMed  Google Scholar 

  20. Okubo K, Kamiya M, Urano Y, Nishi H, Herter JM, Mayadas T, Hirohama D, Suzuki K, Kawakami H, Tanaka M (2016) Lactoferrin suppresses neutrophil extracellular traps release in inflammation. EBioMedicine 10:204–215

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zovkic IB, Guzman-Karlsson MC, Sweatt JD (2013) Epigenetic regulation of memory formation and maintenance. Learn Mem 20:61–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Srivas S, Thakur MK (2017) Epigenetic regulation of neuronal immediate early genes is associated with decline in their expression and memory consolidation in scopolamine-induced amnesic mice. Mol Neurobiol 54:5107–5119

    Article  CAS  PubMed  Google Scholar 

  23. Morris MJ, Na ES, Autry AE, Monteggia LM (2016) Impact of DNMT1 and DNMT3a forebrain knockout on depressive-and anxiety like behavior in mice. Neurobiol Learn Mem 135:139–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gräff J, Tsai L-H (2013) The potential of HDAC inhibitors as cognitive enhancers. Annu Rev Pharmacol Toxicol 53:311–330

    Article  PubMed  CAS  Google Scholar 

  25. Jiang Y, Liu Z, Holenz J, Yang H (2016) Competitive intelligence-based lead generation and fast follower approaches. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

    Book  Google Scholar 

  26. Sarris J, Panossian A, Schweitzer I, Stough C, Scholey A (2011) Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsychopharmacol 21:841–860

    Article  CAS  PubMed  Google Scholar 

  27. Cacabelos R (2019) Epigenetics and pharmacoepigenetics of neurodevelopmental and neuropsychiatric disorders. In: Cacabelos R (ed) Pharmacoepigenetics, 1st edn. Academic Press, Oxford, UK, pp 609-709

    Chapter  Google Scholar 

  28. Costa E, Chen Y, Dong E, Grayson DR, Kundakovic M, Maloku E, Ruzicka W, Satta R, Veldic M, Zhubi A (2009) GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability. Expert Rev Neurother 9:87–98

    Article  CAS  PubMed  Google Scholar 

  29. Jiang B, Song L, Huang C, Zhang W (2016) P7C3 attenuates the scopolamine-induced memory impairments in C57BL/6J mice. Neurochem Res 41:1010–1019

    Article  CAS  PubMed  Google Scholar 

  30. Preethi J, Singh HK, Rajan KE (2016) Possible involvement of standardized Bacopa monniera extract (CDRI-08) in epigenetic regulation of reelin and brain-derived neurotrophic factor to enhance memory. Front Pharmacol 7:166

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Guidotti A, Auta J, Chen Y, Davis J, Dong E, Gavin D, Grayson D, Matrisciano F, Pinna G, Satta R (2011) Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology 60:1007–1016

    Article  CAS  PubMed  Google Scholar 

  32. Goyal K, Koul V, Singh Y, Anand A (2014) Targeted drug delivery to central nervous system (CNS) for the treatment of neurodegenerative disorders: trends and advances. Cent Nerv Syst Agents Med Chem 14:43–59

    Article  CAS  PubMed  Google Scholar 

  33. Calabresi P, Centonze D, Gubellini P, Pisani A, Bernardi G (1998) Endogenous ACh enhances striatal NMDA-responses via M1-like muscarinic receptors and PKC activation. Eur J Neurosci 10:2887–2895

    Article  CAS  PubMed  Google Scholar 

  34. Hota SK, Barhwal K, Baitharu I, Prasad D, Singh SB, Ilavazhagan G (2009) Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment. Neurobiol Dis 34:23–39

    Article  CAS  PubMed  Google Scholar 

  35. Gallo FT, Katche C, Morici JF, Medina JH, Weisstaub NV (2018) Immediate early genes, memory and psychiatric disorders: focus on c-Fos, Egr1 and Arc. Front Behav Neurosci 12:79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Korb E, Finkbeiner S (2011) Arc in synaptic plasticity: from gene to behavior. Trends Neurosci 34:591–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. El-Osta A, Wolffe AP (2001) DNA methylation and histone deacetylation in the control of gene expression: basic biochemistry to human development and disease. Gene Expr J Liver Res 9:63–75

