Mercury: Exposure, Lab Tests, & Treatment

Dr. James Pendleton


Though used since ancient times, only now are we beginning to realize just how toxic mercury is.  Being a liquid at room temperature, this heavy metal has versatile properties that make it almost irreplaceable in our daily lives.


Mercury is still used in medicine, dentistry, electronics, mining, paints, pesticides, fungicides, factory production, preservatives, thermometers, and even skin creams.  While opportunities abound for exposure due to human contributions, the earth’s crust is also emitting a considerable amount due to natural phenomena.


Two Major Forms of Mercury 
Most mercury exposure occurs in two flavors, elemental, and methyl mercury.  The elemental form is the purest, being the silvery liquid you probably remember from school.  Methyl Mercury, the other form we are concerned with, is more abundant in animal tissues.  Elemental mercury can cause contact dermatitis and produces vapors that damage the lungs, though fairly nontoxic when ingested.  Methyl mercury on the other hand is extremely absorbable when ingested, and damages many tissues throughout the body.


Exposure to Mercury
Some instances of exposure to the elemental form would include having silver amalgam fillings –or having them removed, breaking a thermometer, or performing experiments in a school physics lab.  When elemental mercury sits at room temperature it gives off toxic vapors.  Gaseous mercury, being heavier than air, tends to sink towards the floor where small children are prone to breathe it in.  When elemental mercury gets into the bloodstream through cuts or gastrointestinal lesions (like stomach ulcers) it becomes much more dangerous, like the methyl form.


Mercury from Animal Tissues is Easily Absorbed when Ingested
The formation of methyl mercury involves the modification of the elemental form by bacteria and algae.  These microbes become little factories that add molecules to the metal to make it more absorbable and available in animal tissues.  Ingested methyl mercury is almost completely absorbed during digestion, and stays in the tissues.  Predators now tend to have high tissue levels of mercury because they collect and concentrate it from their prey.  As we climb the food chain we find very high levels in large fish like tuna and shark.  While fish is touted as a healthy food, the US government now recommends stringent intake limits from local sources and completely prohibits the ingestion of some fish species.  Most waterways and lakes in the US and Canada have some kind of warning when it comes to mercury and many regions of the US are now so contaminated that fishing is strictly prohibited.  


Toxic Properties of Mercury in Humans
When methyl mercury is assimilated into organ systems of the body it wreaks havoc.  It suppresses the immune system, affects vision, and disrupts brain and nervous tissue.  It also decreases the filtering ability of the kidneys and damages the liver.  While also impacting memory, psychological symptoms include insomnia, irritability, excitability, temper, quarreling, fear, anxiety, restlessness, and depression.  There are theorized models with methyl mercury the culprit in conditions such as  Alzheimer’s, Multiple Sclerosis, ALS, chronic fatigue syndrome, dementia, and many others.   The use of mercury as a preservative in vaccines has become controversial, with a probable link to autism.  It is thought that some children may be genetically lacking in certain enzymes that protect against the cellular damage that mercury inflicts.


Multiple Mechanisms for Mercury’s Toxicity
Surprisingly little is still known regarding mercury’s mechanisms of toxicity -but we think that it disrupts cellular functions by sticking to vulnerable parts of proteins used in the machinery of the cell.  It also causes oxidation of the membranes of cells, making them age and deteriorate rapidly.  Enzymes are small, yet complex molecules of protein that guide and facilitate chemical reactions to occur in an orderly fashion in cells.  Mercury appears to stick to certain amino acid building blocks of these enzymes and stop them from working.  In the most drastic of circumstances this kills the cell by ceasing its ability to burn fuel using oxygen.

Ways to Determine Mercury Exposure using Blood, Hair, Urine, and Saliva
Though controversy exists – and some with vested interests still oppose- thankfully, we now have efficient –substantiated- laboratory testing to determine the extent of mercury exposure. To date, the most useful appears to be hair analysis but this could change as technology advances. Tests using hair, blood, or urine are relatively easy and inexpensive.






Naturopathic Physicians Tailor Healthy Mercury Removal Plans
With these results, physicians can tailor a safe program specific to the individual, using nutrition, botanicals, and sometimes, powerful chelating agents.  Chelating agents are safe yet powerful drugs, vitamins, and herbs that grab onto toxins like mercury and facilitate their elimination in the urine.  Sometimes during this elimination, patients may feel a little sick because they are liberating toxins that have been stored away in the body for a long time.  Naturopathic physicians are good at avoiding this because they monitor the patient, modulating the dosages and length of treatment to their constitution.






Helpful References
Patrick, L., and others. “Mercury Toxicity and Antioxidants: Part 1: Role of Glutathione and Alpha-lipoic Acid in the Treatment of Mercury Toxicity.” Alternative Medicine Review: a Journal of Clinical Therapeutic 7, no. 6 (2002): 456.


Boening, D.W. “Ecological Effects, Transport, and Fate of Mercury: a General Review.” Chemosphere 40, no. 12 (2000): 1335–1351.


Gill, US, HM Schwartz, and L. Bigras. “Results of Multiyear International Interlaboratory Comparison Program for Mercury in Human Hair.” Archives of Environmental Contamination and Toxicology 43, no. 4 (2002): 466–472.


Koos, BJ, L.D. Longo, and others. “Mercury Toxicity in the Pregnant Woman, Fetus, and Newborn Infant. A Review.” American Journal of Obstetrics and Gynecology 126, no. 3 (1976): 390.


Simmons-Willis, T.A., A.S. Koh, T.W. Clarkson, and N. Ballatori. “Transport of a Neurotoxicant by Molecular Mimicry: The methylmercury-L-cysteine Complex Is a Substrate for Human L-type Large Neutral Amino Acid Transporter (LAT) 1 and LAT2.” Biochemical Journal 367, no. Pt 1 (2002): 239.


Keating, M.H., K.R. Mahaffey, R. Schoeny, GE Rice, and OR Bullock. Mercury Study Report to Congress. Volume 1. Executive Summary. Environmental Protection Agency, Research Triangle Park, NC (United States). Office of Air Quality Planning and Standards, 1997.


Helpful Books on Amazon

Revisiting Theanine!

 Today looking at  l-theanine (again!)
"aka Zen in a bottle :)"


One of my favorite materials to formulate with!

Over the years I've written some general articles about its use in cognitive support, modulating caffeine, and even endurance recovery... Super safe, no adverse effects,

 Here's a link to a Suite101 article!



Standard dosage -at least 50 mg/day...





OK, here are some recent studies:


Zarse, K., S. Jabin, et al. (2012). "L: -Theanine extends lifespan of adult Caenorhabditis elegans." Eur J Nutr.
PURPOSE: Compounds that delay aging in model organisms may be of significant interest to anti-aging medicine, since these substances potentially provide pharmaceutical approaches to promote healthy lifespan in humans. We here aimed to test whether pharmaceutical concentrations of L: -theanine, a putative anti-cancer, anti-obesity, blood pressure-lowering, and neuroprotective compound contained in green tea (Camellia sinensis), are capable of extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. METHODS: Adult C. elegans roundworms were maintained on agar plates, were fed E. coli strain OP50 bacteria, and L: -theanine was applied to agar to test (1) whether it may increase survival upon paraquat exposure and (2) whether it may promote longevity by quantifying survival in the presence and absence of the compound. RESULTS: L: -theanine increases survival of C. elegans in the presence of paraquat at a concentration of 1 micromolar. L: -theanine extends C. elegans lifespan when applied at concentrations of 100 nM, as well as 1 and 10 micromolar. CONCLUSIONS: In the model organism C. elegans, L: -theanine is capable of promoting paraquat resistance and longevity suggesting that this compound may as well promote healthy lifespan in mammals and possibly humans.

