Quercetin has neuroprotective effects

Quercetin and quercetin glycosides

by Makoto Aihara, MD., PhD.

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Background

Flavonoids comprise a large family of plant-derived compounds widely distributed in fruits and vegetables.(Heim et al. 2002)(Ross & Kasum 2002) There is growing evidence from human nutrition studies that the absorption and bioavailability of specific flavonoids is much higher than originally believed.(Ross & Kasum 2002)(Manach et al. 2005) Flavonoids are believed to exert protective and/or beneficial effects on multiple disease states, including cancer, cardiovascular disease, and neurodegenerative disorders.(Middleton 1998; Middleton et al. 2000)(Ross & Kasum 2002) These physiological benefits of flavonoids are generally thought to be derived from their antioxidant activity and free radical scavenging. (Ishige et al. 2001).

Quercetin is an important flavonoid and is ordinarily present bound to a sugar as a glycoside. For example, quercetin 3-O-rutinoside (rutin) is one of the quercetin glycosides, which is rich in buckwheat and tartary buckwheat, commonly ingested in Japan and other Asian countries, and amazingly accounting for as high as 1% of the total weight of buckwheat and tartary buckwheat.(Kim et al. 2009)(Fabjan et al. 2003)

RGC death in glaucoma is believed to be induced by apoptotic mechanisms triggered by multiple stimuli, including ischemia, oxidative stress, or elevation of glutamate levels.(Quigley 1999)(Wax & Tezel 2002) Numerous studies have demonstrated that excessive glutamate induces RGC death in vitro and in vivo,(Sucher et al. 1997) and that the glutamate receptor antagonists MK801 or memantine can ameliorate RGC death caused by elevated intraocular pressure.(Lipton 2003)(Chaudhary et al. 1998)(Hare et al. 2004)(Lagrèze et al. 1998)(WoldeMussie et al. 2002) Oxidative stress induced either by increased levels of reactive oxygen species (ROS) or mitochondrial dysfunction is also implicated in glaucomatous, ischemic, and hereditary optic neuropathies.(Carelli et al. 2009)(Tezel 2006) Accordingly, flavonoids including quercetin may also have neuroprotective potential in glaucoma.

Neuroprotection in non-retinal neurons

in vitroculture studies, Quercetin showed an ameliorating effect on oxidative stress-induced PC12 cell death (Dajas et al. 2003) or midbrain culture of rat,(Mercer et al. 2005) and also other kinds of stress-induced cell death, such as beta-amyloid induced PC12 cell death(Zhu et al. 2007) or kainite/NMDA induced rat neuronal death.(Silva et al. 2008) Quercetin also induced neuroprotective effect by modulating inflammatory responses in astroglia by IL1beta.(Sharma et al. 2007) In vivo, quercetin was effective in rat brain trauma model(Schultke et al. 2005) and cerebrovascular insults.(Ossola et al. 2009)

Neuroprotection in retinal neurons

Only five studies describing the potential effects of flavonoids on RGC death induced by oxidative stress or pressure stress using RGC-5 transgenic cell lines or in vivo rodent models have been reported.(Zhang et al. 2007)(Maher & Hanneken 2008)(Maher & Hanneken 2005)(Jung et al. 2008)(Liu et al. 2007) Liu et al reported a neuroprotective effect of quercetin on pressure-induced RGC-5 death.(Liu et al. 2007)

Drug delivery of quercetin and quercetin glycoside

A few reports have indicated that repeated intake of several hundred milligrams of quercetin-rutinoside resulted in a plasma concentration of 100nM or higher.(Boyle et al. 2000)(Erlund et al. 2000)(Graefe et al. 2001) Moreover, flavonoids can penetrate into the central nervous system through the blood-brain barrier.(Youdim et al. 2004) Interestingly, quercetin itself may not be effective in neurodegenerative disease such as Parkinson disease model rat,(Zbarsky et al. 2005) because it penetrates the blood brain barrier less efficiently than quercetin glycosides.(Ossola et al. 2009) This may be the reason for its beneficial effects in rat brain trauma or cerebrovascular insults.(Ossola et al. 2009)(Schultke et al. 2005)

Mechanism of neuroprotective action

Although the precise mechanism of action remains unclear, the beneficial activity of flavonoids is generally attributed to their antioxidative efficacy.(Schultke et al. 2005)(Silva et al. 2008)(Ishige et al. 2001) The antioxidant capacity of flavonoids depends on the arrangement of functional groups surrounding the flavonol nucleus, which may directly affect glutathione metabolism, antioxidant capacity, or the ability to maintain low Ca^2+^ levels despite high levels of reactive oxygen species. (Heim et al. 2002)(Ishige et al. 2001)

