How Citrus Peel May Support A Healthy Nervous System

Our previous two articles explored how some of the active agents in citrus peel have been found to help reduce glycation[1], oxidative stress[2],[3], and inflammation[4],[5],[6],[7],[8],[9],[10] all of which can degrade tissue and eventually lead to some kind of breakdown.

In this article, we’re going to take a look at some of the effects nobiletin (one of the chemicals in citrus peel) has on the nervous system, and why it matters.

Why Protecting Your Nervous System is So Important

If you imagine all of your body processes as a massively complex orchestra, your brain is the conductor of that orchestra. If the conductor starts sending bad signals or starts missing beats, the orchestra won’t stay together very well. If your body gets out of sync with itself, you’ve got serious trouble ahead, and it could show up in all sorts of places.

Scientists are just starting to map out all the ways that your body functions as an information system, but the nervous system’s role in central regulation is already well established.

What’s exciting is that nobiletin has been shown to support and protect the nervous system in a number of synergistic ways.

Nerves Need Protection from Stress

A number of stressors can cause nerve cells to stop coding proteins correctly, which usually leads to the death of the nerve cell. Damage from stress is also common in the energy centers of nerve cells (mitochondria).

Nerve cells need extra protection from stress because they don’t divide and renew the way other cells do. When they go bad, it's a worse situation than say, your skin cells.

But there’s some exciting evidence coming in that nobiletin may help reduce this stress response and keeps nerve cells alive, both in and out of the mitochondria [11],[12] In fact, nobiletin seems to provide a broad spectrum of protection to nerves and brain cells when they’re stressed,[13] most likely through its ability to combat inflammation and oxidative stress.[14]

It appears to have particularly strong effects in the area of the brain that manages spatial navigation (the hippocampus), and which helps turn short term memory into long-term memory. [15]

Athletes and martial artists ought to take note here: Long-term memory is where mastery lives, and all athletic activity relies on heavily spatial navigation at its core. Don't expect to be able to maneuver with effortless precision with a damaged hippocampus.

Triggering New Nerve Growth is a Key to Neurological Health

In addition to its defense mechanisms, nobiletin may activate a gene signal that triggers new nerve growth, a key in fighting the degeneration that accompanies the diseases of aging. [16]

Again, nerve cells don’t divide the way normal cells do, so you have to trigger new growth in order to keep your brain and the rest of your nervous system in top shape.

It should come as no surprise, then, that nobiletin has been shown in some studies to improve memory and protect against neural degeneration [17],[18],[19], Here’s a few of the interesting ones:

  • Several studies have shown that it may help reduce beta-amyloid plaque, which can lead to Alzheimer’s when it builds up. [20],[21]
  • One study showed some protection against stroke damage.[22]
  • Others noted that it may reduce the motor and cognitive deficits caused by Parkinson’s[23], specifically by protecting and triggering new growth in dopamine neurons. [24]

Again, athletes should take note. Your dopamine neurons are deeply involved with physical activity of all kids, especially those that require intensity, focus and strong motivation.

Keep in mind: none of these studies claim that nobiletin is a cure for neurological diseases. What they do seem to demonstrate is that a nervous system with some protection puts up a better fight that one without it. Whatever protection is supplied by nobiletin is likely occurring through many of the same pathways it’s been shown to work in other parts of the body: by modulating the stress response, reducing inflammation, fighting oxidative stress, etc.

Interested in Trying Some Citrus Peel?

We offer a high quality tangerine peel (called Chen Pi in TCM) that you can put into decoction, or simply add to a tea or a smoothie. If you're interested in tea specifically, we also recommend our green tea / citrus peel blend.

Up Next …

We’re going to take a look at some of the effects of citrus peel on digestion and gut health.


