A New Oldie but Goodie for an …

Improved Galantamine
Formulation at No Extra Cost

Hesperidin Found to Be Neuroprotective—So
We Have Added It to Our Galantamine Formulation

By Durk Pearson & Sandy Shaw

O

ldies but goodies can sneak up on you. You think you know them, but your knowledge may be many years out of date because the research doesn’t stop with the first data finding beneficial effects. They may seem to be oldies because you learned some interesting facts about them years ago, but the new findings keep on piling up and can come as a real surprise if you’ve written off these old dietary components as nutrition that is all understood, as if the science has been settled, nothing new going on here, move along folks.

Hesperidin is one of those oldies but goodies that remains a research subject of interest because scientists keep finding new aspects of its functionality that continually refreshes the totality of the evidence concerning it.

“Everybody knows” that citrus fruits are healthful, right? Sure, but we bet you didn’t know about some of these new findings about how hesperidin, a flavonoid found plentifully in citrus fruits, can help protect your brain from the ravages of aging and, based on newer discoveries about it, may help reduce the risk of Alzheimer’s disease. So, without further adieu, here’s an update on hesperidin, one of the oldies but goodies that has far surpassed earlier expectations. Here’s why we’ve added it to our galantamine formulation without adding a single penny to the price. (The formulation is a premium-priced dietary supplement because of the natural cholinesterase inhibitor galantamine contained in it, which is currently a very costly ingredient—one reason for this is that FDA forces you to jump through hoops at Customs to make it as difficult as possible to import the ingredient. There is no health or safety reason for this—the FDA is just a bully that wants to support prescription drug companies that will sell it at a much higher price as an FDA-approved drug.)

Hesperidin Protects Against Amyloid Beta-Induced Neurotoxicity Thereby Helping Protect Against Damage Leading to Alzheimer’s Disease

A recent paper1 reports protective effects of hesperidin against amyloid beta-induced toxicity in PC-12 neuronal cells. As amyloid beta is thought to be a critical part of the neurodegenerative process of Alzheimer’s disease, this protection could be a valuable addition to our galantamine formulation. Treatment of these cells with 20 μM of amyloid beta25–35, an active toxic fragment of amyloid beta1–42, induced approximately 50% cell death. Then, adding various concentrations of hesperidin to the toxin-treated cells was used to test whether hesperidin could provide protection against the toxic effects of the amyloid beta25–35. Results showed that pretreatment with hesperidin (10, 25, and 50 μM for one hour prior to the administration of the amyloid beta25–35 decreased the apoptotic rate (death of the cells) to 24.12, 15.27, and 8.32%, respectively.

Moreover, hesperidin pretreatment also attenuated in a dose-dependent manner the mitochondrial stress-induced opening of the mitochondrial permeability transition pore, a measure of mitochondrial dysfunction. As the authors explain, “[t]he Abeta [amyloid beta] peptide damages neurons by inducing free radical generation and calcium dysregulation, both of which are potent inducers of mPTP [mitochondrial permeability transition pore] opening.”1 One indication of mitochondrial dysfunction is the release of cytochrome c from mitochondria into the cellular cytosol. The researchers found that pretreatment with 50 μM hesperidin significantly attenuated the release of cytochrome c into the cytosol, demonstrating hesperidin mitochondrial protection.

Hesperidin Shown to Improve Neuronal Survival Under Unfavorable Conditions

Two recent papers2A,2B report protection by hesperidin of neuronal survival when in the presence of reactive oxygen species, enzymes of oxidation-reduction pathways, and excess levels of transition metal cations. Studying the effects of hesperidin in cultures of cortical cells, the cells were treated with 10 μM of either hesperidin or rutin. Quantitative analysis showed that the cells treated with hesperidin had a 50% decrease in neuronal death.2A The authors2A found that the hesperidin protection was mediated by activation of the PI3K and MAPK kinase pathways. They also referred to in vivo studies showing that hesperidin and other flavonoids are highly potent in preventing striatal dopamine depletion in mice as well as substantia nigra dopaminergic neuron loss resulting from exposure to MPTP, a Parkinsonism-inducing toxin.2A

