Announcing Durk & Sandy’s…

New Lithium Formulation
Lithium, an Essential Nutrient, Has Neuroprotective Effects at Low Dosage

By Durk Pearson & Sandy Shaw

L ithium salts act as a drug at high doses, but act as a neurologically beneficial essential nutrient at much, much, smaller amounts.

First, a brief description of the very high dose medical use of lithium—it can be effective as a drug treatment for manic-depressive (or bipolar) illness. It provides nearly complete protection against attacks in about 1/3rd of bipolar patients, improved symptoms in another 1/3rd, and is ineffective in the remaining 1/3rd.A However, the treatment of bipolar illness requires high doses of lithium, close to the toxic dose. The clinically effective dose range is 0.6–1.0 μM serum level, while the toxic level begins at about 1.2 μM or greater. Symptoms in the dose range of 1.2–2.0 μM are said to be usually mild and to seldom cause death or permanent neurological damage.1 Lithium is excreted via the kidneys or in sweat. Because the toxic dose is not much higher than the therapeutic dose and because prolonged exposure to serum levels of 2μM or greater may cause liver and kidney damage1 though, it is necessary for those receiving pharmacological doses for bipolar disorder to receive periodic blood tests to ensure the lithium blood levels remain in the therapeutic range and that liver and kidney functions remain normal.

What is more interesting to us than its use at the highest level that is tolerable before toxic effects ensue is what lithium does at low doses, a dose so low that it would NOT be an effective treatment for bipolar disorder and, hence, we can assume the mechanisms of its actions differ from those that take place at a high dose. It is particularly interesting in light of the fact that lithium at small amounts has been found to be an essential mineralB with a suggested RDA of 1 mg/day for a 70 kg adult human.B

Lithium in Spring Water Reported to Be Positively and Significantly Associated with Brain Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is an important growth factor involved in many cognitive processes including learning and memory, emotional processes, and sometimes psychopathological conditions such as addiction. The effect depends on the specific tissue in which the BDNF is released, the conditions under which it is released, and the dosage released.

In a study of 43 Japanese subjects who did not have psychiatric dysfunction, the participants drank 3.64 liters of spring water from two springs, one of which contained 6.1 mg/liter of lithium and the other contained 15.7 mg/liter, much lower than lithium in clinical use (900 to 1800 mg/day of lithium carbonate, containing 170–340 mg lithium/day) but at much higher levels than generally contained in lithium-containing tap water (generally much less than 1 mg/liter). Their serum lithium levels increased from 0.026 to 0.073 mEq/L, a much lower level than if they had been treated with bipolar treatment levels of lithium. The results of a Profile of Mood States indicated that most ratings were significantly improved (though whether this was caused by lithium is unclear—the authors suggested it could be a placebo effect). More interestingly, however, serum lithium levels were significantly and positively associated with BDNF levels. BDNF was also negatively and significantly associated with changes in the State-Trait of Anxiety Inventory scores. The researchers cited an earlier study in which lithium had been reported to increase BDNF levels. As this1 was a small open (no blinding, no placebo control) study, the authors rightly noted that further studies are needed to confirm these findings.

German studies have reported the effects of lithium-deficient diets in animals such as goats, pigs, cattle, broiler chickens, and rats.2 For example, one such study of a 13 year investigation with lithium-deficient goats reported that 41% of the lithium-deficient goats but only 7% of the controls (lithium adequate) died during the first experimental year indicating a highly significant difference (p<0.001) between the groups. Moreover, by the end of the third experimental year, all lithium-deficient goats had died, but 18% of the controls were still alive.2

The same paper2 also described the analyses of various types of bottled water that included spring water, mineral waters, etc. from 28 countries, finding that natural lithium concentration varied over 5 orders of magnitude, from 0.057 to 5,460 μg/l. The waters of the Friedrich-Quelle, a famous curative spring in Baden-Baden, Germany, were reported to be 8.7 mg/l. The upper crust of European society visits there for restorative effects. While there, visitors are encouraged to drink only the spring water.