Attia, S. (2012). "Modulation of irinotecan-induced genomic DNA damage by theanine." Food Chem Toxicol.
The possible chemoprotective activity of theanine against irinotecan-induced genomic DNA damage towards mouse bone marrow cells was investigated. Chromosomal aberrations, DNA damage, micronuclei formation and mitotic activity were studied in the current study as markers of genomic damage. Oxidative DNA stress markers such as 8-hydroxydeoxyguanosine, lipid peroxidation, reduced and oxidized glutathione levels were assessed as a possible mechanism underlying this amelioration. Theanine was neither genotoxic nor cytotoxic in mice at doses equivalent to 30 or 60mg/kg for 12days. Pretreatment of mice with theanine significantly reduced irinotecan-induced genomic damage in the bone marrow cells and these effects were dose dependent. Irinotecan induced marked biochemical alterations characteristic of oxidative DNA stress, including increased 8-hydroxydeoxyguanosine, enhanced lipid peroxidation and reduction in the reduced/oxidized glutathione ratio. Prior administration of theanine ahead of irinotecan challenge ameliorated these oxidative DNA stress markers. Overall, this study provides for the first time that theanine has a protective role in the abatement of irinotecan-induced genomic damage in the bone marrow cells of mice that resides, at least in part, on its ability to modulate the cellular antioxidant levels and consequently protect bone marrow from irinotecan genotoxicity.

Shibakusa, T., T. Mikami, et al. (2012). "Enhancement of postoperative recovery by preoperative oral co-administration of the amino acids, cystine and theanine, in a mouse surgical model." Clin Nutr.
BACKGROUND & AIMS: Glutathione (GSH) is important in the control of immune responses, and its levels decline following trauma. We previously reported that the oral administration of cystine/theanine (CT) increased GSH synthesis and that CT intake inhibited intense exercise-induced inflammation. Based on these results, we hypothesised that CT inhibits surgically induced inflammation and promotes postoperative recovery. Our aim was to confirm this hypothesis using a mouse surgical model. METHODS: CT or a vehicle (V) was administered orally to mice once a day for 5 days, until the day of surgery. On the day of surgery, a sham operation or an intestinal manipulation was performed 2 h after the oral administration of CT or V. Levels of IL-6 in the blood and GSH in the intestine were analysed 2 h after surgery. Behavioural analysis was also undertaken after surgery. RESULTS: Treatment with CT inhibited the manipulation-induced increase in IL-6 in the blood and decrease in GSH in the intestine. There was a significant negative correlation between IL-6 in the blood and GSH in the intestine. In addition, behavioural analysis revealed that CT administration improved locomotor activity and food intake after surgery. CONCLUSION: These results suggest that CT suppresses inflammatory responses by inhibiting the surgically induced decrease in GSH in the small intestine and promotes postoperative recovery.


Foxe, J. J., K. P. Morie, et al. (2012). "Assessing the effects of caffeine and theanine on the maintenance of vigilance during a sustained attention task." Neuropharmacology.
Caffeine and l-theanine, both naturally occurring in tea, affect the ability to make rapid phasic deployments of attention to locations in space as reflected in behavioural performance and alpha-band oscillatory brain activity (8-14 Hz). However, surprisingly little is known about how these compounds affect an aspect of attention that has been more popularly associated with tea, namely vigilant attention: the ability to maintain focus on monotonous tasks over protracted time-periods. Twenty-seven participants performed the Sustained Attention to Response Task (SART) over a two-hour session on each of four days, on which they were administered caffeine (50 mg), theanine (100 mg), the combination, or placebo in a double-blind, randomized, cross-over fashion. Concurrently, we recorded oscillatory brain activity through high-density electroencephalography (EEG). We asked whether either compound alone, or both in combination, would affect performance of the task in terms of reduced error rates over time, and whether changes in alpha-band activity would show a relationship to such changes in performance. When treated with placebo, participants showed a rise in error rates, a pattern that is commonly observed with increasing time-on-task, whereas after caffeine and theanine ingestion, error rates were significantly reduced. The combined treatment did not confer any additional benefits over either compound alone, suggesting that the individual compounds may confer maximal benefits at the dosages employed. Alpha-band oscillatory activity was significantly reduced on ingestion of caffeine, particularly in the first hour. This effect was not changed by addition of theanine in the combined treatment. Theanine alone did not affect alpha-band activity.

Jang, H. S., J. Y. Jung, et al. (2012). "L-theanine partially counteracts caffeine-induced sleep disturbances in rats." Pharmacol Biochem Behav 101(2): 217-221.
L-theanine has been reported to inhibit the excitatory effects of caffeine. The present study examined the effects of L-theanine on caffeine-induced sleep disturbances in rats. Rats received the following drug pairings: saline and saline (Control), 7.5mg/kg caffeine and saline, or 7.5mg/kg of caffeine followed by various doses of L-theanine (22.5, 37.5, 75, or 150mg/kg). Vigilance states were divided into: wakefulness (W), transition to slow-wave sleep (tSWS), slow-wave sleep (SWS), and rapid-eye-movement sleep (REMS). Caffeine significantly increased the duration of W and decreased the duration of SWS and REMS compared to the Control. Although L-theanine failed to reverse the caffeine-induced W increase, at 22.5 and 37.5mg/kg (but not at 75 and 150mg/kg), it significantly reversed caffeine-induced decreases in SWS. In conclusion, low doses of L-theanine can partially reverse caffeine-induced reductions in SWS; however, effects of L-theanine on caffeine-induced insomnia do not appear to increase dose-dependently.

Song, J., H. Xu, et al. (2012). "Tea and cognitive health in late life: current evidence and future directions." J Nutr Health Aging 16(1): 31-34.
This review summarizes the literature on the association between tea consumption and cognitive health in late life. Population-based studies reviewed in this article suggest that tea drinking has beneficial effects on cognitive function of elderly persons. However, a cause-effect relationship between tea consumption and cognitive decline and dementia could not be drawn given inconsistent findings from only two longitudinal cohort studies. The neuroprotective effects of tea consumption could be due to catechins, L-theanine and other compounds in tea leaves. More longitudinal observational study is needed. Information on life-time tea consumption and blood concentrations of catechins and L-theanine could be collected in future studies.

Lyon, M. R., M. P. Kapoor, et al. (2011). "The effects of L-theanine (Suntheanine(R)) on objective sleep quality in boys with attention deficit hyperactivity disorder (ADHD): a randomized, double-blind, placebo-controlled clinical trial." Altern Med Rev 16(4): 348-354.
INTRODUCTION: The purpose of this study was to investigate the efficacy and safety of L-theanine as an aid to the improvement of objectively measured sleep quality in a population of 98 male children formally diagnosed with attention-deficit/hyperactivity disorder (ADHD). METHODS: A randomized, double-blind, placebo-controlled trial was conducted involving boys, ages 8-12 years, who had been previously diagnosed with ADHD. An experienced physician confirmed the diagnosis of ADHD in each subject. Randomization was stratified based upon current use of stimulant medication to ensure an equal distribution of stimulant/non-stimulant treated subjects into active and placebo treated groups. Participants consumed two chewable tablets twice daily (at breakfast and after school), with each tablet containing 100 mg of L-theanine (total 400 mg daily Suntheanine(R), Taiyo Kagaku, Yokkaichi, Japan) or identical tasting chewable placebo for six weeks. Subjects were evaluated for five consecutive nights using wrist actigraphy at baseline, and again at the end of the six-week treatment period. The Pediatric Sleep Questionnaire (PSQ) was completed by parents at baseline and at the end of the treatment period. RESULTS: Actigraph watch data findings indicated that boys who consumed L-theanine obtained significantly higher sleep percentage and sleep efficiency scores, along with a non-significant trend for less activity during sleep (defined as less time awake after sleep onset) compared to those in the placebo group. Sleep latency and other sleep parameters were unchanged. The PSQ data did not correlate significantly to the objective data gathered from actigraphy, suggesting that parents were not particularly aware of their children's sleep quality. L-theanine at relatively high doses was well tolerated with no significant adverse events. CONCLUSIONS: This study demonstrates that 400 mg daily of L-theanine is safe and effective in improving some aspects of sleep quality in boys diagnosed with ADHD. Since sleep problems are a common co-morbidity associated with ADHD, and because disturbed sleep may be linked etiologically to this disorder, L-theanine may represent a safe and important adjunctive therapy in childhood ADHD. Larger, long-term studies looking at the wider therapeutic role of this agent in this population are warranted.

