Skip to main content

Effects of Melissa officinalis L. (Lemon Balm) Extract on Neurogenesis Associated with Serum Corticosterone and GABA in the Mouse Dentate Gyrus

Abstract

Lemon balm, leaves of Melissa officinalis L., has been used for anti-anxiety and spasmolytics. We observed the extract of Melissa officinalis L. (MOE) on cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus (DG) of middle-aged mice (12 months of age) using Ki67 and doublecortin (DCX), respectively. We also observed changes in corticosterone, GAD67 and GABA-transaminase (GABA-T) to check their possible mechanisms related to neurogenesis. We administered 50 or 200 mg/kg MOE to the animals once a day for 3 weeks. For labeling of newly generated cells, we also administered 5-bromodeoxyuridine (BrdU) twice a day for 3 days from the day of the first MOE treatment. Administration of 50 or 200 mg/kg MOE dose-dependently increased Ki67 positive nuclei to 244.1 and 763.9% of the vehicle-treated group, respectively. In addition, 50 or 200 mg/kg MOE significantly increased DCX positive neuroblasts with well-developed (tertiary) dendrites. Furthermore, MOE administration significantly increased BrdU/calbindin D-28 k double labeled cells (integrated neurons into granule cells in the DG) to 245.2% of the vehicle-treated group. On the other hand, administration of MOE reduced corticosterone levels in serum and decreased GABA-T levels in the DG homogenates. These results suggest that MOE increases cell proliferation, neuroblast differentiation and integration into granule cells by decreasing serum corticosterone levels as well as by increasing GABA levels in the mouse DG.

This is a preview of subscription content, access via your institution.

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

References

  1. 1.

    Arida RM, Scorza FA, Scorza CA, Cavalheiro EA (2009) Is physical activity beneficial for recovery in temporal lobe epilepsy? Evidences from animal studies. Neurosci Biobehav Rev 33:422–431

    PubMed  Article  Google Scholar 

  2. 2.

    Schaeffer EL, Novaes BA, da Silva ER, Skaf HD, Mendes-Neto AG (2009) Strategies to promote differentiation of newborn neurons into mature functional cells in Alzheimer brain. Prog Neuropsychopharmacol Biol Psychiatry 33:1087–1102

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Alvarez-Buylla A, Lim DA (2004) For the long run: maintaining germinal niches in the adult brain. Neuron 41:683–686

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Liu Z, Fan Y, Won SJ et al (2007) Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38:146–152

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Ohm TG (2007) The dentate gyrus in Alzheimer’s disease. Prog Brain Res 163:723–740

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Li B, Yamamori H, Tatebayashi Y et al (2008) Failure of neuronal maturation in Alzheimer disease dentate gyrus. J Neuropathol Exp Neurol 67:78–84

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Rodríguez JJ, Jones VC, Tabuchi M et al (2008) Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS One 3:e2935

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Limoli CL, Giedzinski E, Baure J, Doctrow SR, Rola R, Fike JR (2006) Using superoxide dismutase/catalase mimetics to manipulate the redox environment of neural precursor cells. Radiat Prot Dosimetry 122:228–236

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Kennedy DO, Little W, Scholey AB (2004) Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm). Psychosom Med 66:607–613

    PubMed  Article  Google Scholar 

  11. 11.

    Ulbricht C, Brendler T, Gruenwald J et al (2005) Lemon balm (Melissa officinalis L.): an evidence-based systematic review by the Natural Standard Research Collaboration. J Herb Pharmacother 5:71–114

    PubMed  Article  Google Scholar 

  12. 12.

    Wheatley D (2005) Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability. J Psychopharmacol 19:414–421

    PubMed  Article  Google Scholar 

  13. 13.

    Kennedy DO, Little W, Haskell CF, Scholey AB (2006) Anxiolytic effects of a combination of Melissa officinalis and Valeriana officinalis during laboratory induced stress. Phytother Res 20:96–102

    PubMed  Article  Google Scholar 

  14. 14.

    Mencherini T, Picerno P, Scesa C, Aquino R (2007) Triterpene, antioxidant, and antimicrobial compounds from Melissa officinalis. J Nat Prod 70:1889–1894

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Pereira RP, Fachinetto R, de Souza Prestes A et al (2009) Antioxidant effects of different extracts from Melissa officinalis, Matricaria recutita and Cymbopogon citratus. Neurochem Res 34:973–983

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT (2009) Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity. Phytother. Res 23:1075–1081

    CAS  Google Scholar 

  17. 17.

    Lópex V, Martín S, Gómez-Serranillos MP, Carretero ME, Jäger AJ, Calvo MI (2009) Neuroprotective and neurological properties of Melissa officinalis. Neurochem Res 34:1955–1961

    Article  CAS  Google Scholar 

  18. 18.

