Journal of Natural Medicines

, Volume 71, Issue 1, pp 181–189 | Cite as

Nobiletin improves emotional and novelty recognition memory but not spatial referential memory

  • Jiyun Kang
  • Jung-Won Shin
  • Yoo-rim Kim
  • Kelley M. Swanberg
  • Yooseung Kim
  • Jae Ryong Bae
  • Young Ki Kim
  • Jinwon Lee
  • Soo-yeon Kim
  • Nak-Won Sohn
  • Sungho Maeng
Original Paper
  • 310 Downloads

Abstract

How to maintain and enhance cognitive functions for both aged and young populations is a highly interesting subject. But candidate memory-enhancing reagents are tested almost exclusively on lesioned or aged animals. Also, there is insufficient information on the type of memory these reagents can improve. Working memory, located in the prefrontal cortex, manages short-term sensory information, but, by gaining significant relevance, this information is converted to long-term memory by hippocampal formation and/or amygdala, followed by tagging with space–time or emotional cues, respectively. Nobiletin is a product of citrus peel known for cognitive-enhancing effects in various pharmacological and neurodegenerative disease models, yet, it is not well studied in non-lesioned animals and the type of memory that nobiletin can improve remains unclear. In this study, 8-week-old male mice were tested using behavioral measurements for working, spatial referential, emotional and visual recognition memory after daily administration of nobiletin. While nobiletin did not induce any change of spontaneous activity in the open field test, freezing by fear conditioning and novel object recognition increased. However, the effectiveness of spatial navigation in the Y-maze and Morris water maze was not improved. These results mean that nobiletin can specifically improve memories of emotionally salient information associated with fear and novelty, but not of spatial information without emotional saliency. Accordingly, the use of nobiletin on normal subjects as a memory enhancer would be more effective on emotional types but may have limited value for the improvement of episodic memories.

Keywords

Nobiletin Donepezil Working memory Contextual memory Emotional memory Visual recognition memory 

Abbreviations

PKA

Protein kinase A

ERK

Extracellular signal-regulated kinase

CREB

Cyclic-AMP-responsive-element-binding protein

LTP

Long-term potentiation

AMPA

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Amyloid-beta

NMDA

N-Methyl-d-aspartate

ANOVA

Analysis of variation

Tukey’s HSD

Tukey’s honest significant difference

SEM

Standard error of the mean

Notes

Acknowledgements

The authors have no conflicts of interest to disclose. Financial support and preparation of the article was provided by the corresponding author. The research was conduct mainly by the first two authors. Other co-authors contributed to study design, data analysis and interpretation. No funding sources were involved.