Zhao, Y. and B. Zhao (2012). "Natural antioxidants in prevention and management of Alzheimer's disease." Front Biosci (Elite Ed) 4: 794-808.
Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia in the elderly. As the aging population increases, the prevalence of AD has increased remarkably worldwide and AD has become one of the leading causes of disability and death among the elderly. A number of drugs have been approved for the treatment of AD; however, they produce only modest benefits and have a wide range of side effects. Therefore, extensive studies are underway to identify effective drugs that are free of undesirable side effects. As accumulating evidences have implicated oxidative stress in the initiation and progression of AD, the potential of using nature antioxidants for prevention and treatment of AD has attracted considerable attention. The present review discusses the involvement of oxidative stress in the pathogenesis of AD and the neuroprotective effects of natural antioxidants, such as Ginkgo biloba flavonoids, soybean isoflavones, theanine and nicotine in cell culture and AD transgenic animal models, specifically, their inhibition on Abeta-induced neurotoxicity and the underlined molecular mechanisms.

Cooper, R. (2012). "Green tea and theanine: health benefits." Int J Food Sci Nutr 63 Suppl 1: 90-97.
Historically, the medicinal use of green tea dates back to China 4700 years ago and drinking tea continues to be regarded traditionally in Asia as a general healthful practice. Numerous scientific publications now attest to the health benefits of both black and green teas, including clinical and epidemiological studies. Although all tea contains beneficial antioxidants, high-quality green and white teas have them in greater concentrations than black tea. Today, scientists believe that the main active ingredients of green tea include the polyphenols, in particular the catechins and the amino acid, theanine. Studies on the health benefits of drinking tea, particularly green tea, are finding exciting results, particularly in cancer research. Modern studies in both Asia and the West have provided encouraging results indicating that drinking green tea contributes to fighting many different kinds of cancers including stomach, oesophageal, ovarian and colon. Recent studies describing the health benefits of these compounds will be reviewed.

Li, G., Y. Ye, et al. (2012). "l-Theanine prevents alcoholic liver injury through enhancing the antioxidant capability of hepatocytes." Food Chem Toxicol 50(2): 363-372.
l-Theanine is a unique amino acid in green tea. We here evaluated the protective effects of l-theanine on ethanol-induced liver injury in vitro and in vivo. Our results revealed that l-theanine significantly protected hepatocytes against ethanol-induced cell cytotoxicity which displayed by decrease of viability and increase of LDH and AST. Furthermore, the experiments of DAPI staining, pro-caspase3 level and PARP cleavage determination indicated that l-theanine inhibited ethanol-induced L02 cell apoptosis. Mechanically, l-theanine inhibited loss of mitochondrial membrane potential and prevented cytochrome c release from mitochondria in ethanol-treated L02 cells. l-Theanine also prevented ethanol-triggered ROS and MDA generation in L02 cells. l-Theanine restored the antioxidant capability of hepatocytes including GSH content and SOD activity which were reduced by ethanol. In vivo experiments showed that l-theanine significantly inhibited ethanol-stimulated the increase of ALT, AST, TG and MDA in mice. Histopathological examination demonstrated that l-theanine pretreated to mice apparently diminished ethanol-induced fat droplets. In accordance with the in vitro study, l-theanine significantly inhibited ethanol-induced reduction of mouse antioxidant capability which included the activities of SOD, CAT and GR, and level of GSH. These results indicated that l-theanine prevented ethanol-induced liver injury through enhancing hepatocyte antioxidant abilities.

Wakabayashi, C., T. Numakawa, et al. (2012). "Behavioral and molecular evidence for psychotropic effects in L-theanine." Psychopharmacology (Berl) 219(4): 1099-1109.
RATIONALE: L-Theanine (N-ethyl-L: -glutamine) is an amino acid uniquely found in green tea and historically considered to be a relaxing agent. It is a glutamate derivative and has an affinity for glutamatergic receptors. However, its psychotropic effects remain unclear. OBJECTIVES: To elucidate effects of L: -theanine on psychiatric disease-related behaviors in mice and its molecular basis focusing on brain-derived neurotrophic factor (BDNF) and N-methyl-D: -aspartate (NMDA) receptor. METHODS: We examined the effects of L: -theanine on behaviors in mice by using the open-field test (OFT), forced swim test (FST), elevated plus-maze test (EPMT), and prepulse inhibition (PPI) of acoustic startle. By western blot analysis, we looked at the effect of L: -theanine on the expression of BDNF and related proteins in the hippocampus and cerebral cortex. To determine whether L: -theanine has agonistic action on the NMDA receptor, we performed Fluo-3 intracellular Ca(2+) imaging in cultured cortical neurons. RESULTS: Single administration of L: -theanine significantly attenuated MK-801-induced deficits in PPI. Subchronic administration (3-week duration) of L: -theanine significantly reduced immobility time in the FST and improved baseline PPI. Western blotting analysis showed increased expression of BDNF protein in the hippocampus after subchronic administration of L: -theanine. In cultured cortical neurons, L: -theanine significantly increased the intracellular Ca(2+) concentration, and this increase was suppressed by competitive and non-competitive NMDA receptor antagonists (AP-5 and MK-801, respectively). CONCLUSIONS: Our results suggest that L: -theanine has antipsychotic-like and possibly antidepressant-like effects. It exerts these effects, at least in part, through induction of BDNF in the hippocampus and the agonistic action of L: -theanine on the NMDA receptor.

Takeda, A., H. Tamano, et al. (2012). "Unique induction of CA1 LTP components after intake of theanine, an amino acid in tea leaves and its effect on stress response." Cell Mol Neurobiol 32(1): 41-48.
Theanine, gamma-glutamylethylamide, is one of the major amino acid components in green tea. This study was undertaken to evaluate the effect of theanine intake on long-term potentiation (LTP) induction at hippocampal CA1 synapses and exposure to acute stress. Young rats were fed water containing 0.3% theanine after birth. Key findings: Serum corticosterone level was markedly decreased by theanine intake. Because this decrease can modify synaptic plasticity, the effect of theanine intake was examined focused on CA1 LTP induction. CA1 LTP induced by a 100-Hz tetanus for 1 s was almost the same extent in hippocampal slices from theanine-administered rats, whereas that induced by a 200-Hz tetanus for 1 s was significantly attenuated. 2-Amino-5-phosphonovalerate (APV), an N-methyl-D: -aspartate (NMDA) receptor antagonist, significantly attenuated CA1 LTP induced by a 200-Hz tetanus in the control rats, but not in theanine-administered rats. Interestingly, APV completely blocked CA1 LTP induced by a 100-Hz tetanus in the control rats, while scarcely blocking it in theanine-administered rats. These results indicate that theanine intake reduces NMDA receptor-dependent CA1 LTP, while increasing NMDA receptor-independent CA1 LTP. Furthermore, neither 100-Hz tetanus-induced LTP nor 200-Hz tetanus-induced LTP was attenuated in theanine-administered rats after exposure to tail suspension stress, suggesting that the lack of NMDA receptor-dependent CA1 LTP by theanine intake is involved in ameliorating the attenuation of CA1 LTP after tail suspension. This study is the first to indicate that theanine intake modifies the mechanism of CA1 LTP induction.

Vuong, Q. V., M. C. Bowyer, et al. (2011). "L-Theanine: properties, synthesis and isolation from tea." J Sci Food Agric 91(11): 1931-1939.
Theanine is a non-protein amino acid that occurs naturally in the tea plant (Camellia sinensis) and contributes to the favourable taste of tea. It is also associated with effects such as the enhancement of relaxation and the improvement of concentration and learning ability. It is also linked with health benefits including the prevention of certain cancers and cardiovascular disease, the promotion of weight loss and enhanced performance of the immune system. Thus, there has been a significant rise in the demand for theanine. While theanine has been chemically and biologically synthesised, techniques to isolate theanine from natural sources remain an important area of research. In this review article, the properties and health benefits of theanine are summarised and the synthesis and isolation of theanine are reviewed and discussed. Future perspectives for the isolation of theanine from natural sources are also outlined.

