Skip to main content
SpringerLink
Log in

d-Ribose–l-cysteine exhibits adaptogenic-like activity through inhibition of oxido-inflammatory responses and increased neuronal caspase-3 activity in mice exposed to unpredictable chronic mild stress

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Adaptogens are substances that act nonspecifically to combat stress by regulating the key elements involved in stress-induced pathologies. d-Ribose–l-cysteine (DRLC), a potent glutathione (GSH) booster, has been recommended for relief of stress. Hence, we investigated its adaptogenic-like effect in mice subjugated to unpredictable chronic mild stress (UCMS). Thirty six male Swiss mice were assigned to 6 groups (n = 6): group 1 received saline (p.o, non-stress control), group 2 (stress-control) also had saline, groups 3 to 5 received DRLC (25, 50 and 100 mg/kg, p.o) whereas group 6 had ginseng (50 mg/kg, p.o). The animals in groups 2–6 were subjugated to UCMS 30 min later, daily for 21 days and afterwards, tested for memory and anxiety. Blood glucose, serum corticosterone concentrations and adrenal weight were determined. The brain tissues were processed for estimation of malondialdehyde (MDA), GSH, superoxide-dismutase (SOD), catalase, tumor necrosis factor-alpha (TNF-α), interleukin-6, acetyl-cholinesterase, and caspase-3 activities. The histomorphologic features and neuronal viability of the hippocampus, amygdala and prefrontal cortex were also determined. DRLC (25–100 mg/kg) reduces anxiety, memory deficit, adrenal gland enlargement, glucose, and corticosterone concentrations in UCMS-mice. The increased brain contents of MDA, TNF-α, interleukin-6, acetyl-cholinesterase and decreased antioxidant (GSH, SOD and catalase) status induced by UCMS were attenuated by DRLC. The DRLC increased caspase-3 activity and reduces histomorphological distortions of neuronal cells of the hippocampus, amygdala and prefrontal cortex of stressed-mice. These findings suggest that DRLC has adaptogenic-like effect which might be related to modulation of corticosterone-mediated oxido-inflammatory processes and altered caspase-3 activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

GSH:

Glutathione

DRLC:

d-Ribose–l-cysteine

UCMS:

Unpredictable chronic mild stress

MDA:

Malondialdehyde

SOD:

Superoxide-dismutase

TNF-α:

Tumor necrosis factor-alpha

IL-6:

Interleukin-6

AChE:

Acetyl-cholinesterase

HPA:

Hypothalamic–pituitary–adrenal

IOAA:

Index of open arm avoidance

References

  1. Panossian A, Wikman G (2010) Effects of adaptogens on the central nervous system and the molecular mechanisms associated with their stress-protective activity. Pharmaceuticals 3:188–224

    Article  CAS  Google Scholar 

  2. Panossian A (2017) Understanding adaptogenic activity: specificity of the pharmacological action of adaptogens and other phytochemicals. Ann NY Sci 1401:49–67

    Article  CAS  Google Scholar 

  3. McEwen BS, Gray JD, Nasca C (2015) Recognizing resilience: learning from the effects of stress on the brain. Neurobiol Stress 1:1–11

    Article  Google Scholar 

  4. Panossian A, Seo E, Efferth T (2018) Novel molecular mechanisms for the adaptogenic effects of herbal extracts on isolated brain cells using systems biology. Phytomedicine 50:257–284

    Article  Google Scholar 

  5. Wiegant FAC, Limandjaja G, de Poot SAH (2008) Plant adaptogens activate cellular adaptive mechanisms by causing mild damage. In: Lukyanova L, Takeda N, Singal PK (eds) Adaptation biology and medicine. Narosa Publishing House Pvt Ltd, New Delhi, pp 319–332

    Google Scholar 

  6. Hovhannisyan AS, Nylander M, Panossian AG (2015) Efficacy of adaptogenic supplements on adapting to stress: a randomized, controlled trial. J Athlet Enhanc 4:4

