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Summary of Uncaria rhynchophylla
Primary Information, Benefits, Effects, and Important Facts
Uncaria rhynchophylla (not to be confused with Uncaria Tomentosa) is a traditional chinese medicine and Japanese medicine that is used for the treatment of hypertension, convulsive disorders (epilepsy), and for various head ailments such as headache or dizziness. It contains a variety of alkaloid structures, most notably the one named after it (Rhynchophylline) and a potent drug-like alkaloid with the acronym of GME (Geissoschizine methyl ether). It is a component of the popular japanese medicinal formula known as Yokukansan, where it alongside glycyrrhiza uralensis (licorice) seem to mediate the neuroprotective effects.
Studies that use oral ingestion of the herb or isolated alkaloids are only in the animal phases of research at this point in time, but it appears that GME has antipsychotic properties very similar to Aripiprazole (pharmaceutical) on the serotonin and dopamine receptors. The influence on the serotonin receptors also confers some anxiety reducing properties, and can reduce social aggression (thought to be the reason why Yokukansan reduces agitation in elderly persons with dementia).
There is also a neuroprotective effect that is mostly based on preventing the brain's support cells (glial cells, which support the neurons) from activating in response to inflammation. This antiinflammatory effect in the brain appears to underlie anti-epileptic properties with oral ingestion of the herb.
Beyond that, there is potential for this herb to reduce blood pressure secondary to activating nitric oxide signalling but this has not yet been investigated in living systems.
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Things To Know & Note
Is a Form Of
Primary Function:
Also Known As
Uncariae uncis cum ramulus, Choto-ko, Choto-san, pulvis uncariae, Diao-teng-san, Gou-teng,
Do Not Confuse With
Cat's Claw (Uncaria tomentosa or guianensis)
Caution NoticeExamine.com Medical Disclaimer
How to Take Uncaria rhynchophylla
Recommended dosage, active amounts, other details
There is currently no evidence in humans to recommend an ideal human dose, but based on the rat studies conducted noting efficacy with the water extract at 250-1,000 mg/kg oral intake a preliminary guess at the dosages would be:
2,700-11,000 mg for a 150lb person
3,600-14,500 mg for a 200lb person
4,500-18,000 mg for a 250lb person
The formulation known as Yokukansan (one serving is 20.5 grams) which is given to humans contains three grams of uncaria rhynchophylla, and this may be a prudent starting dose even if using it in isolation.
Research Breakdown on Uncaria rhynchophylla
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Uncaria rhynchophylla (of the family Rubiaceae) is a traditional chinese medicine and frequently used in Japanese (Kampo) medicine for the treatment of convulsive disorders,[1] headaches, vertigo and dizziness, epilepsy,[2] and as an antipyretic and antihypertensive medication.[2] It is known as Chotoko in Japanese medicine (and the dust from this plant, or pulvis uncariae, is called Uncariae uncis cum ramulus[3]) and Gou-teng in Chinese medicine.[4][5]
This plant is also sometimes called Cat's Claw or Fish Hook Vine (referring to the hook structures on the plant) but this is a term that is used to describe the entire genera of uncaria and, when used colloquiolly, tends to refer to the Amazonian species Uncaria tomentosa or uncaria guianensis. The reason the plants in this genera are called such is because the plants bear 'hooks' which is what the entire genera is named after (uncus is latin for hook), and this is the branch of the plant which is modified into a hook shape to allow the plant to climb upon the vines of other plants.