Further data have emerged from studies of populations consuming naturally varying lithium content drinking water. In one study2 in 24 counties of Texas with a total population of 6,000,000, during the period of 1967–1969, a significant inverse relationship was found between lithium content of local drinking water and the admitting rates for four major mental disorders (psychosis, neurosis, schizophrenia, personality problems) as well as homicide rates. Another study, that included all 99 districts of Austria, showed that the overall suicide rate and the suicide SMR (suicide standardized mortality ratio) between 2005 and 2009 were inversely associated with lithium levels in drinking water (ranging between 3.3 to 82.3 μg/l).2

Not much data are available on what mechanisms are operative at the very low doses of lithium (except possibly for an increase in BDNF, as discussed above) as compared to mechanisms that help explain the therapeutic effects of high-dose lithium in the treatment of bipolar disorder. Lithium has been reported to inhibit phosphatases in both plant and animal cells, but we didn’t find any specific data on how this might be involved in (for example) suicide or homicide rates.

Lithium is reported to have a small ionic radius that results in lithium having the highest electronegativity and strongest polarization power among all alkali metal ions and is said to have a relatively large stable radius of the hydrated ion.2 The implications of all this obviously bears upon its biological effects. We await with great interest an elaboration of the effects of lithium that provide mechanistic data explaining its biological properties.

Possible Life Extending Effects of Low Dose Lithium

A large epidemiological study has reported that there was an inverse correlation between drinking water lithium concentrations and all-cause mortality in 18 neighboring Japanese municipalities with a total population of 1,206,174 people. The researchers also found that lithium chloride, at a similar dose to that ingested by the humans in their drinking water, extended lifespan in C. elegans.3

The authors3 adjusted the mortality data for suicide rates (higher levels that would still be considered low dose lithium has already been found to be associated with reduced suicide rate) and found that overall mortality rate was still inversely associated with tap water lithium levels. In the roundworm Caenorhabditis elegans, mortality in populations exposed to 10 μM of lithium chloride was reduced, while roundworms exposed to 1 μM of lithium chloride showed no effect on mortality rate. These results are consistent with a possible life extending effect of low dose lithium. A dose of 6 mg/day of lithium for an adult human will provide well above the lithium level found to be effective in the roundworms.

Chronic Supplementation with Low Dose Lithium May Protect Against Ischemic Damage as Occurs in Stroke

A further study of low dose lithium4 reports neuroprotective effects in a rat model of ischemia (inducing ischemia by middle cerebral artery occlusion for 90 minutes followed by reperfusion). The experimental animals received lithium at 1 mmol/kg (given subcutaneously) for 14 days prior to middle cerebral artery occlusion and then 2 days following. Lithium chloride significantly reduced the infarct volume (number of cells killed by the procedure) by 32.7% compared to the animals receiving vehicle containing no lithium. The chronic treatment with low-dose lithium increased the expression of the antiapoptotic protein Bcl-2 and reduced the expression of the apoptotic-inducing proteins p53 and Bax. The low dosage administered to the experimental animals here was about six times higher than would be ingested from a single serving of our lithium capsules (6 mg per cap).

Neuroprotective Effects of Chronic Low Dose Lithium in Traumatic Brain Injury in Mice

Considering the high number of automobile accidents and falls resulting in injury or death in the U.S. every year, it would be expected that many incidents of traumatic brain injury occur. The sequelae of such injuries may take place over a period of time and may not receive timely or adequate treatment to prevent temporary (or even permanent) cognitive dysfunction. It is of considerable interest, therefore, to find that, as reported in a recent paper,5 chronic low dose lithium can provide substantial protective effects against a negative outcome in traumatic brain injuries, at least as demonstrated in a mouse model. Since the mechanisms responsible for the damaging effects of such injuries are very similar for mice and men, we consider low dose lithium a likely prophylactic against brain damage, as could occur in a car accident or a fall.

In fact, falls are becoming much more common as the population ages and can result in considerable disability or even death as a result of brain damage. Sandy’s mother and father both died as a result of falls. Even at 85 (her mother) and 91 (her father), they might have lived on for years had they not fallen. Sandy’s mother died of a neck fracture after falling, while her father died of a stroke resulting from brain damage induced by the fall. We reported earlier (in Vol. 6 No. 3 of the June 2003 issue of this newsletter) the results of a human clinical trial of 122 elderly women in a geriatric long-stay care facility, who received 1200 mg calcium plus 800 iu of cholecalciferol (vitamin D) per day over 12 weeks. The combination of calcium plus Vitamin D resulted in a 49% reduction in falls as compared to calcium alone!*


* Bischoff et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Min Res. 18(2):343-51 (2003).