In another paper,2B researchers report that hesperidin-primed astrocytes (a type of brain cell that, among other things, protects neurons from damaging insults) protected against neuronal cell death. Flavonoids such as hesperidin have also been reported to have anti-amyloidogenic effects, hence, helping prevent the type of damage that leads to Alzheimer’s disease.2B

Pre-treatment With Hesperidin Shown to Protect Against Ischemia-Reperfusion Injury in Rats Attenuating Mitochondrial Dysfunction and Memory Impairment

One of the common mechanisms of injury and, in the long run, contributing to aging and cardiovascular and neurodegenerative diseases of aging, is ischemia-reperfusion (I/R) injury as occurs when blood flow to a tissue is temporarily blocked or reduced and then flow is restored. When severe enough, I/R can result in heart attack or stroke, causing long-lasting damage or even death. Hence, improving natural protective mechanisms to ameliorate such damage is a good idea if you want to live a long time in good health.

A recent paper3 reports on the results of a study of male Wistar rats, subjected to a common model of I/R injury (bilateral carotid occlusion for 30 minutes followed by 24 hours of reperfusion), and pretreated for seven days before I/R injury with hesperidin (50 and 100 mg/kg p.o.) or subject to I/R but not pretreated with hesperidin (I/R controls). One of the major mechanisms causing damage during I/R involves excitotoxicity (glutamate release resulting from excess generation of nitric oxide by inducible nitric oxide synthase and neuronal nitric oxide synthase). Increased expression of neuronal nitric oxide synthase has also been shown to take place in the hippocampi of patients with Alzheimer’s disease and to occur in various experimental models of stroke.3 Administration of an anti-nitric oxide molecule, L-NAME, along with the lower dose of hesperidin significantly potentiated the protective effect of hesperidin whereas administration of L-arginine, precursor of nitric oxide, along with hesperidin reduced the protective effect of hesperidin; the authors suggest, therefore, that hesperidin may work in part by decreasing excess generation of nitric oxide during I/R.

Another major effect of I/R injury is decreased blood levels of glutathione, possibly the most important antioxidant defense molecule. Changes in behavior in rats as a result of I/R injury includes memory impairments and cognitive deficits.

I/R rats pretreated with either dose of hesperidin had significantly reduced decreases in blood glutathione. Muscle strength, as determined by how long rats could hang onto a rotarod, showed significant delay in falloff time in the rats pretreated with hesperidin. Similarly, memory retention in a elevated plus maze was significantly protected against I/R-induced deficits in the hesperidin pretreated rats.

Cytoprotective Effects of Hesperetin and Hesperidin Against Amyloid Beta-induced Impairment of Glucose Transport in Neuro-2A Neuroblastoma Cell Line

Another proposed mechanism of the damaging effects of amyloid beta in the pathway leading to Alzheimer’s disease is impairment of neuronal energy metabolism by reducing cellular glucose uptake. The authors of another recent paper4 propose that the reduced cellular glucose uptake induces autophagy, a process whereby some cellular components are broken down and the resulting materials used for other purposes when energy supplies are limited. The process is complicated by the fact that autophagy itself is an energy-requiring process and, hence, is not always desirable. The researchers report that insulin-stimulated neuronal glucose uptake could be increased by reducing amyloid beta-induced autophagy. They tested the hypothesis that hesperidin or hesperitin might downregulate neuronal autophagy induced by amyloid beta.

The cells were pretreated with hesperetin or hesperidin (1 and 20 μM) for 6 hours, then exposed to amyloid beta1–42 (500 nM) for 24 and 48 hours, followed by incubation with 100 nM insulin for 30 minutes, and their glucose uptake in response to insulin was evaluated.