Uncaria rhynchophylla (Choto-ko) is a herb that has traditionally been used to treat head ailments (headache, dizziness) and for the treatment of epilepsy and hypertension. It is most well known for being a component of Yokukansan, a Kampo medicine for the treatment of agitation and well being in persons with Dementia
The components of uncaria rhynchophylla (the medicinal hooks, unless otherwise specified) include:
Hirsuteine (0.015% of Yokukansan or YKS;[6] 0.08% hook dry weight), the hydrogenated version known Hirsutine (0.013% of YKS;[6] 0.07% hook dry weight), and the isomer of Hirsuteine known as Geissoschizine methyl ether (0.014% of YKS;[6] 0.08% hook dry weight); the latter being structured similar to Geissoschizine (without the methyl ether) and turbinatine (Geissoschizine glycoside[7])
Corynoxeine (0.026% of YKS;[6] 0.25-1.43mg/g[4] or 0.40-2.47mg/g of the dried hook[8] and 0.27-0.82mg/g dry leaf[8]), Isocorynoxeine (0.009% of YKS;[6] 0.60-1.96mg/g[4] or 0.66-4.63mg/g dried hook[8] and 0.74-2.31mg/g dried leaves[8]), Cisocorynoxeine,[9] and 9-hydroxy derivatives;[4] there is also 22-O-β-D-glycopyranosyl glycoside of isocorynoxeinic acid (0.21mg/g hook dry weight or otherwise undetectable; undetectable in leaves[8]) and N-oxide derivatives of corynoxeine (0.02mg/g dry hook weight or otherwise undetectable; not in leaves[8]) and isocorynoxeine (0.08mg/g dry hook weight or less, not in leaves[8])
Rhynchophylline (0.027% of YKS;[6] detected in the range of 0.77-1.44mg/g[4] or 0.50-2.21mg/g dried hook[8] and 0.39-0.96mg/g dried leaves[8]) and Isorhynchophylline (0.005% of YKS;[6] 0.87-4.55mg/g dried hook and 0.81-3.95mg/g in dried leaves[8]) as well as rhynchophylline and isorhynchophylline N-oxide variants (less than 0.12mg/g and 0.15mg/g respectively in the hooks; lesser or nonexistent in the leaves[8])
Rhynchophyllic acid and isorhynchophyllic acids as well as their 22-O-β-glucopyranosides[4]
Corynoxine and corynoxine B (epimers)[4] as well as 18,19-dehydrocorynoxinic and 18,19-dehydrocorynoxinic B (epimers)[8][10]
Specionoxeine and isospecionoxeine[4]
Procyanidin B1 and B2[4]
Alkaloid glycosides such as vincoside lactam (0.21-0.37mg/g[4] or 0.8-0.42mg/g dry hook weight[8] and 2.29-3.98mg/g dry leaf weight[8]) its 11-hydroxy-2′-O-D-glucopyranosyl (0.07-0.20mg/g dried hook[8] and 0.10-0.48mg/g dried leaves[8]), and strictosidine (2.29-3.92mg/g dry leaf weight and 0.07-1.08mg/g dry hook[8])
(+)-catechin (2.56mg/g dried hook)[1][4] and (-)-epicatechin (1.53mg/g dried hook)[1][4]
Chlorogenic acid (5.66mg/g of the dried hook) and neochlorogenic acid[4]
trans-anethole, p-anisaldehyde, and estragole[13] (volatile oils also found in fennel)
The triterpenes 3-oxo-olean-12-en-28-oic acid[13] and ursolic acid[14] as well as the triterpenes with phenolic groups named Uncarinic Acids A-E[15][16] which are either isomers of 3β-hydroxy-27-feruloyloxyurs-12-en-28-oic acid (uncarinic acids C and D) or β-hydroxy-27-coumaroyloxyolean-12-en-28-oic acid (uncarinic acid E)[17]
Rhynchophylline and isorhynchophylline are relatively unique structures known as tetracyclic oxindole alkaloids, and are epimers of each other at the C7 position.[2] Corynoxeine and isocorynoxeine are also oxyindole alkaloids, but geissoschizine methyl ether and both hirsuteine and hirsutine are indole alkaloids.[18]
The components of this plant are essentially the alkaloids, which are present in very low quantities but due to their potencies at the molecular level this small quantity may be sufficient. The are broken down into either oxindole alkaloids or indole alkaloids for the most part, and the main bioactives are probably rhynchophylline (and its isomer) as well as geissoschizine methyl ether
When looking collectively at the groups of alkaloids, the oxindoles (rhynchophyllineand corynoxeine related) 0.26-1.38% dry weight while the alkaloid glycosides (vincoside lactam, its glycoside, and strictosidine) are lesser at 0.02-0.19%.[8] In the leaves, the alkaloid glycosides are much higher (3.8-7.5% dry weight) while the oxindoles are comparatively lower (0.21-0.71% dry weight); the oxindole N-oxides are trace in all aerial parts.[8] The indole alkaloids (hirustine, hirusteine, geissoschizine methyl ether) are somewhat lower than the oxinolde alkaloids.