As the authors of the paper explain, the initial mechanical damage in traumatic brain injury results in blood-brain barrier disruption, cerebral edema, and subsequent increase in intracranial pressure. Later, the secondary effects emerge as a result of an inflammatory response with the release of pro-inflammatory cytokines and the subsequent death of neurons. Cognitive deficits may linger.

The mice were treated daily for 2 weeks with 1 mmol/kg of lithium chloride by intraperitoneal injection and then, under deep anesthesia, were subject to a “controlled cortical impact” to simulate the result of an accidental traumatic brain injury. The researchers found that the animals receiving low dose lithium had significant reduction of loss of hemispheric brain tissue and lesion volume as compared to saline treated controls also subject to traumatic brain injury but receiving no lithium. Low dose lithium also attenuated the learning and memory deficits resulting from the experimental brain injury (as assessed by how long it took the animals to find the hidden platform in the Morris Water Maze).

The authors5 conclude that “[t]aken as a whole, these observations suggest lithium may be a beneficial ‘preventive’ therapeutic approach for reducing the neuronal degeneration and related behavioral dysfunction associated with neurodegenerative illnesses.”

We are personally aware of the extent of cognitive deficits that can ensue following a vehicular accident as a result of what happened to a longtime dear friend of ours. She had been involved in a serious accident while riding a bus and has never been the same since then, a few years later. Since we knew her well before the accident, the changes were very clear to us, that she has problems now with learning and memory that she didn’t have before and overall a substantial decline in her quality of life. She constantly needs reminding of things, even while keeping extensive lists to try to remember. We don’t know how much of this could have been prevented by regular low dose lithium taken before the accident, but we certainly wish she’d had the chance to find out.

Daily Injections of Low Dose Lithium for 14 or 28 Days in Wistar Mice Resulted in Increased Size of Neurons and a Denser Dendrite Network

Finally, a paper partly in French and partly in English reported interesting effects of low dose lithium (80 ng/kg lithium carbonate) in the brain cortex of mice: larger neurons and a denser dendrite network.6 These changes remind us of those observed (via MRI) in the brains of humans receiving lithium at therapeutic levels for bipolar disorder, where brain grey matter volume is increased after 4 weeks of treatment. The increased volume (about 3%) was observed in 8 out of the 10 patients studied.7


References

A. Young. Review of lithium effects on brain and blood. Cell Transplant. 18(9):951-75 (2009).
B. Schrauzer. Lithium: occurence, dietary intakes, and nutritional essentiality. J Am Coll Nutr. 21(1):14-21 (2002).
1. Shiotsuki et al. Drinking spring water and lithium absorption: a preliminary study. German J Psychiatry. 11:103-6 (2008).
2. Schafer. Evaluation of beneficial and adverse effects on plants and animals following lithium deficiency and supplementation, and on humans following lithium treatment of mood disorders. Trace Elem Electrolytes. 29(2):91-112 (2012).
3. Zarse et al. Low-dose lithium uptake promotes longevity in humans and metazoans. Eur J Nutr. 50:387-389 (2011).
4. Xu et al. Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death. Stroke. 34:1287-1292 (2003).
5. Zhu et al. Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull 83:272-7 (2010).
6. Nciri et al. Effects of low doses of Li carbonate injected into mice. Functional changes in kidney seem to be related to the oxidative status. C R Biol. 331:23-31 (2008).
7. Moore et al. Lithium-induced increase in human brain grey matter. The Lancet. 356:1241-2 (2000).


DEPRESSED?
HAVING PAIN?
TURMERIC ROOT TO THE RESCUE!

Here we explain why we have added turmeric root to our new Lithium formulation.

Mechanisms for Antidepressant Property of Curcumin

Complete Relief of Pain from Bursitis of the Hip Provided by Turmeric Root

PAIN. We received correspondence from a fan of our turmeric root powder in capsules telling us that she and her sister have bursitis of the hip and have experienced complete relief of all pain with turmeric root powder in caps. Our thanks to this fan for the tip. Not all pain responds the same to pain relievers, but in this case, bursitis was responsive to turmeric root powder.