Hesperetin or Hesperidin May Help Prevent the Progression of Alzheimer’s Disease

The researchers found that treatment with hesperitin or hesperidin improved amyloid-beta-impaired glucose utilization by inhibiting amyloid-beta-induced autophagy in the neuronal cells.4 The authors suggest, therefore, that “… hesperetin or hesperidin may be a potential agent in the preventing of Alzheimer’s disease progression.”4

Hesperidin Reduces Neuroinflammation and Ameliorates Dysfunction in Experimental Model of Stroke

Another recent paper5 reports improved outcome in a rat model of stroke (middle cerebral artery occlusion for 2 hours followed by 22 hours of reperfusion). Hesperidin pretreated rats had significantly reduced expression of inflammatory mediators such as TNF-alpha, IL-1beta, and iNOS, and improved muscular coordination and grip strength as compared to the animals subject to the stroke procedure but not receiving hesperidin.

Hesperidin Improves Results of Continuous and Interval Swimming Exercise in Rats

A new paper6 reports changes in biochemical and oxidative biomarkers in rats subjected to either continuous or interval swimming exercise with or without hesperidin supplementation. Continuous exercise was defined as moderate to intense exercise of extended duration where fatty acids are the predominant energy source; interval exercise was defined as high intensity exercise with passive or active pauses between bouts of exercise where glucose is the predominant energy source.6 The results showed, among other things, that continuous or interval swimming combined with hesperidin lowered total cholesterol (–16%, p<0.05), LDL cholesterol (–50%, p<0.05) and triglycerides (–19%, p<0.05), and increased HDL cholesterol (+48%, p<0.05). The authors note that previous studies have reported hesperidin to inhibit the enzyme HMG CoA-reductase that synthesizes cholesterol (this is the same enzyme that is inhibited by statin drugs to reduce LDL cholesterol). Hesperidin was also found in the current study6 to increase the expression of the LDL receptor, an important part of a major mechanism for lowering LDL levels.


Based on newer discoveries,
hesperidin may help reduce the risk
of Alzheimer’s disease.


Hesperidin was administered by gavage for four weeks at a dose of 100 mg/kg body mass to those animals receiving hesperidin. The authors reported that “[s]erum glucose concentration was significantly decreased when the animals were treated with hesperidin, whether associated with swimming or not.”

Happy Juice?
Hesperidin Also Has Antidepressant Properties

Hesperidin has antidepressant-like effects in animal models of depression. One recent paper7 found that hesperidin (tested at doses of 0.1, 0.3, and 1 mg/kg) decreased immobility time at all three doses in the forced swimming test (the immobility refers to the freezing response of animals in a scary situation, such as being tossed into a container of water and having to swim for their lives—freezing up isn’t very helpful). Interestingly, the antidepressant effect was mediated by activation at the kappa opioid receptor (not associated with addiction) and could be prevented by administering naloxone, an opioid antagonist.

“Clinical findings indicate that depressed patients displayed a deficiency of endogenous opioid activity, while manic patients display excess opioid activity.”7 The release of endogenous opioids by exercise is thought to be one reason for the antidepressant effect of exercise.

The same group of scientists that published the paper cited as #7 also published another paper on hesperidin’s antidepressant effects7B in mice subjected to the tail suspension test in which they reported that these antidepressant effects were dependent on interactions with the serotonergic 5-HT1A receptors. In that study,7B administration of a combination of hesperidin and fluoxetine (Prozac®) at subeffective doses (neither was antidepressant at the low doses administered) resulted in an antidepressant-like effect in mice subjected to the tail suspension test.

A review7C of several natural polyphenols in the management of major depression reported some of the data discussed on hesperidin above plus additional data on hesperidin as an antidepressant, concluding that “[h]esperidin seems to be a viable candidate for the treatment of major depression.”

Have We Reached the Bottom of the Bag of Tricks for Hesperidin? Not Yet

Hesperidin has been reported to have other interesting properties as well, though these are of lesser importance in relation to a cognition enhancing product like advanced galantamine formulation. For example, hesperidin has been reported to have mild sedative, tranquilizing, and antinociceptive (anti-pain) properties. Interestingly, the pain-reducing effects are partially blocked by naltrexone, a nonselective opioid antagonist, suggesting that opioid receptors are involved in the pain-reducing effects of hesperidin. In a 2008 paper,8 researchers showed that the co-administration of hesperidin with alprazolam, a benzodiazepine anti-anxiety drug), in adult male Swiss mice resulted in potentiation of the antipain effects of the combination as compared to hesperidin alone. Earlier studies cited by the authors8 had identified antiinflammatory and analgesic effects of hesperidin in rats and mice.