The branches/hooks of uncaria rhynchophylla contain a decent amount of the oxindole and indole alkaloids. The leaves (not usually used medicinally) have much higher levels of the alkaloid glycosides
Rhynchophylline and isorhynchophylline appear to be poorly soluble, limiting their usage in in vitro studies past 100µM despite usage of DMSO.[2]
Apparently ("it is traditionally known that"[5]) uncaria rhynchophylline is unstable in high temperatures; it was mentioned in the aforementioned study following hot water extraction at 60-70°C (and 2 hour evaporation at 60°C) as a reason to avoid further extraction.
There is a formulation called Yokukansan or Choto-san in Japanese medicine (Yi-Gan San in Chinese) which contains the powder of uncaria rhynchophylla (referred to as Uncariae uncis cum ramulus) at 3g alongside the rhizome of Atractylodes lancea (4g), the mushroom Poria cocos (4g), the rhizome from Cnidium officinale (3g), the root of Angelica acutiloba (3g), the root of Bupleurum falcatum (2g), and licorice root (Glycyrrhiza uralensis at 1,500mg). This formulation is recommended for restlessness in children or for treating agitation in dementia.
Yokukansan is a compound formulation used for the treatment of aggression and enhancement of well being in elderly persons with dementia or other cognitive disorders. The role uncaria rhynchophylla plays in this formulation is thought to be the antiagressive effect (see the serotonin section) and alongside glycyrrhiza uralensis it adds some neuroprotective properties
Another formulation including uncaria rhynchophylla (synonymous with Choto-ko) is called Choto-san. This formulation also appears to be used for the treatment of cognitive decline and dementia.
Choto-san is five parts Gypsum Fibrosum to one part Ginger rhizome to three parts of each of the following: chrysanthemi flower, aurantii nobilis Pericar, ophiopogonis tuber, ginseng root, hoelen, ledebouriellae root, pinelliae tuber, and licorice root (glycyrrhiza uralensis);[19] by weight, it is 9.7% uncaria rhynchophylla[19]
Choto-san is another formulation which contains 'Choto-ko' (ie. uncaria rhynchophylla) and also serves as an anti-cognitive decline compound formulation
Rhynchophylline appears to have the potential to block L-type voltage gated calcium channels, and was able to attenuate the release of calcium in response to caffeine and potassium.[20] Hirsutine can suppress calcium efflux in endothelial cells that is induced by noradrenaline or potassium in the 3-30µM range (approximately 20-70%; less potent than 10µM vermapril), although direct binding to calcium channels was not investigated.[21]
Rhynchophylline does not appear to significantly interact with calcium-activated potassium channels[20] although 30μM rhynchophylline has been noted to accelerate the slow-type (C-type) inactivation of voltage-gated potassium currents in an extracellular manner, functionally changing them into something more like an A-type potassium channels (those that are rapidly inactivated).[22]
The alkaloids are known to directly interact with ion channels, particularly by inhibiting calcium channels and possibly modifying slow-type voltage gated potassium channels into ones that act similar to fast-type channels; these occur at higher than normal concentrations that are found in the blood following oral ingestion, and their physiological relevance following supplementation of uncaria rhynchophylla has not yet been proven and is doubtful
Oral administration of 1-4g/kg Yokukansan to rats (150-600mg/kg uncaria rhynchophylla) has been noted to increase plasma levels (measured one hour after ingestion) of geissoschizine methyl ether (2.1-9.0ng/mL; 5.73-24.5nM), rhynchophylline (1.8-10.8ng/mL; 4.68-28.1nM), Isorhynchophylline (0.7ng/mL at the higher dose; 1.8nM), corynoxeine (1.9-14.5ng/mL; 4.97-37.9nM), hirsutine (0.6-1.6ng/mL; 1.68-4.34nM), and hirsuteine (1.0-6.0ng/mL; 2.73-16.39nM) but not isocorynoxeine.[23]
Oral ingestion of 37.5mg/kg rhychnophylline to rats results in serum levels of rhychnophylline peaking at three hours (Tmax) to a concentration of 351.5ng/mL (Cmax) which then are normalized to baseline levels after 8 hours.[24]