DEPRESSION. Meanwhile, a recent paper provides new details on the antidepressant properties of curcumin (a major component of turmeric root powder).1 The authors explore several mechanisms that may account for these effects.

Surprisingly, the researchers1 note, in some earlier studies on curcumin’s effects on pain in rodent models of depression, curcumin had similar antidepressant efficacy to fluoxetine (Prozac®) in the forced swimming test and the tail suspension test. The sorts of behavior that are considered signs of depression in these animals include decreased interest in drinking a sucrose solution and immobility when subjected to stressful conditions.

Depression Associated with Higher Levels of Pro-inflammatory Cytokines

Importantly, the researchers explain, “[t]hree recent meta-analyses have all confirmed that depression is associated with elevated levels of pro-inflammatory cytokines and other inflammatory mediators.”1 Pro-inflammatory cytokines that have been reported at higher levels during depression-like episodes in animals include C-reactive protein, interleukin-1, interleukin-6, and tumor necrosis factor-alpha. (We suggest that you try to include measurements of blood IL-6 and TNF-alpha when you have lab blood tests. Although C-reactive protein is becoming a fairly common lab test, it will still require a request to get the other pro-inflammatory cytokines measured as well. Most doctors will not have heard of IL-6 and TNF-alpha. But—see below—a 2014 paper has reported that an inflammatory index looking at the levels of serum IL-6 and soluble tumor necrosis factor-alpha receptor 1 provides an accurate prediction of 10 year all-cause mortality.2)

Not all depressed individuals have increased inflammation, but it is an important feature of at least a sizeable subset of depressed persons. (One problem with these cytokine tests is that they are currently not standardized and the measurements determined by different tests cannot generally be directly compared with one another. Hopefully, as interest in the clinical implications of inflammatory cytokines increases, we will see the development of standardized tests that will make it much easier to compare and interpret them. In the meantime, you can check to see where your TNF-alpha level falls in the normal range provided by the laboratory that measured the TNF-alpha (a lab using a different test may report a different normal range). If it is at the high end, you may want to consider supplementation to reduce inflammation, whereas if it is at the low end of the normal range, this is probably a positive indication that your level of inflammation is relatively low.)

Human studies that have reported antiinflammatory activity of curcumin were cited and described in paper #1, including a study of osteoarthritis patients, a study of patients with diabetic nephropathy (reduced TGF-beta and IL-8 with curcumin), and in type 2 diabetics, curcumin lowered TNF-alpha and IL-6.1

Increased Serotonin Induced by Curcumin

Another mechanism for curcumin’s antidepressant properties1 was its dose-dependent increase of serotonin in rats. One way it does this is to reduce the activity of the enzyme indoleamine dioxygenase (IDO), which breaks down tryptophan. As part of the body’s immune response to bacteria (lipopolysaccharide), IDO is increased which decreases the availability of tryptophan to invading bacteria. This is beneficial, but increased expression of IDO can result in depression because of depleted supplies of tryptophan for making serotonin.

Decreased Gut Hyperpermeability (“Leaky Gut”) with Curcumin

Lipopolysaccharide, an inflammation-causing compound produced by many harmful bacteria, is known to increase gut permeability, which permits some of the trillions of bacteria in the gut to reach other areas of the body. (The importance of maintaining the gut barrier has been known since Elie Metchnikoff’s time, when he predicted that eating yogurt would be a way to protect the gut barrier and perhaps extend lifespan. See Metchnikoff, The Prolongation of Life, G. P. Putnam’s Sons, (1908). Depression increases gut permeability and this effect can be ameliorated by curcumin.1

Other Papers Report Anti-Depressant Properties of Curcumin

Several other papers we found in a PubMed search for curcumin and depression reported the turmeric-derived component to be effective in a rat model of chronic, unpredictable, mild stress-induced depressive-like behavior,3 to reverse impaired hippocampal neurogenesis and to increase brain-derived neurotrophic factor in chronically stressed rats,4 another study showing antidepressant-like activity in chronically mildly stressed rats (partially due to curcumin’s anti-inflammatory effects),5 and effective treatment of depressive-like behavior in mice. Finally, curcumin was reported to be safe and effective in major depressive disorder in a human randomized controlled trial.6 YOU DON’T NEED TO BE A RODENT TO GET ANTIDEPRESSANT EFFECTS FROM A CURCUMIN SUPPLEMENT!