References

  1. 1.
    Bauer PJ (2015) Development of episodic and autobiographical memory: the importance of remembering forgetting. Dev Rev 38:146–166CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Picard F, Friston K (2014) Predictions, perception, and a sense of self. Neurology 83(12):1112–1118CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mansouri FA, Rosa MG, Atapour N (2015) Working memory in the service of executive control functions. Front Syst Neurosci 9:166CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bekinschtein P, Katche C, Slipczuk L, Gonzalez C, Dorman G, Cammarota M et al (2010) Persistence of long-term memory storage: new insights into its molecular signatures in the hippocampus and related structures. Neurotox Res 18(3–4):377–385CrossRefPubMedGoogle Scholar
  5. 5.
    Dickerson BC, Eichenbaum H (2010) The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology 35(1):86–104CrossRefPubMedGoogle Scholar
  6. 6.
    Desmedt A, Marighetto A, Richter-Levin G, Calandreau L (2015) Adaptive emotional memory: the key hippocampal–amygdalar interaction. Stress 18(3):297–308CrossRefPubMedGoogle Scholar
  7. 7.
    White AO, Wood MA (2014) Does stress remove the HDAC brakes for the formation and persistence of long-term memory? Neurobiol Learn Mem 112:61–67CrossRefPubMedGoogle Scholar
  8. 8.
    Vallee M, Mayo W, Darnaudery M, Corpechot C, Young J, Koehl M et al (1997) Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus. Proc Natl Acad Sci USA 94(26):14865–14870CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Grayson B, Leger M, Piercy C, Adamson L, Harte M, Neill JC (2015) Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents. Behav Brain Res 285:176–193CrossRefPubMedGoogle Scholar
  10. 10.
    Nagase H, Omae N, Omori A, Nakagawasai O, Tadano T, Yokosuka A et al (2005) Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities. Biochem Biophys Res Commun 337(4):1330–1336CrossRefPubMedGoogle Scholar
  11. 11.
    Matsuzaki K, Miyazaki K, Sakai S, Yawo H, Nakata N, Moriguchi S et al (2008) Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus. Eur J Pharmacol 578(2–3):194–200CrossRefPubMedGoogle Scholar
  12. 12.
    Matsuzaki K, Yamakuni T, Hashimoto M, Haque AM, Shido O, Mimaki Y et al (2006) Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer’s disease model rats. Neurosci Lett 400(3):230–234CrossRefPubMedGoogle Scholar
  13. 13.
    Nakajima A, Yamakuni T, Haraguchi M, Omae N, Song SY, Kato C et al (2007) Nobiletin, a citrus flavonoid that improves memory impairment, rescues bulbectomy-induced cholinergic neurodegeneration in mice. J Pharmacol Sci 105(1):122–126CrossRefPubMedGoogle Scholar
  14. 14.
    Nakajima A, Yamakuni T, Matsuzaki K, Nakata N, Onozuka H, Yokosuka A et al (2007) Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-d-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling. J Pharmacol Exp Ther 321(2):784–790CrossRefPubMedGoogle Scholar
  15. 15.
    Yamamoto Y, Shioda N, Han F, Moriguchi S, Nakajima A, Yokosuka A et al (2009) Nobiletin improves brain ischemia-induced learning and memory deficits through stimulation of CaMKII and CREB phosphorylation. Brain Res 1295:218–229CrossRefPubMedGoogle Scholar
  16. 16.
    Nakajima A, Aoyama Y, Nguyen TT, Shin EJ, Kim HC, Yamada S et al (2013) Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse. Behav Brain Res 250:351–360CrossRefPubMedGoogle Scholar
  17. 17.
    Nakajima A, Aoyama Y, Shin EJ, Nam Y, Kim HC, Nagai T et al (2015) Nobiletin, a citrus flavonoid, improves cognitive impairment and reduces soluble Aβ levels in a triple transgenic mouse model of Alzheimer’s disease (3XTg-AD). Behav Brain Res 289:69–77CrossRefPubMedGoogle Scholar
  18. 18.
    Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D et al (2008) Nobiletin, a citrus flavonoid, improves memory impairment and Aβ pathology in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 326(3):739–744CrossRefPubMedGoogle Scholar
  19. 19.
    Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 83(3):482–504CrossRefPubMedGoogle Scholar
  20. 20.
    Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 31(1):47–59CrossRefPubMedGoogle Scholar
  21. 21.
    Hughes RN (2004) The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci Biobehav Rev 28(5):497–505CrossRefPubMedGoogle Scholar
  22. 22.
    Yang JH, Han SJ, Ryu JH, Jang IS, Kim DH (2009) Ginsenoside Rh2 ameliorates scopolamine-induced learning deficit in mice. Biol Pharm Bull 32(10):1710–1715CrossRefPubMedGoogle Scholar
  23. 23.
    Brandeis R, Brandys Y, Yehuda S (1989) The use of the Morris water maze in the study of memory and learning. Int J Neurosci 48(1–2):29–69CrossRefPubMedGoogle Scholar
  24. 24.