    Article  Google Scholar 

  7. Chakravarty S, Reddy BR, Sudhakar SR, Saxena S, Das T, Meghah V, BrahmendraSwamy CV, Kumar A, Idris MM (2013) Chronic unpredictable stress (CUS)-induced anxiety and related mood disorders in a Zebra fish model: altered brain proteome profile implicates mitochondrial dysfunction. PLoS ONE 8:63302

    Article  Google Scholar 

  8. Willner P, Mitchell PJ (2002) The validity of animal models of predisposition to depression. Behav Pharmacol 13:169–188

    Article  CAS  Google Scholar 

  9. Anisman H, Matheson K (2005) Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev 29:525–546

    Article  Google Scholar 

  10. Umukoro S, Aluko OM, Eduviere AT, Owoeye O (2016) Evaluation of adaptogenic-like property of methyl jasmonate in mice exposed to unpredictable chronic mild stress. Brian Res Bull 121:105–114

    Article  CAS  Google Scholar 

  11. Roberts JC, Francetic DJ (1991) Mechanisms of chemoprotection by ribo-cysteine, a thiazolidineprodrug of L-cysteine. Med Chem Resp 1:213–219

    CAS  Google Scholar 

  12. KaderT PCM, Williams MJ, Gieseg SP, McCormick SP (2014) Ribose-cysteine increases glutathione-based antioxidant status and reduces LDL in human lipoprotein(a) mice. Atherosclerosis 237:725–733

    Article  Google Scholar 

  13. Aoyama K, Nakaki T (2013) Impaired glutathione synthesis in neurodegeneration. Int J Mol Sci 14:21021–21044

    Article  Google Scholar 

  14. Falana B, Adeleke O, Orenolu M, Osinubi A, Oyewopo A (2017) Effect of D-ribose-L-cysteine on aluminum induced testicular damage in male Sprague-Dawley rats. JBRA Assisted Reproduction 21:94–100

    Article  Google Scholar 

  15. Omran H, Illien S, MacCarter D (2003) D-Ribose improves diastolic function and quality of life in congestive heart failure patients: a prospective feasibility study. Eur J Heart Fail 5:615–619

    Article  CAS  Google Scholar 

  16. Teitelbaum JE, Johnson C, St. Cyr J (2006) The use of d-ribose in chronic fatigue syndrome and fibromyalgia: a pilot study. J Altern Complemen Med 12:857–862

    Article  Google Scholar 

  17. Emokpae O, Ben-Azu B, Ajayi AM, Umukoro S (2020) D-Ribose-l-cysteine attenuates lipopolysaccharide-induced memory deficits through inhibition of oxidative stress, release of proinflammatory cytokines, and nuclear factor-kappa B expression in mice. Naunyn-Schmied Arch Pharm 393:909–925

    Article  CAS  Google Scholar 

  18. Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathionereductase and glutathione S-transferase activities in rat lung and liver. Biochem Biophys Acta 582:67–78

    Article  CAS  Google Scholar 

  19. Okhawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1995:351–358

    Google Scholar 

  20. Misra HP, Fridovich I (1972) The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175

    CAS  PubMed  Google Scholar 

  21. Goth LA (1991) Simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 196:143–151

    Article  CAS  Google Scholar 

  22. Green LC, Tannenbaum SR, Goldman P (1981) Nitrate synthesis in the germ free and conventional rat. Science 212:56–58

    Article  CAS  Google Scholar 

  23. Gornall AG, Bardawill CJ, David MM (1949) Determination of serum protein by means of biuret reaction. J Biol Chem 177:751

    CAS  PubMed  Google Scholar 

  24. Ellman GL, Courtney KD, Andre JV, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  Google Scholar 

  25. Alò R, Mele M, Fazzari G, Avolio E, Canonaco M (2015) Exposure to sub-chronic unpredictable stress accounts for antidepressant-like effects in hamsters treated with BDNFandCNQX. Brain Res Bull 118:65–77