The alkaloids are all detectable in serum following oral ingestion, although with the standard dose of uncaria rhynchophylla (via Yokukansan) it appears to reach the low nanomolar range. A full pharmacokinetic study of the herb by itself, rather than the context of Yokukansan, has not yet been conducted (which is important, since many of these formulations have 'support' herbs that increase bioavailability of the primary pharmacological agents such as how licorice or black pepper extract are used)
Following oral ingestion of 37.5mg/kg rhychnophylline to rats, rhychnophylline is hydroxylated at either the 10-carbon or the 11-carbon by CYP enzymes (CYP1A1/2, CYP2D, and CYP2C but not CYP3A4 are implicated) which are then both glucuronidated to form the end products of 10-Hydroxyrhynchophylline 11-O-β-D-Glucuronide and 11-Hydroxyrhynchophylline 11-O-β-D-Glucuronide.[24] Metabolism into the 11-hydroxy or the 10-hydroxy metabolite are pretty much even for both rhynchophylline[24] and its isomer which follows similar hydroxylation and glucuronidation.[25]
Hirsuteine and hirsutine both follow similar hydroxylation (via CYP2C) and glucurondation following oral ingestion to rats.[26]
All alkaloids studied appear to undergo hydroxylation by CYP enzymes (thought to be CYP2C) followed by glucuronidation by Phase II enzymes; at this moment in time no alternate metabolic pathway is detectable
In an in vitro model or blood brain barrier (BBB) permeability, it appears that geissomethyl ether can cross the BBB with a permeability rate of 27.3%; higher than the other uncaria rhynchophylla alkaloids.[23]
In rats treated with Yokukansan (4g/kg; 600mg/kg uncaria rhynchophylla) there is a detectable brain concentration of hirsuteine (3.9ng/g), corynoxeine (1.7ng/g), and geissoschizine methyl ether (5.9ng/g) whereas no other metabolites were detected at this oral dose and only geissoschizine methyl ether was detected at an oral dose of 1g/kg Yokukansan (150mg/kg uncaria rhynchophylla) at 1.6ng/g.[23] Following oral ingestion of rhychnophylline at 37.5mg/kg, it can reach brain concentrations of 0.650+/-0.018ng/g after three hours;[24] since rhychnophylline reached 351.5ng/mL in plasma at this time, it appears to have very poor transportation into the brain.[24]
Most alkaloids (at the practically relevant low nanomolar concentrations in the blood) do not reach the brain, but geissoschizine methyl ether appears to be pretty well absorbed while hirsuteine and corynoxeine are present. Rhychnophylline (and it is assume isorhychnophylline) appear to have poor transportation into the brain
Rhychnophylline and its metabolites (the glucuronidated forms) can be detected in bile after oral ingestion, and after six hours accounts for around 5.9% of the ingested dose;[24] these end products are pretty much identical to those of isorhynchophylline[25] which reaches 10% after 12 hours.[25]
The overall amount of rhychnophylline fecally excreted after 24 hours is about five-fold higher than that in the urine,[24] and 12.6% of the ingested dose of rhychnophylline is excreted in the urine (so about 63% of the oral dose was detected in the feces after 24 hours, and around 25% still within tissue after 24 hours).[24] These numbers are similar to its isomer, since 71.6% and 13.8% of isorhynchophylline is detectable in the feces and urine, respectively, after 24 hours.[25] Hirsiteine and hirsutine (free and conjugated forms) have about 14% and 26% of the total ingested dosage get urinated out, whereas 35% and 46% are fecally excreted (and after 24 hours, 52% and 28% still remaining in tissue).[26]
Some unconjugated and unmetabolized rhychnophylline can be detected in both urine and the feces[24] although the fecal excretion of isorhynchophylline is mostly (80%) unconjugated and unmetabolized which is thought to be due to poor intestinal absorption.[25] Hirsuteine and hirsutine also have unmetabolized forms detectable in the urine and feces.[26]
Urinary and fecal elimination are involved in handling these alkaloids, with about one part urinary excretion to five parts fecal excretion. The gluruconide metabolites are the most prominent end product, although there is a small amount of unchanged alkaloids in the urine
Isorhynychophylline appears to have anti-arrythmic properties in rats and guinea pigs where arrythmia is induced by oubain or calcium chloride.[27]