In animal studies, reports of depression are always referred to as depressive-like behavior because we can only observe what the animals do, not whether they are feeling what humans feel when they are depressed and behaving similarly to the putatively depressed animals. Theory of Mind is an important cognitive tool that has developed evolutionarily in humans as a means of evaluating the mental state of another human, but is of course more difficult to apply to a non-human species that can’t tell you directly how he or she feels.

Human Pilot Trial of Curcumin Finds it to be About as Effective as Fluoxetine (Prozac®) as an Antidepressant

Paper #4 reports that turmeric (Curcuma longa) “is a major constituent of Xiaoyao-san, the traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China.”

A small human trial,6 randomized and observer masked, in which patients took 500 mg of curcumin twice a day orally found this regimen to be similarly efficacious as compared to the group receiving 20 mg/day of fluoxetine. The group receiving both that dose of fluoxetine and 1000 mg of curcumin a day had a greater reduction in depression (based on the Hamilton Depression Rating Scale) but the difference was not statistically significant compared to the fluoxetine alone. (Since there were only 60 patients in the trial, it may not have been able to detect a small improvement in efficacy of the combination, if it were present.) The mechanisms for curcumin and fluoxetine differed, of course, since curcumin is not a serotonin reuptake inhibitor.


References

1. Lopresti et al. Multiple antidepressant potential modes of action of curcumin: a review of its anti-inflammatory, monoaminergic, antioxidant, immune-modulating, and neuroprotective effects. J Psychopharmacol. 26:1512-24 (2012).
2. Varadhan et al. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. J Gerontol A Biol Sci Med Sci. 69(2):165-73 (2014).
3. Xu et al. Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res. 1162:9-18 (2007).
4. Zhang et al. Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behavior and structural plasticity in the lateral amygdala of rats. Int J Neuropsychopharmacol. 9:1-14 (2014).
5. Jiang et al. Antidepressant-like effects of curcumin in chronic mild stress of rats: involvement of its anti-inflammatory action. Prog Neuropsychopharmacol Biol Psychiatry. 47:33-39 (2013).
6. Sanmukhani et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. (2013) DOI: 10.1002/ptr.5025.


NEW! LITHIUM FORMULATION
WHY HAVE WE ADDED A PHYSIOLOGICALLY RELEVANT AMOUNT OF TAURINE TO IT?

(Answer: Because It Has Potent Antiinflammatory, Neuroprotective Activity and Because it’s a NAD+, NAD+, NAD+, NAD+ World)


*See our newsletter series on “It’s a NAD+, NAD+, NAD+, NAD+ World” for an introduction to this vital life-sustaining molecule. “NAD+ - Don’t Leave Home Without It!”


A very interesting paper1 reports that the sulfur-containing amino acid taurine protects rats in an experimental stroke model by reducing inflammation, and that one way it does that is by down-regulating the activities of PARP and NFkappaB. PARP (poly (ADP-ribose) polymerase) is a DNA repair molecule that is activated when moderate DNA damage takes place. However, when severe DNA damage occurs, as in a stroke, it has been found that excessive activation of PARP reduces the availability of NAD+, an important molecule required for energy metabolism that may be implicated in aging. The viability of cells in which NAD+ depletion occurs can be seriously impaired or the cells even killed. Under conditions such as a stroke, decreasing PARP activity can be protective by increasing NAD+ supplies. For background information, see our newsletter series on “It’s a NAD+, NAD+, NAD+, NAD+ World.”

NFkappaB is an important transcription factor in the regulation of inflammation. It controls a host of immune-activated genes, such as TNF alpha (tumor necrosis factor alpha), IL-1beta (interleukin 1beta), iNOS (inducible nitric oxide synthase) and ICAM-1 (intracellular adhesion molecule 1). Although inflammation is generally associated with immune activation, it can occur under conditions where there are no pathogenic organisms (when it is called “sterile inflammation”), such as under conditions of oxidative stress. NFkappaB is activated during a stroke, for example, and studies of animal models of stroke have shown that inhibiting NFkappaB can be protective.1 Studies have further shown that NFkappaB activity is reduced in PARP knockout animals (which do not have ANY PARP activity—not recommended) or in experimental animals that have been treated with PARP inhibitors.1,1B

Interestingly, two researchers have published papers2,3 in which they suggest that PARP might actually act as a co-activator of NFkappaB in inflammatory disorders such as type 1 diabetes and septic shock.