    Maren S, Fanselow MS (1996) The amygdala and fear conditioning: has the nut been cracked? Neuron 16(2):237–240CrossRefPubMedGoogle Scholar
  25. 25.
    Kunimasa K, Kuranuki S, Matsuura N, Iwasaki N, Ikeda M, Ito A et al (2009) Identification of nobiletin, a polymethoxyflavonoid, as an enhancer of adiponectin secretion. Bioorg Med Chem Lett 19(7):2062–2064CrossRefPubMedGoogle Scholar
  26. 26.
    Yabuki Y, Ohizumi Y, Yokosuka A, Mimaki Y, Fukunaga K (2014) Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neurosci 259:126–141CrossRefGoogle Scholar
  27. 27.
    Spencer JP, Middleton LJ, Davies CH (2010) Investigation into the efficacy of the acetylcholinesterase inhibitor, donepezil, and novel procognitive agents to induce gamma oscillations in rat hippocampal slices. Neuropharmacology 59(6):437–443CrossRefPubMedGoogle Scholar
  28. 28.
    Yi LT, Xu HL, Feng J, Zhan X, Zhou LP, Cui CC (2011) Involvement of monoaminergic systems in the antidepressant-like effect of nobiletin. Physiol Behav 102(1):1–6CrossRefPubMedGoogle Scholar
  29. 29.
    Bhutada P, Mundhada Y, Bansod K, Bhutada C, Tawari S, Dixit P et al (2010) Ameliorative effect of quercetin on memory dysfunction in streptozotocin-induced diabetic rats. Neurobiol Learn Mem 94(3):293–302CrossRefPubMedGoogle Scholar
  30. 30.
    Stokes MG (2015) ‘Activity-silent’ working memory in prefrontal cortex: a dynamic coding framework. Trends Cogn Sci 19(7):394–405CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Anderson R, Higgins GA (1997) Absence of central cholinergic deficits in ApoE knockout mice. Psychopharmacology 132(2):135–144CrossRefPubMedGoogle Scholar
  32. 32.
    Tsunekawa H, Noda Y, Mouri A, Yoneda F, Nabeshima T (2008) Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25–35). Behav Brain Res 190(2):224–232CrossRefPubMedGoogle Scholar
  33. 33.
    Yamada M, Hayashida M, Zhao Q, Shibahara N, Tanaka K, Miyata T et al (2011) Ameliorative effects of yokukansan on learning and memory deficits in olfactory bulbectomized mice. J Ethnopharmacol 135(3):737–746CrossRefPubMedGoogle Scholar
  34. 34.
    Guo HB, Cheng YF, Wu JG, Wang CM, Wang HT, Zhang C et al (2015) Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation. Neuroscience 290:530–542CrossRefPubMedGoogle Scholar
  35. 35.
    Kwon KJ, Kim MK, Lee EJ, Kim JN, Choi BR, Kim SY et al (2014) Effects of donepezil, an acetylcholinesterase inhibitor, on neurogenesis in a rat model of vascular dementia. J Neurol Sci 347(1–2):66–77CrossRefPubMedGoogle Scholar
  36. 36.
    Giustino TF, Maren S (2015) The role of the medial prefrontal cortex in the conditioning and extinction of fear. Front Behav Neurosci 9:298CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ennaceur A, Neave N, Aggleton JP (1996) Neurotoxic lesions of the perirhinal cortex do not mimic the behavioural effects of fornix transection in the rat. Behav Brain Res 80(1–2):9–25CrossRefPubMedGoogle Scholar
  38. 38.
    Gaffan D (1994) Dissociated effects of perirhinal cortex ablation, fornix transection and amygdalectomy: evidence for multiple memory systems in the primate temporal lobe. Exp Brain Res 99(3):411–422PubMedGoogle Scholar
  39. 39.
    Meunier M, Bachevalier J, Mishkin M, Murray EA (1993) Effects on visual recognition of combined and separate ablations of the entorhinal and perirhinal cortex in rhesus monkeys. J Neurosci 13(12):5418–5432PubMedGoogle Scholar
  40. 40.
    Mumby DG, Pinel JP (1994) Rhinal cortex lesions and object recognition in rats. Behav Neurosci 108(1):11–18CrossRefPubMedGoogle Scholar
  41. 41.
    Didic M, Felician O, Barbeau EJ, Mancini J, Latger-Florence C, Tramoni E et al (2013) Impaired visual recognition memory predicts Alzheimer’s disease in amnestic mild cognitive impairment. Dement Geriatr Cogn Disord 35(5–6):291–299CrossRefPubMedGoogle Scholar
  42. 42.
    Spilman P, Descamps O, Gorostiza O, Peters-Libeu C, Poksay KS, Matalis A et al (2014) The multi-functional drug tropisetron binds APP and normalizes cognition in a murine Alzheimer’s model. Brain Res 1551:25–44CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan 2016

Authors and Affiliations

  • Jiyun Kang
    • 1
  • Jung-Won Shin
    • 1
  • Yoo-rim Kim
    • 1
  • Kelley M. Swanberg
    • 1
  • Yooseung Kim
    • 2
  • Jae Ryong Bae
    • 1
  • Young Ki Kim
    • 1
  • Jinwon Lee
    • 1
  • Soo-yeon Kim
    • 1
  • Nak-Won Sohn
    • 1
  • Sungho Maeng
    • 1
    • 3
  1. 1.Graduate School of East-West Medical ScienceKyung Hee UniversityYonginRepublic of Korea
  2. 2.Department of Clinical Korean Medicine Graduate SchoolKyung Hee UniversitySeoulRepublic of Korea
  3. 3.East-West Medical Research InstituteKyung Hee UniversitySeoulRepublic of Korea

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