    Tozuka Y, Fukuda S, Namba T, Seki T, Hisatsune T (2005) GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47:803–815

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Ge S, Goh ELK, Sailor KA, Kitabatake Y, Ming G-I, Song H (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439:589–593

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Kee N, Sivalingam S, Boonstra R, Wojtowicz JM (2002) The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis. J Neurosci Methods 115:97–105

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Francis F, Koulakoff A, Boucher D et al (1999) Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23:247–256

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Gleeson JG, Lin PT, Flanagan LA, Walsh CA (1999) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23:257–271

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Ibarra A, Feuillere N, Roller M, Lesburgere E, Beracochea D (2010) Effects of chronic administration of Melissa officinalis L. extract on anxiety-like reactivity and on circadian and exploratory activities in mice. Phytomedicine 17:397–403

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Brown J, Cooper-Kuhn CM, Kempermann G, van Praag H et al (2003) Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci 17:2042–2046

    PubMed  Article  Google Scholar 

  25. 25.

    Couillard-Despres S, Winner B, Schaubeck S et al (2005) Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci 21:1–14

    PubMed  Article  Google Scholar 

  26. 26.

    Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  27. 27.

    Choi EY, Jang SH, Choi SY (1996) Human brain GABA transaminase is immunologically distinct from those of other mammalian brains. Neurochem Int 28:597–600

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Choi EY, Jang SH, Kim I, Park SK, Choi SY (1993) Production and characterization of monoclonal antibodies to bovine brain GABA transaminase. Mol Cells 3:452–455

    Google Scholar 

  29. 29.

    Hwang IK, Yoo KY, Li H et al (2008) Time course of changes in immunoreactivities of GABA degradation enzymes in the hippocampal CA1 region after adrenalectomy in gerbils. Neurochem Res 33:938–944

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Sloviter RS, Valiquette G, Abrams GM et al (1989) Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 243:535–538

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Gould E, Woolley CS, McEwen BS (1990) Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus. Neuroscience 37:367–375

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Montaron MF, Piazza PV, Aurousseau C, Urani A, Le Moal M, Abrous DN (2003) Implication of corticosteroid receptors in the regulation of hippocampal structural plasticity. Eur J Neurosci 18:3105–3111

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Pinnock SB, Herbert J (2008) Brain-derived neurotropic factor and neurogenesis in the adult rat dentate gyrus: interactions with corticosterone. Eur J Neurosci 27:2493–2500

    PubMed  Article  Google Scholar 

  34. 34.

    Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y (2007) EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. FASEB J 21:2400–2408

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Yoo DY, Nam Y, Kim W et al (2010) Effects of Ginkgo biloba extract on promotion of neurogenesis in the hippocampal dentate gyrus in C57BL/6 mice. J Vet Med Sci. doi:10.1292/jvms.10-0294

  36. 36.

    Yoo KY, Park OK, Hwang IK et al (2008) Induction of cell proliferation and neuroblasts in the subgranular zone of the dentate gyrus by aqueous extract from Platycodon grandiflorum in middle-aged mice. Neurosci Lett 444:97–101

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26:3–11

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Tillakaratne NJ, Medina-Kauwe L, Gibson KM (1995) γ-Aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A Physiol 112:247–263

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Awad R, Levac D, Cybulska P, Merali Z, Trudeau VL, Arnason JT (2007) Effects of traditionally used anxiolytic botanicals on enzymes of the γ-aminobutyric acid (GABA) system. Can J Physiol Pharmacol 85:933–942

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Mayo W, Lemaire NV, Malaterre J et al (2005) Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging 26:103–114

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Wadiche LO, Bromberg DA, Bensen AL, Westbrook GL (2005) GABAergic signalling to newborn neurons in dentate gyrus. J Neurophysiol 94:4528–4532

    CAS  Article  Google Scholar 

  42. 42.

    Wang L-P, Kempermann G, Kettenmann H (2005) A subpopulation of precursor cells in the mouse dentate gyrus receives synaptic GABAergic input. Mol Cell Neurosci 29:181–189

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Methippara M, Bashir T, Suntsova N, Szymusiak R, McGinty D (2010) Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in rats. J Sleep Res 19:384–393

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Mr. Seung Uk Lee and Mrs. Hyun Sook Kim for their technical help in this study. This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0010580), and by a grant (2010K000823) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Education, Science and Technology, the Republic of Korea.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Moo-Ho Won or In Koo Hwang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yoo, D.Y., Choi, J.H., Kim, W. et al. Effects of Melissa officinalis L. (Lemon Balm) Extract on Neurogenesis Associated with Serum Corticosterone and GABA in the Mouse Dentate Gyrus. Neurochem Res 36, 250–257 (2011). https://doi.org/10.1007/s11064-010-0312-2

Download citation

Keywords

  • Lemon balm
  • Hippocampus
  • Cell proliferation
  • Ki67
  • Neuroblast differentiation
  • Doublecortin
  • GABA