Miodownik, C., R. Maayan, et al. (2011). "Serum levels of brain-derived neurotrophic factor and cortisol to sulfate of dehydroepiandrosterone molar ratio associated with clinical response to L-theanine as augmentation of antipsychotic therapy in schizophrenia and schizoaffective disorder patients." Clin Neuropharmacol 34(4): 155-160.
OBJECTIVES: L-Theanine (gamma-glutamylethylamide) augmentation to antipsychotic therapy ameliorates positive, activation, and anxiety symptoms in schizophrenia and schizoaffective disorder patients. This study examines the association between circulating levels of neurochemical indicators and the beneficial clinical effects of L-theanine augmentation. METHODS: Serum levels of neurochemical indicators such as brain-derived neurotrophic factor (BDNF), dehydroepiandrosterone (DHEA), its sulfate (DHEAS), cortisol, cholesterol, and insulin were monitored in 40 schizophrenia and schizoaffective disorder patients during an 8-week, double-blind, randomized, placebo-controlled trial with L-theanine (400 mg/d). Multiple regression analysis was applied for searching association between improvement in symptom scores and changes in circulating levels of neurochemical indicators for an 8-week trial. RESULTS: Regression models among L-theanine-treated patients indicate that circulating levels of BDNF and cortisol-to-DHEAS*100 molar ratio were significantly associated with the beneficial clinical effects of L-theanine augmentation. Variability of serum BDNF levels accounted for 26.2% of the total variance in reduction of dysphoric mood and 38.2% in anxiety scores. In addition, the changes in cortisol-to-DHEAS*100 molar ratio accounted for 30% to 34% of the variance in activation factor and dysphoric mood scores and for 15.9% in anxiety scores. Regression models among placebo-treated patients did not reach significant level. CONCLUSIONS: These preliminary results indicate that circulating BDNF and cortisol-to-DHEAS*100 molar ratio may be involved in the beneficial clinical effects of L-theanine as augmentation of antipsychotic therapy in schizophrenia and schizoaffective disorder patients.

Takeda, A., K. Sakamoto, et al. (2011). "Facilitated neurogenesis in the developing hippocampus after intake of theanine, an amino Acid in tea leaves, and object recognition memory." Cell Mol Neurobiol 31(7): 1079-1088.
Theanine, gamma-glutamylethylamide, is one of the major amino acid components in green tea. In this study, cognitive function and the related mechanism were examined in theanine-administered young rats. Newborn rats were fed theanine through dams, which were fed water containing 0.3% theanine, and then fed water containing 0.3% theanine after weaning. Theanine level in the brain was under the detectable limit 6 weeks after the start of theanine administration. Theanine administration did not influence locomotor activity in the open-field test. However, rearing behavior was significantly increased in theanine-administered rats, suggesting that exploratory activity is increased by theanine intake. Furthermore, object recognition memory was enhanced in theanine-administered rats. The increase in exploratory activity in the open-field test seems to be associated with the enhanced object recognition memory after theanine administration. On the other hand, long-term potentiation (LTP) induction at the perforant path-granule cell synapse was not changed by theanine administration. To check hippocampal neurogenesis, BrdU was injected into rats 3 weeks after the start of theanine administration, and brain-derived neurotropic factor (BDNF) level was significantly increased at this time. Theanine intake significantly increased the number of BrdU-, Ki67-, and DCX-labeled cells in the granule cell layer 6 weeks after the start of theanine administration. This study indicates that 0.3% theanine administration facilitates neurogenesis in the developing hippocampus followed by enhanced recognition memory. Theanine intake may be of benefit to the postnatal development of hippocampal function.

Kakuda, T. (2011). "Neuroprotective effects of theanine and its preventive effects on cognitive dysfunction." Pharmacol Res 64(2): 162-168.
Theanine (gamma-glutamylethylamide) characteristically present in tea leaves (Camellia sinensis). It has a similar chemical structure to glutamate, which is a neurotransmitter related to memory. Theanine passes through the blood-brain barrier and has been shown to have a cerebroprotective effect and a preventive effect on neuronal cell death after transient cerebral ischemia. The neuroprotective effect is partly due to the antagonistic action of theanine on glutamate receptor subtype AMPA and kainate receptors, but the affinity is very low. Theanine also acted on glutamine (Gln) transporter strongly and inhibited the incorporation of extracellular Gln into neurons, which in turn suppressed the conversion of Gln to glutamate by glutaminase, a reaction required for condensation into synaptic vesicles to form a neurotransmitter pool responsible for subsequent exocytotic release upon stimuli. In an investigation of elderly persons with normal or slight cognitive dysfunction, volunteers who ingested powdered green tea containing a high theanine concentration (equivalent to 47.5mgday(-1) of theanine) showed significantly lower decline in cognitive function compared with that of the placebo group. This result suggested that theanine might have improved a slight cognitive dysfunction in elderly persons.

Park, S. K., I. C. Jung, et al. (2011). "A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study." J Med Food 14(4): 334-343.
A combination of green tea extract and l-theanine (LGNC-07) has been reported to have beneficial effects on cognition in animal studies. In this randomized, double-blind, placebo-controlled study, the effect of LGNC-07 on memory and attention in subjects with mild cognitive impairment (MCI) was investigated. Ninety-one MCI subjects whose Mini Mental State Examination-K (MMSE-K) scores were between 21 and 26 and who were in either stage 2 or 3 on the Global Deterioration Scale were enrolled in this study. The treatment group (13 men, 32 women; 57.58 +/- 9.45 years) took 1,680 mg of LGNC-07, and the placebo group (12 men, 34 women; 56.28 +/- 9.92 years) received an equivalent amount of maltodextrin and lactose for 16 weeks. Neuropsychological tests (Rey-Kim memory test and Stroop color-word test) and electroencephalography were conducted to evaluate the effect of LGNC-07 on memory and attention. Further analyses were stratified by baseline severity to evaluate treatment response on the degree of impairment (MMSE-K 21-23 and 24-26). LGNC-07 led to improvements in memory by marginally increasing delayed recognition in the Rey-Kim memory test (P = .0572). Stratified analyses showed that LGNC-07 improved memory and selective attention by significantly increasing the Rey-Kim memory quotient and word reading in the subjects with MMSE-K scores of 21-23 (LGNC-07, n = 11; placebo, n = 9). Electroencephalograms were recorded in 24 randomly selected subjects hourly for 3 hours in eye-open, eye-closed, and reading states after a single dose of LGNC-07 (LGNC-07, n = 12; placebo, n = 12). Brain theta waves, an indicator of cognitive alertness, were increased significantly in the temporal, frontal, parietal, and occipital areas after 3 hours in the eye-open and reading states. Therefore, this study suggests that LGNC-07 has potential as an intervention for cognitive improvement.

Ritsner, M. S., C. Miodownik, et al. (2011). "L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study." J Clin Psychiatry 72(1): 34-42.
OBJECTIVE: L-theanine is a unique amino acid present almost exclusively in the tea plant. It possesses neuroprotective, mood-enhancing, and relaxation properties. This is a first study designed to evaluate the efficacy and tolerability of L-theanine augmentation of antipsychotic treatment of patients with chronic schizophrenia and schizoaffective disorder. METHOD: 60 patients with DSM-IV schizophrenia or schizoaffective disorder participated in an 8-week, double-blind, randomized, placebo-controlled study. 400 mg/d of L-theanine was added to ongoing antipsychotic treatment from February 2006 until October 2008. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), the Hamilton Anxiety Rating Scale (HARS), the Cambridge Neuropsychological Test Automated Battery (CANTAB) for neurocognitive functioning, and additional measures of general functioning, side effects, and quality of life. RESULTS: 40 patients completed the study protocol. Compared with placebo, L-theanine augmentation was associated with reduction of anxiety (P = .015; measured by the HARS scale) and positive (P = .009) and general psychopathology (P < .001) scores (measured by the PANSS 3-dimensional model). According to the 5-dimension model of psychopathology, L-theanine produced significant reductions on PANSS positive (P = .004) and activation factor (P = .006) scores compared to placebo. The effect sizes (Cohen d) for these differences ranged from modest to moderate (0.09-0.39). PANSS negative and CANTAB task scores, general functioning, side effect, and quality of life measures were not affected by L-theanine augmentation. L-theanine was found to be a safe and well-tolerated medication. CONCLUSIONS: L-theanine augmentation of antipsychotic therapy can ameliorate positive, activation, and anxiety symptoms in schizophrenia and schizoaffective disorder patients. Further long-term studies of L-theanine are needed to substantiate the clinically significant benefits of L-theanine augmentation.