Isolated hirsutine is able to preserve cardiomyocytes from damage from a lack of oxygen (hypoxia; reduced viability to 45.1+/-2.1% of control) at 1μM (76.8+/-2.1% viability) and 10μM (85.6+/-3.1 viability) although the protective effect at 100nM was not significant but still redued LDH leakage somewhat (indicating minor protective effects on the cell membrane).[28] This protective effect was thought to be secondary to stimulating superoxide dismutase (SOD) activity, which was reduced to 65.7U/mg protein after hypoxia, to 77.4-102U/mg in the range of 0.1-10μM.[28]
The alkaloids are technically cardioprotective. Practical significance of this information is not known due to higher than normal concentrations being required
A hot water extract of uncaria rhynchophylline (2.5:1 concentration) is able to relax precontracted endothelial vessels (noradrenaline) whether the vessel has its endothelium intact (18.67-80.13% relaxation at 40-400µg/mL) or if it is denuded (0.43-18.55% at the same concentration range; 59.75% at 4mg/mL), conferring EC50 values of 94µg/mL and 2.4mg/mL.[5] This relaxing effect was not reversed with washout, and the lower concentrations (endothelium intact) were fully blocked with NMMA suggesting the involvement of nitric oxide;[5] acetylcholine receptors did not appear to be involved.[5]
Geissoschizine methyl ether (GME) appears to be able to relax adrenaline precontracted endothelium with an EC50 of 744nM, a potency about 14-fold greater than that of hirsutine (10.6µM) and 10-fold greater than hirsuteine (7.6µM).[29] Other individual alkaloids were weaker, having EC50 values of 10.47µM (isorhynchophylline), 31.1µM (rhynchophylline), 34.2µM (Isocorynoxeine), and 37.1µM (Corynoxeine); similar to the hot water extract, the low concentrations of all alkaloiids are fully inhibited by L-NAME (nitric oxide inhibitor) while higher concentrations are not.[29]
The alkaloids in uncaria rhychnophylla appear to reduce blood pressure by one of two mechanisms, either blocking calcium channels (to prevent their contractile effects) or by releasing nitric oxide to cause relaxation. The concentrations required for blocking calcium channels is much higher than is seen following ingestion of this plant, and the lower concentration of geissoschizine methyl ether and hirsuteine (fully mediated by nitric oxide) are likely relevant to oral ingestion of the plant
Corynoxeine (5-50µM) appears to reduce the proliferation of vascular smooth muscle cells (VSMCs) in response to platelet derived growth factor (PDGF) by 25-88% and the DNA synthesis from PDGF by 32.8-76.9%;[30] this is thought to be associated with inhibiting ERK1/2 activity since there was no influence on MEK, PLCγ1, or Akt activation and the receptor for PDGF was unaffected.[30]
Higher than normal concentrations of corynoxeine may reduce VSMC proliferation, which is a mechanism thought to reduce atherosclerotic progression
Secondary to its antioxidant properties, Uncaria rhynchophylla is able to reduce lipid peroxidation to the red blood cell membrane in the concentration range of 250-1,000µg/mL (full protection at 1,000µg/mL) and 571mg/kg oral uncaria rhynchophylla to rats is able to prevent 20-30% of lipid peroxidation to red blood cells when the blood cells are tested ex vivo (extracted at 120-240 minutes after ingestion).[19]
The antioxidant properties appear to be protective of red blood cells, and this appears to occur in rats following oral ingestion of the basic plant extract
Both (+)-catechin and (-)-epicatechin from this plant can inhibit MAO-B with IC50 concentrations of 88.6µM and 58.9µM and Ki values of 74µM and 21µM, respectively.[1] Despite the low potency from the catechins, a 50% methanolic extract of uncaria rhynchophylla has been able to inhibit MAO-B with an IC50 value of 30µg/mL[31] which suggests other bioactives since (+)-catechin and (-)-epicatechin are only present up to 0.25% and 0.14% of the hook's dry weight respectively.[4]
While the catechins are likely inactive in practical situations (too high of a concentration), the overall methanolic extract did seem to be active at a lower concentration. It is possibly active in the body, but requires further evidence to confirm