Conclusion

Quercetin and its glycosides have neuroprotective effect and may be effective on glaucomatous optic neuropathy. However there was no clinical evidence to use them as a neuroprotective agent. The major concerns of quercetin intake as a supplement are its poor penetration into the retina(Ossola et al. 2009)(Youdim et al. 2004) and its specific inhibitory effect on HSP72 induction,(Kretz et al. 2006)(Kwong et al. 2003) which may lead to deteriorate neuroprotective effect by HSP72. Further studies are needed using glaucoma animal model and human studies.

Source

World Glaucoma Congress 2010 Consensus Document

Section 8: Non-pharmaceutical medications and approaches

Makoto Araie, Robert Ritch, Clement Tham

Makoto Aihara, Aiko Iwase, Sandra Fernando, Michael S Kook, Simon Law, Robert Nussenblatt, Vincenzo Parisi, Nathan Radcliffe, Douglas Rhee, Kwok-Fai So, Raymond Chuen-Chung CHANG, He Wei, Lori Ventura

Overall Consensus points

• Plant extracts have been used medicinally throughout history. Every society has plants used medicinally
• Even dogs eat grass when sick, while chimpanzees consume a variety of non-food plants medicinally. This is learned behavior.
• Our modern pharmacopoiea of drugs were originally synthesized from plants used medicinally. These include vitamin C, digitalis, penicillin, and pilocarpine.
• Chinese traditional medicine in its written form dates back 5000 years.
• Technically speaking, vitamins fall into this category. We depend on essential vitamins from food for survival. There is a fine line between nutrition and medicinal uses of plants.
• It was only in the 20^th^ century, with the advent of single molecule products synthesized and patented by pharmaceutical companies and U.S. medical school philosophiesthat other non-pharmaceutical traditional medications came under attack, leading often to their being ridiculed and held in contempt.Thus, in order to get away from this view, we prefer the term “non-pharmaceutical therapy” to “alternative” or “complementary”
• Many available natural compounds used as “non-pharmaceutical therapy” have been reported to show beneficial effects on circulation, the immune system, and neuroprotective activities in vitro and in vivo.
• The mechanism of action of neuroprotection most common to natural compounds is antioxidant/free radical scavenging activity. However, many other actions are present and some extracts, such as Gingko biloa and curcumin have widespread activity on a number of enzyme systems.
• Comment: Some of these compounds reportedly modify expression of enzymes relating to excitotoxicity, apoptosis, inflammation, lipid peroxidation, or immune stimulation. Some of these compounds have undergone clinical trials to evidence their effects on systemic diseases, including neurodegenerative disorders.

Comment: There have been several randomized trials with the majority showing a clinical benefit of n-acetyl cysteine therapy of chronic obstructive pulmonary disease. There are currently 33 NIH-sponsored trials involving curcumin.

• There is a relative paucity of clinical trials examining neuroprotective effects of these compounds on ocular diseases, including glaucoma, and most of them were case series.
• Bioavailability of these natural compounds have not been well studied.
• Exercise reduces intraocular pressure (IOP) and influences ocular blood flow. It also protects against Alzheimer’s and cardiovascular disease.

Comment: Stress may also influence IOP and ocular blood flow.

• Acupuncture influences IOP and ocular blood flow, but the reported results are not consistent.
• Clinical trials on many of these extracts and compounds are warranted.

Comment: Funding is a problem, since these compounds are mostly in the pubic domain and not patentable. In addition, end points are seriously inadequate. We need methods of reducing detection of endpoints to months instead of years and reducing the numbers of patients required for clinical trials.

References

Boyle SP, VL Dobson, SJ Duthie & et al (2000): Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr 54: 774-782.

Carelli V, C La Morgia, ML Valentino & et al (2009): Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta 1787: 518-528.

Chaudhary P, F Ahmed & S Sharma (1998): MK801-a neuroprotectant in rat hypertensive eyes. Brain Res 792: 154-158.

Dajas F, F Rivera, F Blasina & et al (2003): Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox Res 5: 425-432.

Erlund I, T Kosonen, G Alfthan & et al (2000): Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 56: 545-553.

Fabjan N, J Rode, IJ Kosir & et al (2003): Tartary buckwheat (Fagopyrum tataricum Gaertn.) as a source of dietary rutin and quercitrin. J Agric Food Chem 51: 6452-6455.