    Article  Google Scholar 

  26. Kuhlmann S, Piel M, Wolf OT (2005) Impaired memory retrieval after psychological stress in healthy young men. J Neurosci 25:2977–2982

    Article  CAS  Google Scholar 

  27. Alfarez DN, Joëls M, Krugers HJ (2003) Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci 17:1928–1934

    Article  Google Scholar 

  28. Tonnies E, Trushina E (2017) Oxidative stress, synaptic dysfunction, and Alzheimer’s disease. J Alzh Dis 57:1105–1121

    Article  Google Scholar 

  29. Ben-Azu B, Emokpae O, Ajayi AM, Jarikre TA, Orhode V, Aderibigbe AO, Umukoro S, Iwalewa EO (2020) Repeated psychosocial stress causes glutamic acid decarboxylase isoform-67, oxidative-Nox-2 changes and neuroinflammation in mice: Prevention bytreatment with a neuroactiveflavonoid, morin. Brain Res 1744:146917

    Article  CAS  Google Scholar 

  30. Stranahan AM, Mattson MP (2012) Recruiting adaptive cellular stress responses for successful brain ageing. Nat Rev Neurosci 13:209–216

    Article  CAS  Google Scholar 

  31. Slee EA, Adrain C, Martin SJ (2001) Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 276:7320–7326

    Article  CAS  Google Scholar 

  32. Amelio MD, Cavallucci V, Cecconi F (2010) Neuronal caspase-3 signaling: not only cell death. Cell Death Differ 17:1104–1114

    Article  Google Scholar 

  33. Dash PK, Blum S, Moore AN (2000) Caspase activity plays an essential role in long-term memory. NeuroReport 11:2811–2816

    Article  CAS  Google Scholar 

  34. Khalil H, Peltzer N, Walicki J, Yang J, Dubuis G, Gardiol N, Held W, Bigliardi P, Marsland B, Liaudet L, Widmann C (2012) Caspase-3 protects stressed organs against cell death. Mol Cell Biol 32:4523–4533

    Article  CAS  Google Scholar 

  35. Fernando P, Brunette S, Megeney LA (2005) Neural stem cell differentiation is dependent upon endogenous caspase 3 activity. FASEB J 19:1671–1673

    Article  CAS  Google Scholar 

Download references

Acknowledgement

Authors thank the technical staff of the Department of Pharmacology and Therapeutics as well as Dr T. Aina of the Department of Veterinary Pathology of the University of Ibadan for their assistance in the biochemical and histological studies during the course of the research.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria

    Love Okoh, Abayomi M. Ajayi, Benneth Ben-Azu, Osagie Emokpae & Solomon Umukoro

  2. Department of Pharmacology, Faculty of Basic Medical Sciences, PAMO University of Medical Sciences, Port Harcourt, River States, Nigeria

    Benneth Ben-Azu

  3. Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria

    Elizabeth T. Akinluyi

Authors
  1. Love Okoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abayomi M. Ajayi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benneth Ben-Azu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elizabeth T. Akinluyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Osagie Emokpae
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Solomon Umukoro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Solomon Umukoro.

Ethics declarations

Conflicts of interest

Authors declare that they have no conflict of interest.

Ethical approval

The experimental procedures were approved by the University of Ibadan Animal Care and Use Research Ethics Committee (UI-ACURE/18/0086) and performed in accordance with the care and use of Laboratory Animals of the NIH Guidelines.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okoh, L., Ajayi, A.M., Ben-Azu, B. et al. d-Ribose–l-cysteine exhibits adaptogenic-like activity through inhibition of oxido-inflammatory responses and increased neuronal caspase-3 activity in mice exposed to unpredictable chronic mild stress. Mol Biol Rep 47, 7709–7722 (2020). https://doi.org/10.1007/s11033-020-05845-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05845-1

Keywords

Search

Navigation