The alkaloids from uncaria rhynchophylla have once failed to show any binding affinity for NMDA receptors at a concentration up to 100µM and failed to significantly inhibit calcium influx by glutamate by more than 20% at 100µM,[32] this study tested isorhynchophylline but not rhynchophylline, and elsewhere both of these alkaloids (in Xenopus oocytes expressing NMDA receptors) reduced NMDA-evoked currents by 25.5-54.9% and 33-60.3% at 3-100µM respectively;[2] the IC50 values were measured at 48.3μM (range of 35.4–65.8μM) and 43.2μM (range of 26.0–72.0μM) respectively in the presence of 100µM NDMA and were neither voltage dependent, use dependent, or altered by NMDA modulators such as spermine, dithiothreitol, zinc, or alterations of pH.[2] NDMA antagonism has been noted with the plant extract elsewhere[33] and in vitro with the methanolic extract of the plant 1-10μg/mL is able to inhibit currents evoked by both glutamate (16.5-27.2%; not concentration dependent) and NMDA (37.3-45%; concentration dependent) in hippocampal cells[34] which is replicated with the alkaloids.[35]
The study that noted inhibitory effects against NMDA currents by rhynchophylline and isorhynchophylline failed to find an inhibitory effect against kainate or AMPA mediated currents[2] and the methanolic extract has similarly failed to inhibit these currents;[34] if anything, 1-10μg/mL of the methanolic extract had a mild (10-20%) enhancement of AMPA currents.[34]
Although one study failed to find an effect, it appears that the alkaloids in this plant are NMDA receptor inhibitors. While the IC50 values are too high for what is normally found in the brain, it is possible that mild inhibition (less than 20%) may occur with high doses. Kainate receptors are unaffected, and low concentrations of the methanolic extract may weakly enhance AMPA receptors
GABAA signalling is known to be theapeutic for epilepsy[36] and during a seizure the sensitivity of these receptors seems to be reduced[37] since repetitive activation of mossy fibers releases zinc into the synapse which blocks GABAA signalling.[38] The receptor level does not appear to be influenced (in a rat model of kainic acid induced seizures) and uncaria rhynchophylline does not modify GABAA receptor levels either over the short term[39] or after six weeks of oral ingestion.[40]
No known interactions with GABAergic neurotransmission
An ethyl acetate extraction of uncaria rhyncophylla appears to inhibit acetylcholinesterase in the concentration range of 600µg/mL by 25.9+/-0.43%;[13] the most effective molecule appeared to be trans-anethole (8.2-39.2% inhibition at 30-150µg/mL) but was significantly weaker than tacrine as reference drug (94.1% inhibition at 30µg/mL).[13]
Geissoschizine methyl ether appears to have more potency as an acetylcholinesterase inhibitor, with an IC50 of 3.7+/-0.3µM (noncompetitive inhibition) whereas other tested alkaloids (Hisuteine, histine, vallesiachotamine, corynoxeine, cisocorynoxeine, and isorhynchophylline) were not significantly effective.[9]
There is a possibly relevant inhibition of acetylcholinesterase with geissoschizine methyl ether
The decrease in acetylcholinesterase associated with cognitive function can be attenuated with oral ingestion of a dose of uncaria rhynchophylline sufficient to attenuate amnesia.[41]
The alterations in cholinergic neurotranmission seen with neurotoxicity are attenuated when said neurotoxicity is attenuated from this herb
Geissoschizine methyl ether is an alkaloid in uncaria rhynchopylla which acts on the 5-HT1A receptors. It is able to outcompete 8-OH-DPAT binding to the receptor with an IC50 and Ki value of 904nM and 517nM (respectively) and activated the receptor in the contration range of 0.1–100μM (although it had 40% the potency as serotonin itself);[6] this has been noted elsewhere, where a Ki value of 800nM was reported for 5-HT1A receptors[42] and an EC50 in activating them was measured at 4.6+/-7μM, reaching maximal activation (Emax) of 85+/-3% the potency of 1μM serotonin.[43]
There appears to be affinity for 5-HT2C (Ki 900nM)[42] which was later found to be inhibition, possessing an IC50 of 5.07+/-0.41μM[43] although higher concentrations (20μM) have weak activating abilities suggesting it is a partial agonist.[43]