Cross, D. R., G. Kellermann, et al. (2011). "A randomized targeted amino acid therapy with behaviourally at-risk adopted children." Child Care Health Dev 37(5): 671-678.
BACKGROUND: Increasing numbers of children are at-risk for behavioural and emotional disorders, a phenomenon contributing to increased use of pharmacological interventions for paediatric clients. Adverse side effects and other risks associated with pharmacological approaches have helped fuel interest in nutritional interventions for behaviourally at-risk children. METHODS: The current randomized clinical trial evaluates the efficacy of a neurochemical intervention involving the glutamine and glutamate analogue L-theanine and 5-hydroxytryptophan, the precursor for serotonin, with children adopted from traumatic backgrounds. RESULTS: Results include significant increases in urinary levels of the biomarkers for serotonin and gamma-aminobutyric acid, coupled with significant decreases in parent reports of the children's behaviour problems. CONCLUSIONS: While further research is needed, these initial findings are encouraging and are consistent with a growing number of studies indicating the efficacy of nutritional approaches to help behaviourally at-risk children.

Giesbrecht, T., J. A. Rycroft, et al. (2010). "The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness." Nutr Neurosci 13(6): 283-290.
The non-proteinic amino acid L-theanine and caffeine, a methylxanthine derivative, are naturally occurring ingredients in tea. The present study investigated the effect of a combination of 97 mg L-theanine and 40 mg caffeine as compared to placebo treatment on cognitive performance, alertness, blood pressure, and heart rate in a sample of young adults (n = 44). Cognitive performance, self-reported mood, blood pressure, and heart rate were measured before L-theanine and caffeine administration (i.e. at baseline) and 20 min and 70 min thereafter. The combination of moderate levels of L-theanine and caffeine significantly improved accuracy during task switching and self-reported alertness (both P < 0.01) and reduced self-reported tiredness (P < 0.05). There were no significant effects on other cognitive tasks, such as visual search, choice reaction times, or mental rotation. The present results suggest that 97 mg of L-theanine in combination with 40 mg of caffeine helps to focus attention during a demanding cognitive task.

Salidroside - Glucoside from Rhodiola...

Today working on a constituent of Rhodiola, etc.  called Salidroside.

HERE'S A LINK to MY SUITE101 ARTICLE-->  LINK

Preparative isolation and purification of salidroside from the
Chinese medicinal plant Rhodiola sachalinensis by high-speed
counter-current chromatograph

BTW, I use both Zotero and Endnote -Zotero is free!




Synonyms
Rhodioloside
Formal Name 2-​(4-​hydroxyphenyl)ethyl-​β-​D-​glucopyranoside
CAS Number 10338-51-9
Molecular Formula C14H20O7
Formula Weight 300.3
Formulation A crystalline solid
Purity ≥97%
Stability 2 years
Storage -20°C
Shipping Room temperature in continental US; may vary elsewhere
SMILES Copy OC1=CC=C(C=C1)​CCO[C@H]​2[C@H]​(O)​[C@@H]​(O)​[C@H]​(O)​[C@@H]​(CO)​O2





Helpful references!

^ Perfumi M, Mattioli L. Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice. Phytotherapy Research. 2007 Jan;21(1):37-43. doi:10.1002/ptr.2013 PMID 17072830
^ Mattioli L, Funari C, Perfumi M. Effects of Rhodiola rosea L. extract on behavioural and physiological alterations induced by chronic mild stress in female rats. Journal of Psychopharmacology. 2008 May 30. doi:10.1177/0269881108089872 PMID 18515456
^ Panossian A, Nikoyan N, Ohanyan N, Hovhannisyan A, Abrahamyan H, Gabrielyan E, Wikman G. Comparative study of Rhodiola preparations on behavioral despair of rats. Phytomedicine. 2008 Jan;15(1-2):84-91. doi:10.1016/j.phymed.2007.10.003 PMID 18054474



Binge Eating:

Physiol Behav. 2010 Dec 2;101(5):555-62. Epub 2010 Sep 15.
Effect of salidroside, active principle of Rhodiola rosea extract, on binge eating.
Cifani C, Micioni Di B MV, Vitale G, Ruggieri V, Ciccocioppo R, Massi M.
Source
School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino (MC), Italy. carlo.cifani@unicam.it
Abstract
Stress is a key determinant of binge eating (BE). Since Rhodiola rosea is known to modulate stress responses, its effect in a model of BE was investigated. BE for highly palatable food (HPF) was evoked in female rats by three 8-day cycles of food restriction/re-feeding (for 4days 66% of the usual chow intake; for 4days food ad libitum) and acute stress on the test day (day 25). R. rosea dry extract (3% rosavin, 3.12% salidroside) or its active principles were given by gavage 1h before access to HPF. Only rats exposed to both food restrictions and stress exhibited BE in the first 15-60min after the stressful procedure. R. rosea extract 10mg/kg significantly reduced and 20mg/kg abolished the BE episode. R. rosea extract 20mg/kg abolished also stress-induced increase in serum corticosterone levels. The R. rosea active principle salidroside, but not rosavin, at doses present in the extract, dose-dependently reduced or abolished BE for the period in which it was elicited. In conclusion results indicate that R. rosea extracts may have therapeutic properties in bingeing-related eating disorders and that salidroside is the active principle responsible for this effect.




Wu, Y., Piao, D., Han, X., et al. Protective effects of salidroside against acetaminophen-induced toxicity in mice. Biol Pharm Bull 31(8) 1523-1529 (2008).

Han, X., Zhang, T., Wei, Y., et al. Separation of salidroside from Rhodiola crenulata by high-speed counter-current chromatography. J Chromatogr A 971 237-241 (2002).

Tan, C., Gao, M., Xu, W., et al. Protective effects of salidroside on endothelial cell apoptosis induced by cobalt chloride. Biol Pharm Bull 32(8) 1359-1363 (2009).

Panossian, A., and Wikman, G. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol 4 198-219 (2009).

Cai, L., Wang, H., Li, Q., et al. Salidroside inhibits H2O2-induced apoptosis in PC12 cells by preventing cytochrome c release and inactivating of caspase cascade. Acta Biochim Biophys Sin 40(9) 796-802 (2008).

Ma, C., Tang, J., Wang, H., et al. Preparative purification of salidroside from Rhodiola rosea by two-step adsorption chromatography on resins. J Sep Sci 32 185-191 (2009).


Here are some abstracts from recent research:



Li, X., J. Sipple, et al. (2012). "Salidroside stimulates DNA repair enzyme Parp-1 activity in mouse HSC maintenance." Blood.
Salidroside is a phenylpropanoid glycoside isolated from the medicinal plant Rhodiola rosea that has potent antioxidant properties. Here we show that Salidroside prevented the loss of hematopoietic stem cells (HSCs) in mice under oxidative stress. Quiescent HSCs were recruited into cell cycling upon in vivo challenge with oxidative stress, which was blocked by Salidroside. Surprisingly, Salidroside does not prevent the production of reactive oxygen species (ROS) but reduces hydrogen peroxide-induced DNA-strand breaks in bone marrow cells enriched for HSCs. We tested whether Salidroside enhances oxidative DNA damage repair (ODDR) in mice deficient for five DNA repair pathways known to be involved in oxidative DNA damage repair; we found that Salidroside activated poly(ADP-ribose)polymerase-1 (PARP-1), a component of the base excision repair pathway, in mouse bone marrow HSCs as well as primary fibroblasts and human lymphoblasts. PARP-1 activation by Salidroside protects quiescent HSCs from oxidative stress-induced cycling in native animals and self-renewal defect in transplanted recipients, which was abrogated by genetic ablation or pharmacologic inhibition of PARP-1. Together, these findings suggest that activation of PARP-1 by Salidroside could affect the homeostasis and function of HSCs and contribute to the antioxidant effects of Salidroside.