[1] Joglekar MM, Panaskar SN, Chougale AD, Kulkarni MJ, Arvindekar AU. A novel mechanism for antiglycative action of limonene through stabilization of protein conformation. Mol Biosyst 2013 July
[2] Murakami, A., Nakamura, Y., Ohto, Y., Yano, M., Koshiba, T., Koshimizu, K., Tokuda, H., Nishino, H., and Ohigashi, H. Suppressive effects of citrus fruits on free radical generation and nobiletin, an anti-inflammatory polymethoxyflavonoid. Biofactors 2000;12(1-4):187-192.
[3] Rincon, A. M., Vasquez, A. M., and Padilla, F. C. [Chemical composition and bioactive compounds of flour of orange (Citrus sinensis), tangerine (Citrus reticulata) and grapefruit (Citrus paradisi) peels cultivated in Venezuela]. Arch Latinoam Nutr 2005;55(3):305-310.
[4] Murakami, A., Nakamura, Y., Ohto, Y., Yano, M., Koshiba, T., Koshimizu, K., Tokuda, H., Nishino, H., and Ohigashi, H. Suppressive effects of citrus fruits on free radical generation and nobiletin, an anti-inflammatory polymethoxyflavonoid. Biofactors 2000;12(1-4):187-192.
[5] Jang SE, Ryu KR, Park SH, Chung S, Teruya Y, Han MJ, Woo JT, Kim DH. Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38. Int Immunopharmacol. 2013 August 9;17(3):502-507.
[6] Nam SY, Chung CK, Seo JH, Rah SY, Kim HM, Jeong HJ. The therapeutic efficacy of α-pinene in an experimental mouse model of allergic rhinitis. Int Immunopharmacol. 2014 Nov;23(1):273-82.
[7] Henrotin, Y.; C. Lambert; D. Couchourel; C. Ripoll; E. Chiotelli (January 2011). "Nutraceuticals: do they represent a new era in the management of osteoarthritis? – a narrative review from the lessons taken with five products". Osteoarthritis and Cartilage 19 (1): 1–21.
[8] Rufino AT, Ribeiro M, Judas F, Salgueiro L, Lopes MC, Cavaleiro C, Mendes AF. Anti-inflammatory and chondroprotective activity of (+)-α-pinene: structural and enantiomeric selectivity. J Nat Prod. 2014 Feb 28;77(2):264-9.
[9] Lin N, Sato T, Takayama Y, Mimaki Y, Sashida Y, Yano M, Ito A. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem Pharmacol. 2003 Jun 15;65(12):2065-71.
[10] Kummer R, Fachini-Queiroz FC, Estevão-Silva CF, Grespan R, Silva EL, Bersani-Amado CA, Cuman RK. Evaluation of Anti-Inflammatory Activity of Citrus latifolia Tanaka Essential Oil and Limonene in Experimental Mouse Models. Evid Based Complement Alternat Med 2013 May
[11] Takano K, Tabata Y, Kitao Y, Murakami R, Suzuki H, Yamada M, Iinuma M, Yoneda Y, Ogawa S, Hori O. Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. Am J Physiol Cell Physiol. 2007 January 292
[12] Wu JJ, Cui Y, Yang YS, Jung SC, Hyun JW, Maeng YH, Park DB, Lee SR, Kim SJ, Eun SY. Mild mitochondrial depolarization is involved in a neuroprotective mechanism of Citrus sunki peel extract. Phytother Res. 2013 April ;27(4):564-71
[13] Li J, Zhou Y, Liu BB, Liu Q, Geng D, Weng LJ, Yi LT. Nobiletin Ameliorates the Deficits in Hippocampal BDNF, TrkB, and Synapsin I Induced by Chronic Unpredictable Mild Stress. Evid Based Complement Alternat Med. 2013 March
[14] Nakajima A, Aoyama Y, Nguyen TT, Shin EJ, Kim HC, Yamada S, Nakai T, Nagai T, Yokosuka A, Mimaki Y, Ohizumi Y, Yamada K. Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse. Behav Brain Res. 2013 August 1;250:351-60.
[15] Kawahata I, Yoshida M, Sun W, Nakajima A, Lai Y, Osaka N, Matsuzaki K, Yokosuka A, Mimaki Y, Naganuma A, Tomioka Y, Yamakuni T. Potent activity of nobiletin-rich Citrus reticulata peel extract to facilitate cAMP/PKA/ERK/CREB signaling associated with learning and memory in cultured hippocampal neurons: identification of the substances responsible for the pharmacological action. J Neural Transm. 2013 April
[16] Nagase H, Omae N, Omori A, Nakagawasai O, Tadano T, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y. Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities. Biochem Biophys Res Commun. 2005 December 2;337(4)
[17] Hiroshi Onozuka et al. Nobiletin, a Citrus Flavonoid, Improves Memory Impairment and Aβ Pathology in a Transgenic Mouse Model of Alzheimer's Disease. JPET September 2008 vol. 326 no. 3 739-744
[18] Kentaro Matsuzaki et al. Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats. Neuroscience Letters. Volume 400, Issue 3, 12 June 2006, Pages 230–234
[19] Hiroyuki et al. Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities. Biochemical and Biophysical Research Communications. Volume 337, Issue 4, 2 December 2005, Pages 1330–1336.
[20] Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y. Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer's disease. J Pharmacol Exp Ther 2008 September 326(3):739-44
[21] Yamakuni T, Nakajima A, Ohizumi Y. Preventive action of nobiletin, a constituent of AURANTII NOBILIS PERICARPIUM with anti-dementia activity, against amyloid-beta peptide-induced neurotoxicity expression and memory impairment. Yakugaku Zasshi. 2010 Apr;130(4):517-20.
[22] Zhang L, Zhao H, Zhang X, Chen L, Zhao X, Bai X, Zhang J. Nobiletin protects against cerebral ischemia via activating the p-Akt, p-CREB, BDNF and Bcl-2 pathway and ameliorating BBB permeability in rat. Brain Res Bull. 2013 July 96:45-53
[23] Yabuki Y, Ohizumi Y, Yokosuka A, Mimaki Y, Fukunaga K. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice. Neuroscience. 2014 Feb 14;259:126-41.
[24] Hashida K, Kitao Y, Sudo H, Awa Y, Maeda S, Mori K, Takahashi R, Iinuma M, Hori O. ATF6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson's disease. PLoS One. 2012 October.


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