Hesperidin More Effective Than Morphine in One Test of Pain in Mice

The researchers report the unexpected finding that hesperidin was more active than morphine in the acetic acid-induced writhing test of pain, since (they state), “at 1 mg/kg [hesperidin] caused a greater effect than morphine at 2 mg/kg (p<0.01). Even at 0.7 mg/kg, hesperidin was as effective as morphine at 2 mg/kg.”8

Other Effects of Interest

We haven’t discussed hesperidin’s reported hypolipidemic, antihypertensive, anticarcinogenic, protective effects against capillary leakiness, and other properties and clearly, it would require something approaching a book to really cover the subject. So, when we get right down to it, hesperidin is not a mild mannered component of citrus fruits at all, but is more like Superman in disguise.

Broad Spectrum Protective Effects of Hesperidin Suggest a Powerful Molecule

If familiarity breeds contempt, then the moral of this story is: don’t assume you know all there is to know about an old familiar nutrient on the basis of your early acquaintance with it from years ago. (We’ve had it in our high-potency multivitamin antioxidant formulation for decades, but we know a lot more about it now than we did when we originally formulated that product.) Don’t take a chance of overlooking a diamond in the rough thinking that it is a mere glittering piece of old glass. Get reacquainted with hesperidin, now adding value to our galantamine formulation at no extra cost.

How Much Raw Orange Juice Would You Have To Drink To Get the Hesperidin Contained in a Day’s Worth of Our Galantamine Formulation?

Based upon numbers for hesperidin content of OJ,9 you would need to drink 1.2 liters a day of raw orange juice to get the amount of hesperidin contained in the recommended dose of 6 caps/day of our galantamine formulation. YOW! Not only would that contain an awful lot of natural sugars (sucrose, glucose, fructose) and calories, but the cost of the oranges needed to get that much hesperidin would actually be greater than the cost of the recommended daily dose of our galantamine formulation! Actually, because of the high content of calories and sugar, that much OJ is generally not recommended in a healthful diet.

References

1. Wang et al. Protective effects of hesperidin against amyloid-beta (Abeta) induced neurotoxicity through the voltage dependent anion channel 1 (VDAC1)-mediated mitochondrial apoptotic pathway in PC-12 cells. Neurochem Res. 38:1034-44 (2013).
2A. Nones et al. Hesperidin, a flavone glycoside, as mediator of neuronal survival. Neurochem Res. 36:1776-84 (2011).
2B. Nones et al. Effects of the flavonoid hesperidin in cerebral cortical progenitors in vitro: indirect action through astrocytes. Int J Dev Neurosci. 30:303-13 (2012).
3. Gaur and Kumar. Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep. 62:635-48 (2010).
4. Huang et al. Cytoprotective effects of hesperetin and hesperidin against amyloid beta-induced impairment of glucose transport through downregulation of neuronal autophagy. Mol Nutr Food Res. 56:601-9 (2012).
5. Raza et al. Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res. 1420:93-105 (2011).
6. de Oliveira et al. Hesperidin associated with continuous and interval swimming improved biochemical and oxidative biomarkers in rats. J Int Soc Sports Nutr. 10:27 (2013).
7. Filho et al. Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. Eur J Pharmacol. 698:286-91 (2013).
7B. Souza et al. Evidence for the involvement of the serotonergic 5-HT1A receptors in the antidepressant-like effect caused by hesperidin in mice. Prog Neuropsychopharmacol Biol Psychiatry. 40:103-9 (2013).
7C. Pathak et al. Natural polyphenols in the management of major depression. Expert Opin Investig Drugs. 22(7):863-80 (2013).
8. Loscalzo et al. Opioid receptors are involved in the sedative and antinociceptive effects of hesperidin as well as its potentiation with benzodiazepines. Eur J Pharmacol. 580:306-13 (2008).
9. Bhagwat, Haytowitz, Holden. USDA Database for the Flavonoid Content of Selected Foods. pg. 38 (also see method of converting hesperitin content to hesperidin, pg. 6) (June 2013).


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