Zhang, M., H. Zhao, et al. (2012). "[Effect of salidroside on rat bone marrow mesenchymal stem cells differentiation into cholinergic nerve cells]." Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 26(2): 158-165.
OBJECTIVE: To investigate the effect of salidroside on rat bone marrow mesenchymal stem cells (BMSCs) differentiation into the cholinergic nerve cells, so as to provide the theory basis of the combination of salidroside and stem cells for clinical therapy of nervous system diseases. METHODS: BMSCs were isolated from 2 Wistar rats (aged 4-6 weeks,weighing 120 g), which were identified by CD34, CD45, CD90, and CD106 with flow cytometry. According to inducing method, BMSCs at passage 2 were divided into 3 groups: In groups A and B, BMSCs were induced by salidroside (20 microg/mL) and retinoicacid (5 micromol/mL) respectively for 1, 3, 6, and 9 days, in group C, BMSCs were cultured with serum-free DMEM/F12 medium as control. MTT assay was used to detect the cellular proliferation activity. The immunofluorescence chemical technology was used to detect the expressions of nerver growth factor (NGF) and relevant marker molecule of nerve cells, including neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP2), beta-Tubulin III, glial fibrillary acidic protein (GFAP), and the marker of chol inergic neuron, such as Acetylcholine (Ach) and NGF. RT-PCR was used to detect mRNA expressions of NSE, beta-Tubulin III, GFAP,brain derived neurotrophic factor (BDNF),and gamma-aminobutyric acid (GABA). ELISA was used to detect the levels of BDNF and NGF, and the expression level of NGF protein was analyzed by Western blot. RESULTS: The results of the flow cytometry showed that the cultured cells were CD90 and CD106 positive, and CD34 and CD45 negative,which indicated that the cells were BMSCs. The cellular proliferation activity in groups A and B were significantly higher than that in group C at 6 days and 9 days (P < 0.05). RT-PCR results showed that the expression level of NSE,BDNF, beta-Tubulin III,GFAPmRNA were increased in group A at 6 days; In group B, that expression level of NSE mRNA was up-regulated at 6 days, that expression level of BDNF mRNA increased at 1 days and reached the peak at 6 days, and that expression level of beta-Tubulin III mRNA was up-regulated at 3 days, which was significantly higher than that at the other time points, and than that in group C (P < 0.01). But no GABA mRNA expression was detected in each group. Immunofluorescence chemical technology staining showed that the positive rates of NSE, MAP2, beta-Tubulin III, and GFAP were significantly higher in group A than those in group C at 3 days; the positive rates of Ach were significantly higher at 3, 6, and 9 days than those at 1 day in groups A and B, and in groups A and B than in group C (P < 0.01); the positive rates of NGF in groups A and B were significantly higher than those in group C (P < 0.01). The levels of BDNF and NGF in groups A and B were significantly higher than those in group C at 1, 3, 6, and 9 days (P < 0.01), but no significant difference of BDNF was found between groups A and B (P > 0.05). The expression level of NGF protein in groups A and B were significantly higher than that in group C (P < 0.01). The NGF expression reached the peak at 6 days in group A and at 3 days in group B. CONCLUSION: Salidroside could induce rat BMSCs differentiate into cholinergic nerve cells in vitro.


Lu, L., J. Yuan, et al. (2012). "Rejuvenating activity of salidroside (SDS): dietary intake of SDS enhances the immune response of aged rats." Age (Dordr).
It is well known that immune response decreases with aging. Salidroside (SDS), an antioxidant component isolated from the traditional Chinese medicine roseroot Rhodiola rosea, has been demonstrated to possess potent anti-aging and health-promoting activities. However, the mechanism underlying these activities is poorly understood. In this study, we clearly demonstrated that (1) dietary intake of SDS induced a considerable increase in total T cells (CD3(+)) and T helper cells (CD4(+)) in aged (21 months old) Wistar male rats; (2) SDS supplementation significantly increased the DTH response, a T cell-mediated immune response, in aged rats; and (3) SDS supplementation remarkably promoted the production of total anti-KLH IgG, anti-KLH IgG(1), and anti-KLH IgG(2alpha) in aged rats without disturbing immune homeostasis. These indicate that SDS is able to counteract immunosenescence, thereby resulting in rejuvenation. Practically, SDS may be used to help the elderly to generate an improved response to vaccine with stronger humoral and cell-mediated immune responses.


Panossian, A., G. Wikman, et al. (2012). "Adaptogens stimulate neuropeptide y and hsp72 expression and release in neuroglia cells." Front Neurosci 6: 6.
The beneficial stress-protective effect of adaptogens is related to the regulation of homeostasis via mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of the stress response, such as molecular chaperones, stress-activated c-Jun N-terminal protein kinase, forkhead box O transcription factor, cortisol, and nitric oxide (NO). However, it still remains unclear what the primary upstream targets are in response to stimulation by adaptogens. The present study addresses this gap in our knowledge and suggests that an important target for adaptogen mediated stress-protective effector functions is the stress hormone neuropeptide Y (NPY). We demonstrated that ADAPT-232, a fixed combination of adaptogens Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract SHR-5, and its active constituent salidroside, stimulated the expression of NPY and 72 kDa heat shock protein (Hsp72) in isolated human neuroglia cells. The central role of NPY was validated in experiments in which pre-treatment of human neuroglia cells with NPY-siRNA and HSF1-siRNA resulted in the significant suppression of ADAPT-232-induced NPY and Hsp72 release. Taken together our studies suggest that the stimulation and release of the stress hormones, NPY and Hsp72, into systemic circulation is an innate defense response against mild stressors (ADAPT-232), which increase tolerance and adaptation to stress.


Zheng, K. Y., Z. X. Zhang, et al. (2012). "Salidroside stimulates the accumulation of HIF-1alpha protein resulted in the induction of EPO expression: A signaling via blocking the degradation pathway in kidney and liver cells." Eur J Pharmacol 679(1-3): 34-39.
Rhodiolae Crenulatae Radix et Rhizoma (Rhodiola), the root and rhizome of Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba, has been used as a traditional Chinese medicine (TCM) to increase the body resistance to mountain sickness in preventing hypoxia; however, the functional ingredient responsible for this adaptogenic effect has not been revealed. Here, we have identified salidroside, a glycoside predominantly found in Rhodiola, is the chemical in providing such anti-hypoxia effect. Cultured human embryonic kidney fibroblast (HEK293T) and human hepatocellular carcinoma (HepG2) were used to reveal the mechanism of this hematopoietic function mediated by salidroside. The application of salidroside in cultures induced the expression of erythropoietin (EPO) mRNA from its transcription regulatory element hypoxia response element (HRE), located on EPO gene. The application of salidroside stimulated the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) protein, but not HIF-2alpha protein: the salidroside-induced HIF-1alpha protein was via the reduction of HIF-1alpha degradation but not the mRNA induction. The increased HIF-1alpha could account for the activation of EPO gene. These results supported the notion that hematopoietic function of Rhodiola was triggered, at least partially, by salidroside.


Coenye, T., G. Brackman, et al. (2012). "Eradication of Propionibacterium acnes biofilms by plant extracts and putative identification of icariin, resveratrol and salidroside as active compounds." Phytomedicine 19(5): 409-412.
Propionibacterium acnes is a Gram-positive bacterium that plays an important role in the pathogenesis of acne vulgaris. This organism is capable of biofilm formation and the decreased antimicrobial susceptibility of biofilm-associated cells may hamper efficient treatment. In addition, the prolonged use of systemic antibiotic therapy is likely to lead to the development and spread of antimicrobial resistance. In the present study we investigated whether P. acnes biofilms could be eradicated by plant extracts or their active compounds, and whether other mechanisms besides killing of biofilm cells could be involved. Out of 119 plant extracts investigated, we identified five with potent antibiofilm activity against P. acnes (extracts from Epimedium brevicornum, Malus pumila, Polygonum cuspidatum, Rhodiola crenulata and Dolichos lablab). We subsequently identified icariin, resveratrol and salidroside as active compounds in three of these extracts. Extracts from E. brevicornum and P. cuspidatum, as well as their active compounds (icariin and resveratrol, respectively) showed marked antibiofilm activity when used in subinhibitory concentrations, indicating that killing of microbial cells is not their only mode of action.


Chu, H., W. He, et al. (2011). "[Flavonoids and nor-sesquiterpenes of Pedicularis densispica]." Zhongguo Zhong Yao Za Zhi 36(19): 2672-2675.
OBJECTIVE: To study the chemical constituents of the whole plants of Pedicularis densispica. METHOD: The chemical constituents were isolated by various chromatographic methods and their structures were determined by chemical evidences and spectral data. RESULT: Ten compounds were isolated and identified as acacetin (1), apigenin-7-0-beta-glucopyranoside (2), kaempferol-3,7-O-alpha-dirhamnopyranoside (3), scutellarein-7-0-beta-glucopyranoside (4), chrysoeriol-7-O-beta-glucopyranoside (5), pedicutricone A (6), dearabinosyl pneumonanthoside (7), salidroside (8), darendoside B (9), and maltol-beta-D-glucopyranoside (10). CONCLUSION: These compounds were isolated from the titled plant for the first time. Except compounds 6 and 8, the others were obtained for the first time from the genus Pedicularis.