Graefe EU, J Wittig, S Mueller & et al (2001): Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol 41: 492-499.

Hare WA, E WoldeMussie, RK Lai & et al (2004): Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: Functional measures. Invest Ophthalmol Vis Sci 45: 2625-2639.

Heim KE, AR Tagliaferro & D Bobilya (2002): Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 13: 572-584.

Ishige K, D Schubert & Y Sagara (2001): Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med. 30: 433-446.

Jung SH, KD Kang, D Ji & et al (2008): The flavonoid baicalin counteracts ischemic and oxidative insults to retinal cells and lipid peroxidation to brain membranes. Neurochem Int 53: 325-337.

Kim DW, IK Hwang, SS Lim & et al (2009): Germinated buckwheat extract decreases blood pressure and nitrotyrosine immunoreactivity in aortic endothelial cells in spontaneously hypertensive rats. Phytother Res 23: 993-998.

Kretz A, C Schmeer, S Tausch & SS Isenmann (2006): Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo. Neurobiol Dis 21: 421-430.

Kwong JM, TT Lam & J Caprioli (2003): Hyperthermic pre-conditioning protects retinal neurons from N-methyl-D-aspartate (NMDA)-induced apoptosis in rat. Brain Res 970: 119-130.

Lagrèze WA, R Knörle, M Bach & TJ Feuerstein (1998): Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia. Invest Ophthalmol Vis Sci 39: 1063-1066.

Lipton SA (2003): Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Surv Ophthalmol 48 Suppl 1: S38-46.

Liu Q, WK Ju, JG Crowston & et al (2007): Oxidative stress is an early event in hydrostatic pressure induced retinal ganglion cell damage. Invest Ophthalmol Vis Sci 48: 4580-9.

Maher P & A Hanneken (2005): Flavonoids protect retinal ganglion cells from oxidative stress-induced death. Invest Ophthalmol Vis Sci 46: 4796-4803.

Maher P & A Hanneken (2008): Flavonoids protect retinal ganglion cells from ischemia in vitro. Exp Eye Res 86: 366-374.

Manach C, G Williamson, C Morand & et al (2005): Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr; 81: 230S-242S.

Mercer LD, BL Kelly, MK Horne & P Beart (2005): Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: investigations in primary rat mesencephalic cultures. Biochem Pharmacol 69: 339-345.

Middleton E, ]. Jr., (1998): Effect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol 439: 175-182.

Middleton EJ, C Kandaswami & TC Theoharides (2000): The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52: 673-751.

Ossola B, TM Kaariainen & PT Mannisto (2009): The multiple faces of quercetin in neuroprotection. Expert Opin Drug Saf 8: 397-409.

Quigley HA (1999): Neuronal death in glaucoma. Prog Retin Eye Res 18: 39-57.

Ross JA & CM Kasum (2002): Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22: 19-34.

Schultke E, H Kamencic, M Zhao & et al (2005): Neuroprotection following fluid percussion brain trauma: a pilot study using quercetin. J Neurotrauma 22: 1475-1484.

Sharma V, M Mishra, S Ghosh & et al (2007): Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 73: 55-63.

Silva B, PJ Oliveira, A Dias & J Malva (2008): Quercetin, kaempferol and biapigenin from Hypericum perforatum are neuroprotective against excitotoxic insults. Neurotox Res 13: 265-279.

Sucher NJ, SA Lipton & EB Dreyer (1997): Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 37: 3483-3494.

Tezel G (2006): Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Brain Res 25: 490-513.

Wax MB & G Tezel (2002): Neurobiology of glaucomatous optic neuropathy: diverse cellular events in neurodegeneration and neuroprotection. Mol Neurobiol 26: 45-55.

WoldeMussie E, E Yoles, M Schwartz & et al (2002): Neuroprotective effect of memantine in different retinal injury models in rats. J Glaucoma 11: 474-480.

Youdim KA, MZ Qaiser, DJ Begley & et al (2004): Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med. 36: 592-604.

Zbarsky V, KP Datla, S Parkar & et al (2005): Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic Res 39: 1119-25.

Zhang B, R Safa, D Rusciano & NN Osborne (2007): Epigallocatechin gallate, an active ingredient from green tea, attenuates damaging influences to the retina caused by ischemia/reperfusion. Brain Res 1159: 40-53.

Zhu JT, RC Choi, GK Chu & et al (2007): Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloid-induced cell death. J Agric Food Chem 55: 2438-2445.