Taurine Reverses the Excessive PARP Activation and Increased Activity of NFkappaB in Experimental Stroke

The new paper1 reports on taurine treatment of rats subject to 2 hours of ischemia (reduced blood flow) via intraluminal filament (something like a garrote). The taurine (50 mg/kg body weight) in this case was given intravenously, though taurine is usually administered orally; it may have been done this way for convenience (you don’t have to wait for the animals to ingest the taurine) and because it establishes conclusively how much taurine the animals actually got into their circulation. In earlier studies by these same authors, they found neuroprotection of taurine against experimental stroke within a range of 5–50 mg/kg.1 Scaled as a percentage of diet dry weight (or body surface area), 50 mg/kg rat body weight is very roughly equivalent to 200 mg for an adult human.

The taurine provided very substantial protection and, indeed, was shown to prevent the increased activity of PARP and NFkappaB as occurred in the animals subject to experimental stroke that did not receive taurine treatment. It markedly reduced signs such as brain swelling, cell death, neurological deficits, and it decreased the area of cell death (the infarct volume) by 72 hours after ischemia.

This is a very impressive paper because it not only reveals mechanisms (PARP inhibition and reduced expression of NFkappaB) for taurine neuroprotection that have not received as much study as they deserve but because it shows that taurine is able, under adverse conditions, to increase NAD+ supplies in the brain. We have long been interested in increasing NAD+ in our cells because of NAD+’s anti-aging potential.1C

Loss of NAD+ May Determine the Transition from Reversible to Irreversible Ischemic Damage in Heart Cells

Additional evidence as to the importance of NAD+ in ischemic tissue comes from a 1981 study of dogs subject to an ischemic procedure to mimic a heart attack.3B The NAD+ concentration was followed via a chemical assay in which a dye is formed, after which the dye is detected by bioluminescence. The level of tissue damage, meanwhile, was assessed by electron microscopy. “Irreversible cell damage was found to be associated with a 60–70% loss of total NAD.”3B These days, an experiment like this would probably have included another group of dogs that had undergone the same procedure but were treated with a substance that increased NAD+ supplies to demonstrate that the damage could be ameliorated by extra NAD+. That would provide much stronger support for the notion that it is NAD+ depletion that is the cause of and not just associated with the development of irreversible damage. But the results of this study are suggestive of that.

Taurine Blocks the Neurotoxicity of Amyloid beta in Rat Hippocampal and Cortical Neuronal Cells.

GABA Activation May Be One Way Taurine Helps Protect Against Alzheimer’s Disease

Taurine’s activity as a neuroprotectant against glutamergic transmission and excitotoxicity is well known.4 A paper4 reporting on these effects describes experiments in which the researchers found that micromolar doses of taurine could block the neurotoxicity of amyloid beta to rat hippocampal and cortical neurons in culture, suggesting taurine as a prophylactic to help prevent the development of Alzheimer’s disease. It was further found that the protective effect of taurine against the excitotoxicity resulting from high extracellular concentrations of glutamate could be prevented by picrotoxin, a GABA(A) receptor antagonist. Meanwhile, a GABA(A) agonist, muscimol, also blocked neuronal death induced by amyloid beta, suggesting activation of GABA(A) receptors as one mechanism for reducing the risk of developing Alzheimer’s disease and that taurine may work this way.

TAURINE PROTECTS AGAINST STROKE IN ANOTHER WAY

Protection Against Stroke in Rats By Blocking a Mitochondrial Cell Death Pathway

A different study5 reports on rats subjected to 2 hours of ischemia by intraluminal filament and then reperfused for 22 hours; after one hour of ischemia, the experimental rats received intravenous taurine (50 mg/kg), while the other rats received vehicle (no taurine). The study was interesting for the number of different measurements that were made to follow the results of treatment (or not).