Qu, Z. Q., Y. Zhou, et al. (2012). "Protective effects of a Rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat." PLoS One 7(1): e29641.
Previously we have demonstrated that a Rhodiola crenulata extract (RCE), containing a potent antioxidant salidroside, promotes neurogenesis in the hippocampus of depressive rats. The current study was designed to further investigate the protective effect of the RCE on neurogenesis in a rat model of Alzheimer's disease (AD) induced by an intracerebroventricular injection of streptozotocin (STZ), and to determine whether this neuroprotective effect is induced by the antioxidative activity of salidroside. Our results showed that pretreatment with the RCE significantly improved the impaired neurogenesis and simultaneously reduced the oxidative stress in the hippocampus of AD rats. In vitro studies revealed that (1) exposure of neural stem cells (NSCs) from the hippocampus to STZ strikingly increased intracellular reactive oxygen species (ROS) levels, induced cell death and perturbed cell proliferation and differentiation, (2) hydrogen peroxide induced similar cellular activities as STZ, (3) pre-incubation of STZ-treated NSCs with catalase, an antioxidant, suppressed all these cellular activities induced by STZ, and (4) likewise, pre-incubation of STZ-treated NSCs with salidroside, also an antioxidant, suppressed all these activities as catalase: reduction of ROS levels and NSC death with simultaneous increases in proliferation and differentiation. Our findings indicated that the RCE improved the impaired hippocampal neurogenesis in the rat model of AD through protecting NSCs by its main ingredient salidroside which scavenged intracellular ROS.

Li, F., H. Tang, et al. (2011). "Protective effect of salidroside from Rhodiolae Radix on diabetes-induced oxidative stress in mice." Molecules 16(12): 9912-9924.
It has been confirmed that diabetes mellitus (DM) carries increased oxidative stress. This study evaluated the effects of salidroside from Rhodiolae Radix on diabetes-induced oxidative stress in mice. After induction of diabetes, diabetic mice were administered daily doses of 50, 100 and 200 mg/kg salidroside for 28 days. Body weights, fasting blood glucose (FBG), serum insulin, TC (total cholesterol), TG (triglyceride), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were measured. Results showed that salidroside possessed hypoglycemic activity and protective effects against diabetes-induced oxidative stress, which could significantly reduce FBG, TC, TG and MDA levels, and at same time increase serum insulin levels, SOD, GPx and CAT activities. Therefore, salidroside should be considered as a candidate for future studies on diabetes.

Shi, T. Y., S. F. Feng, et al. (2012). "Neuroprotective effects of salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and h(2)o (2)-induced neurotoxicity in vitro." Neurotox Res 21(4): 358-367.
Salidroside (Sal) is a natural antioxidant extracted from the root of Rhodiola rosea L. that elicits neuroprotective effects in vivo and in vitro. Tyrosol galactoside (Tyr), an analog of Sal, was recently synthesized in our laboratory. The purpose of the current study was to investigate and compare the neuroprotective effects of Sal and Tyr against focal cerebral ischemia in vivo and H(2)O(2)-induced neurotoxicity in vitro. Sal and Tyr significantly prevented a cerebral ischemic injury induced by a 2 h middle cerebral artery occlusion and a 24 h reperfusion in rats in vivo. Furthermore, the oxidative insult was markedly attenuated by treatments of Sal and Tyr in the cultured rat cortical neurons after a 30 min exposure to 50 muM of H(2)O(2). Western blot analysis revealed that Sal and Tyr decreased the expression of Bax and restored the balance of pro- and anti-apoptotic proteins. The neuroprotective effects of these two analogues show that Tyr has a better antioxidative action compared with Sal both in vivo and in vitro, and suggest that the antioxidant activity of Sal and Tyr may be partly due to their different substituents in their glycosyl groups. This gives a new insight into the development of therapeutic natural antioxidants against oxidative stress.

Wang, C. Q., J. Chen, et al. (2011). "[Study on preparation of salidroside and polysaccharide in Rhodiola crenulata]." Zhong Yao Cai 34(7): 1122-1125.
OBJECTIVE: To optimize the preparation process of salidroside and polysaccharide in Rhodiola crenulata. METHODS: Water-extraction and alcohol-precipitation was used. The effect of added water volume, decoction time and frequency on water-extracting process was investigated by L9 (3(4)) orthogonal design using extraction rate, content of salidroside and polysaccharide as the assessment indexes. The effect of liquor strength and ethanol concentration on alcohol-precipitating process was investigated as well, using content of salidroside and polysaccharide as the assessment indexes. RESULTS: The optimum conditions for water-extracting process were as follows: decocting 3 times, and each time adding 8 fold of water and extracting 2 h. For alcohol-precipitating process,it was that liquor strength was 0.4 g/mL, and ethanol concentration in liquor was 70%. CONCLUSION: The optimized process has guidance for the development and comprehensive utilization of this plant.

Guan, S., H. Feng, et al. (2011). "Salidroside attenuates LPS-induced pro-inflammatory cytokine responses and improves survival in murine endotoxemia." Int Immunopharmacol 11(12): 2194-2199.
Salidroside is a major component isolated from the Rhodiola rosea. In the present study, we investigated the anti-inflammatory effects of salidroside on cytokine production by lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro, and the results showed that salidroside reduced tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) secretions. This inspired us to further study the effects of salidroside in vivo. Salidroside significantly attenuated TNF-alpha, IL-1beta and IL-6 productions in serum from mice challenged with LPS, and consistent with the results in vitro. In the murine model of endotoxemia, mice were treated with salidroside prior to or after LPS challenge. The results showed that salidroside significantly increased mouse survival. Further studies revealed that salidroside could downregulate LPS-induced nuclear transcription factor-B (NF-B) DNA-binding activation and ERK/MAPKs signal transduction pathways production in RAW 264.7 macrophages. These observations indicated that salidroside modulated early cytokine responses by blocking NF-B and ERK/MAPKs activation, and thus, increased mouse survival. These effects of salidroside may be of potential usefulness in the treatment of inflammation-mediated endotoxemia.

Sun, C., Z. Wang, et al. (2012). "Salidroside inhibits migration and invasion of human fibrosarcoma HT1080 cells." Phytomedicine 19(3-4): 355-363.
Oxidative stress plays an important role in tumorigenesis and metastasis. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant property. Here we investigated the inhibitory effects of salidroside on tumor metastasis in human fibrosarcoma HT1080 cells in vitro. The results indicated that salidroside significantly reduced wound closure areas of HT1080 cells, inhibited HT1080 cells invasion into Matrigel-coated membranes, suppressed matrix metalloproteinases (MMP-2 and MMP-9) activity, and increased tissue inhibitor of metalloproteinase-2 (TIMP-2) expression in a dose-dependent manner in HT1080 cells. Salidroside treatment upregulated the E-cadherin expression, while downregulated the expression of beta1-integrin. As an antioxidant, salidroside inhibited the intracellular reactive oxygen species (ROS) formation in a dose-dependent manner. The results also showed that salidroside could inhibit the activation of protein kinase C (PKC) and the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in a dose-dependent manner. In conclusion, these results suggest that salidroside inhibits tumor cells metastasis, which may due to its interfere in the intracellular excess ROS thereby down-regulated the ROS-PKC-ERK1/2 signaling pathway.