    Article  Google Scholar 

  38. Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42:961–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lande AA, Ambavade SD, Swami US, Adkar PP, Ambavade PD, Waghamare AB (2015) Saponins isolated from roots of Chlorophytum borivilianum reduce acute and chronic inflammation and histone deacetylase. J Integr Med 13:25–33

    Article  PubMed  Google Scholar 

  40. Chatterjee S, Cassel R, Schneider-Anthony A, Merienne K, Cosquer B, Tzeplaeff L, Sinha SH, Kumar M, Chaturbedy P, Eswaramoorthy M (2018) Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator. EMBO Mol Med 10:e8587

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Cabrera SM, McDonough CB, Brindle PK, Abel T (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. J Neurosci 27:6128–6140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 35:870

    Article  CAS  PubMed  Google Scholar 

  43. Itzhak Y, Anderson KL, Kelley JB, Petkov M (2012) Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice. Neurobiol Learn Mem 97:409–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Carlos-Reyes A, López-González JS, Meneses-Flores M, Gallardo-Rincón D, Ruíz-García E, Marchat LA, Astudillo de la Vega H, Hernández de la Cruz ON, López-Camarillo C (2019) Dietary compounds as epigenetic modulating agents in cancer. Front Genet 10:79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Losson H, Schnekenburger M, Dicato M, Diederich M (2016) Natural compound histone deacetylase inhibitors (HDACi): synergy with inflammatory signaling pathway modulators and clinical applications in cancer. Molecules 21:1608

    Article  PubMed Central  CAS  Google Scholar 

  46. McManus KJ, Hendzel MJ (2003) Quantitative analysis of CBP-and P300-induced histone acetylations in vivo using native chromatin. Mol Cell Biol 23:7611–7627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schiltz RL, Mizzen CA, Vassilev A, Cook RG, Allis CD, Nakatani Y (1999) Overlapping but distinct patterns of histone acetylation by the human coactivators p300 and PCAF within nucleosomal substrates. J Biol Chem 274:1189–1192

    Article  CAS  PubMed  Google Scholar 

  48. Preethi J, Singh HK, Venkataraman JS, Rajan KE (2014) Standardised extract of Bacopa monniera (CDRI-08) improves contextual fear memory by differentially regulating the activity of histone acetylation and protein phosphatases (PP1α, PP2A) in hippocampus. Cell Mol Neurobiol 34:577–589

    Article  PubMed  Google Scholar 

  49. Lopez YP, Kenis G, Stettinger W, Neumeier K, de Jonge S, Steinbusch HW, Zill P, van den Hove DL, Myint AM (2016) Effects of prenatal Poly I: C exposure on global histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activity in the mouse brain. Mol Biol Rep 43:711–717

    Article  CAS  Google Scholar 

  50. Amin SA, Adhikari N, Kotagiri S, Jha T, Ghosh B (2019) Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamides. Eur J Med Chem 166:369

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by a grant from Cognitive Science Research Initiative Scheme, Department of Science & Technology (DST), Government of India (SR/CSRI-P1/2017/41). Kritika Goyal is a recipient of fellowship from Council of Scientific & Industrial Research (CSIR), India, Ministry of Human Resource Development (MHRD) and Indian Institute of Technology Delhi (IITD), New Delhi, India. Arpita Konar is a DST-INSPIRE faculty fellow. The authors also thank the Nanoscale Research Facility (NRF), IITD for their advanced instrumentation facilities.

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The manuscript was written with contributions from all authors. All authors have given approval to the final version of the manuscript. AK (Ashish Kumar) and VK (Veena Koul) have contributed equally to the manuscript.

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Goyal, K., Konar, A., Kumar, A. et al. Bacosides Encapsulated in Lactoferrin Conjugated PEG-PLA-PCL-OH Based Polymersomes Act as Epigenetic Modulator in Chemically Induced Amnesia. Neurochem Res 45, 796–808 (2020). https://doi.org/10.1007/s11064-020-02953-z

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