The researchers were particularly focused upon the mitochondrial death pathway whereby injury that is too severe becomes the signal to initiate a complex process for killing the cell. For example, Bax (a member of the Bcl-2 family) is part of this pathway and has been shown, after ischemia, to move from the cellular cytosol to the mitochondria where it promotes the release of cytochrome c from mitochondria as part of apoptosis, programmed cell death. Another member of the Bcl-2 family, Bcl-xL, on the other hand, is anti-apoptotic, and increased expression can protect cells against apoptosis following ischemia. One finding in this study: “Compared with vehicle-treated rats, treatment with taurine markedly reduced the levels of Bax in the cytosolic fraction in the core and in mitochondrial fractions in the penumbra [the injured but still living cells at the outer edges of the ischemic tissue] and core (p<0.05, 0.01, and 0.05, respectively), and enhanced the level of Bcl-xL …” (p<0.05). Taurine also significantly reduced the necrotic cell death in the penumbra and core as compared to vehicle-treated rats.

The authors also point out that taurine’s antioxidant, anti-inflammatory, and osmotic regulatory properties also contributed to its neuroprotective effects.

Protection By Taurine Against Stroke: 8 Hour Window of Opportunity in Mice

A different paper6 by the authors of paper #5 provides additional information on the efficacy of taurine administered intravenously at 50 mg/kg in preventing tissue damage in experimental stroke: their data suggest that “the therapeutic window of taurine against experimental stroke is of at least 8 h, and suppressing the neutrophil infiltration may be one of the mechanisms of [protection by] delayed administration of taurine against experimental stroke.”


References

1. Sun et al. Anti-inflammatory mechanism of taurine against ischemic stroke is related to down-regulation of PARP and NFkappaB. Amino Acids. 42:1735-47 (2012).
1B. Eliasson et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 3(10):1089-95 (1997).
1C. Massudi et al. NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns. Redox Rep. 17(1):28-47 (2012).
2. Hassa and Hottiger. The functional role of poly(ADP- ribose) polymerase 1 as a novel co-activator of NFkappaB in inflammatory disorders. Cell Mol Life Sci. 59(9):1534-53 (2002).
3. Hassa and Hottiger. A role of poly(ADP-ribose)polymerase in NFkappaB transcriptional activation. Biol Chem. 380(7-8):953-9 (1999).
3B. Klein et al. Loss of canine myocardial nicotinamide adenine dinucleotides determines the transition from reversible to irreversible ischemic damage of myocardial cells. Basic Res Cardiol. 76:612-621 (1981).
4. Paula-Lima et al. Activation of GABA(A) receptors by taurine and muscimol blocks the neurotoxicity of beta-amyloid in rat hippocampal and cortical neurons. Neuropharmacology. 49:1140-8 (2005).
5. Sun et al. Protective functions of taurine against experimental stroke through depressing mitochondria-mediated cell death in rats. Amino Acids. 40:1419-29 (2011).
6. Sun et al. Therapeutic window of taurine against experimental stroke in rats. Transl Res. 160:223-9 (2012).


Hesperidin Found to Be Neuroprotective … So We’ve Added It To Our Lithium Formulation

Oldies 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 have far surpassed earlier expectations. Here’s why we’ve added it to our Lithium formulation.

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

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(click on thumbnail for full sized image)

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 especially valuable since it appears that Alzheimer’s may be a far more common cause of death than previously thought because the death of many Alzheimer’s patients is officially attributed to the proximate cause rather than Alzheimer’s [as Will Block points out in this issue, President Reagan died of Alzheimer’s disease but his death certificate lists his cause of death as pneumonia]. 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, the scientists tested 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) by 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 uM 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 an 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 researchers4 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 lower ed 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.

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 our Lithium 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 Personal Radical Shield for decades, but we know a lot more about it now than we did when we originally formulated PRS.) 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 Lithium formulation at no extra cost. Why buy an ordinary lithium supplement that contains only low-dose lithium when you can get so much more in our Lithium formulation at no extra cost?

How Much Raw Orange Juice Would You Have to Drink to Get the Hesperidin Contained in a Single Capsule of Our Lithium Formulation?

Based upon numbers for hesperidin content of OJ,9 you would need to drink 400 ml a day of raw orange juice to get the amount of hesperidin contained in the recommended dose of one capsule/day of our Lithium formulation. 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 capsule of our Lithium formulation!

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. 36:1776-1784 (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(1):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).


Will Block is the publisher and editorial director of Life Enhancement magazine.

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