Guan, S., J. He, et al. (2011). "Adjuvant effects of salidroside from Rhodiola rosea L. on the immune responses to ovalbumin in mice." Immunopharmacol Immunotoxicol 33(4): 738-743.
Salidroside, a major component of Rhodiola rosea L., was evaluated for its adjuvant effects on the immune responses in mice by ovalbumin (OVA) stimulation. BALB/c mice were immunized subcutaneously with OVA 100 mug or OVA 100 mug dissolved in saline containing alum (100 mug) or salidroside (12.5, 25, or 50 mug) on Days 1 and 15. Two weeks later (Day 28), blood samples were collected to analyze OVA-specific IgG, IgG1, and IgG2b antibodies. Meanwhile, splenocytes were harvested to assess lymphocyte proliferation, cytokines (IL-2, IL-4, and IFN-gamma) production, and CD4(+), CD8(+) lymphocyte subsets. The results indicated that co-administration of salidroside with OVA significantly enhanced the ConA-, LPS-, and OVA-induced splenocyte proliferation, produced more IL-2, IL-4, IFN-gamma, and IgG, IgG1, and IgG2b antibody levels, and increased the percentage of CD4(+), CD8(+) lymphocyte subsets than OVA alone. Thus, salidroside possess immunological adjuvant activity by regulating humoral and cellular immune responses in mice.

Zhu, Y., Y. P. Shi, et al. (2011). "Salidroside protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via PI3K-Akt dependent pathway." DNA Cell Biol 30(10): 809-819.
Oxidative stress induces serious tissue injury in cardiovascular diseases. Salidroside, with its strong antioxidative and cytoprotective actions, is of particular interest in the development of antioxidative therapies for oxidative injury in cardiac diseases. We examined the pharmacological effects of salidroside on H9c2 rat cardiomyoblast cells under conditions of oxidative stress induced by hydrogen peroxide (H2O2) challenge. Salidroside attenuated H2O2-impaired cell viability in a concentration-dependent manner, and effectively inhibited cellular malondialdehyde production, lethal sarcolemmal disruption, cell necrosis, and apoptosis induced by H2O2 insult. Salidroside significantly augmented Akt phosphorylation at Serine 473 in the absence or presence of H2O2 stimulation; wortmannin, a specific inhibitor of PI3K, abrogated salidroside protection. Salidroside increased the intracellular mRNA expression and activities of catalase and Mn-superoxide dismutases in a PI3K-dependent manner. Our results indicated that salidroside protected cardiomyocytes against oxidative injury through activating the PI3K/Akt pathway and increasing the expression and activities of endogenous PI3K dependent antioxidant enzymes.

Liu, Z., X. Li, et al. (2012). "Rhodiola rosea extracts and salidroside decrease the growth of bladder cancer cell lines via inhibition of the mTOR pathway and induction of autophagy." Mol Carcinog 51(3): 257-267.
The incidence of human urinary bladder cancer increases markedly with age, suggesting a mechanistic connection between aging and bladder carcinogenesis and a potential use of anti-aging agents in bladder cancer chemoprevention. Rhodiola rosea, growing in high altitude or cold regions of the world, has been reported to have anti-aging effects in Drosophila. We demonstrated that a R. rosea extract and one of its bioactive components, salidroside, inhibited the growth of bladder cancer cell lines with a minimal effect on nonmalignant bladder epithelial cells TEU-2. Interestingly, the R. rosea extract and salidroside component exhibited a selective ability to inhibit the growth of p53 knockout primary mouse embryo fibroblasts (p53-/- MEFs) compared to their wild-type counterparts. The growth inhibitory effects of the R. rosea extract and salidroside were, however, attenuated in TSC2 and p53 double knock MEFs (TSC2-/-, p53-/- MEFs), suggesting that TSC2 protein is, at least in part, required for the growth inhibitory effects of the R. rosea extract and salidroside. The R. rosea extract and salidroside treatment of UMUC3 cells resulted in an increase of AMP-activated protein kinase (AMPK)-alpha phosphorylation and a decrease of 4E-BP1 phosphorylation, leading to increased binding of 4E-BP1 to m7 GTP. These results indicate that the R. rosea extract and salidroside inhibit translation initiation. Furthermore, both the R. rosea extract and salidroside treatment of UMUC3 cells caused a significant percentage of cells undergoing autophagy. Therefore, the R. rosea extract and salidroside deserve further study as novel agents for chemoprevention of bladder carcinogenesis.


Guan, S., W. Wang, et al. (2011). "Salidroside attenuates hydrogen peroxide-induced cell damage through a cAMP-dependent pathway." Molecules 16(4): 3371-3379.
Salidroside, a major component of Rhodiola rosea L., has shown various pharmacological functions, including antioxidant effects, but the signal transduction pathway of its antioxidant effects is not very clear. In this study, we found that salidroside could attenuate hydrogen peroxide (H(2)O(2))-induced HL-7702 cell damage, inhibit H(2)O(2)-induced cytosolic free Ca2+ ([Ca2+]i) elevation, scavenge reactive oxygen species (ROS) and increase 3'-5'-cyclic adenosine monophosphate (cAMP) level in a dose-dependent manner, but it couldn't influence 3'-5'-cyclic guanosine monophosphate (cGMP) levels. Therefore, these results indicated that the antioxidant effects of salidroside were associated with down-regulation of [Ca2+]i, ROS occur via a cAMP-dependent pathway.

Ye, S. S., Y. Y. Zeng, et al. (2011). "[Effects of salidroside on proliferation, apoptosis, phagocytosis, ROS and NO production of murine peritoneal macrophages in vitro]." Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 27(3): 237-241.
AIM: To investigate the effects of salidroside(Sal) on proliferation, apoptosis, phagocytosis, the production of ROS and NO of murine peritoneal macrophages in vitro as well as its immunoregulation. METHODS: The single cell suspension of murine peritoneal macrophages was prepared under sterile condition, then co-cultured with different concentrations of Sal(80, 160 and 320 mumol/L)for 4 hours prior to stimulation with LPS and IFN-gamma, the proliferation of macrophages was measured by MTT colorimetry. The effect of Sal on the apoptosis of Sytox(R) Green-labelled peritoneal macrophages induced by CHX was detected by Fluorescence enzyme-labelled meter. FCM was used to detect the effect of Sal on phagocytosis of peritoneal macrophages. Fluorescence enzyme-labelled meter was used to measure the effects of Sal on ROS of H(2);DCFDA-labelled macrophages induced by LPS and IFN-gamma. Griess Gragent was used to detect the role of Sal in production of NO in peritoneal macrophages activated by LPS and IFN-gamma. RESULTS: MTT result demonstrated that Sal could promote the proliferation of peritoneal macrophages activated by LPS and IFN-gamma at the final concentrations of 80, 160, 320 mumol/L, respectively (P<0.05). The result of Fluorescence enzyme-labelled meter detected showed that Sal at the final concentration of 160 mumol/L could inhibit apoptosis of peritoneal macrophages induced by CHX(P<0.01). FCM analysis showed that different concentrations of Sal significantly promoted the phagocytosis of peritoneal macrophages which include un-activated and activated by LPS and IFN-gamma(P<0.05). Fluorescence enzyme-labelled meter showed that Sal could reduce the production of ROS in activated peritoneal macrophages induced by LPS and IFN-gamma(P<0.05). Sal also increased the production of NO in activated peritoneal macrophages induced by LPS and IFN-gamma(P<0.05). CONCLUSION: Sal can promote proliferation of peritoneal macrophages stimulated by LPS and IFN-gamma, and it can inhibit apoptosis of peritoneal macrophages induced by CHX, Sal also can promote the phagocytosis of peritoneal macrophages which include un-activated and activated by LPS and IFN-gamma, Sal can reduce the production of ROS in activated peritoneal macrophages induced by LPS and IFN-gamma, while Sal can promote the production of NO in activated peritoneal macrophages induced by LPS and IFN-gamma.

Guo, Y., Y. Zhao, et al. (2010). "Synthesis, biological activity of salidroside and its analogues." Chem Pharm Bull (Tokyo) 58(12): 1627-1629.

Salidroside is a phenylpropanoid glycoside isolated from Rhodiola rosea L., a traditional Chinese medicinal plant, and has displayed a broad spectrum of pharmacological properties. In this paper, about 18 novel salidroside analogues were prepared through Koenigs-Knorr method, the effects of these compounds over PC12 was assessed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The novel compounds differ in the substituents attached to the benzene ring or in the glycosyl donor. According to the data, compounds (3,5-dimethoxyphenyl)methyl beta-D-glucopyranoside and (3,5-dimethoxyphenyl)methyl beta-D-galactopyranoside with methoxy group at 3 and 5-positions of the benzene ring were the most viability at concentration of 300 micromol/l and 60 micromol/l, respectively.

Rhodiola rosea

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