There appears to be affinity for 5-HT2A (Ki 1.4μM)[42] which was later noted to be inhibition; IC50 value of 4.87+/-0.44μM[43] and again higher concentrations (20μM) were noted to be weak agonists (and thus it was a partial agonist).[43]
5-HT7 is also inhibited with an IC50 of 610+/-290nM (blocking serotonin binding)[43] and 340nM (blocking LSD binding)[44] while the ability of geissoschizine methyl ether to block serotonin induced cAMP production is slightly weaker (IC50 6µM).[44]
Corynoxeine, isocorynoxeine, rhynchophylline, and isorhynchophylline fail to interact with the 5-HT1A receptor up to 100µM while hirsuteine and hirsutine were weakly effective (blocked 40% of 8-OH-DPAT binding at 100µM while geissoschizine methyl ether was absolute at 10µM).[6] When testing the overall Yokukansan plant up to 200µg/mL (where uncaria rhynchophylla is thought to mediate the serotonin like effects) there was no influence on 5-HT2B receptors nor the serotonin transporter.[6]
When looking at the level of the receptors, geissoschizine methyl ether is a potent agonist of the 5-HT1A receptors while it is inhibitory at the 5-HT2A, 5-HT2C, and 5-HT7 receptors at the same concentration range, with the possibility of being a partial agonist at higher doses. This profile is very similar to the anti-psychotic drug Aripiprazole
The major traditional combination therapy that uncaria rhynchophylla is a part of (Yokukansan) is known to be recommended for reducing aggression in elderly persons with dementia; aggression is known to be associated with dysfunctions in serotonin signalling[45][46] and Yokukansan has been implicated in modifying the serotonin system (partial agonist of 5-HT1A with no influence on 5-HT2A[47]) which has reduced aggressive symptoms in rodents, yet has its anti-aggressive effects blocked by inhibiting this receptor.[48]
Both acute administration and continual ingestion over four weeks of 75-150mg/kg uncaria rhynchophylla in socially isolated rats appears to reduce the aggressive effects of social isolated in a dose-dependent manner, with 75-150mg/kg being as effective as 500-1,000mg/kg Yokukansan.[6] Isolated geissoschizine methyl ether (75-300µg/kg; equivalent to 53-212mg/kg Yokukansan) failed to reduce aggression acutely (but was effective after two weeks) and enhanced social behaviour at all times;[6] both uncaria rhynchopylla and isolated geissoschizine methyl ether had their effects blocked by a 5-HT1A receptor antagonist.[6]
Due to being a partial agonist of the 5-HT1A receptors, geissoschizine methyl ether appears to confer antiaggressive properties in the oral dose that is found in the uncaria rhynchophylla plant and traditional medicine Yokukansan
Geissoschizine methyl ether has failed to show affinity for adrenergic α1 receptors at concentrations below 10µM,[42] although a screening study in rat prostate cells noted that rhynchophylline and corynoxeine (as well as their isomers) had affintiy to adrenergic α1 receptors in a similar manner to tamsulosin, suggesting inhibition.[49] In regards to the a2 receptors, a few alkaloids show inhibitory activity against the α2A subset in particular (with no affinity for α1 receptors, α2B or α2C recepors, nor β-adrenergic receptors) with IC50 values of 2.4μg/mL (geissoschizine methyl ether), 32μg/mL (hirsuteine), and 17μg/mL (hirsutine).[50]
The α2A adrenergic receptor in particular appears to be inhibited by geissoschizine methyl ether and its related indole alkaloids (hirsutine and hirsuteine); geissoschizine methyl ether may be active centrally whereas the others may be active peripherally
Geissoschizine methyl ether has once failed to show affinity for D2 receptors at concentrations lesser than 15µM (via displacing the ligand spiperone)[42] although at the D2L it can activate signalling with an EC50 of 4.4+/-3.6µM reaching max potency at 50+/-15% the equivalent of dopamine; these were slightly lesser than the drug Aripiprazole with an EC50 value of 7.64+/-0.33µM but an Emax of 68.6+/-13.7%; again similar to aripiprazole, geissoschizine methyl ether had an atypical ability to only activate 53.9% of cells (in a manner blocked by haloperidol) and appeared to at higher concentraitons (20μM) showed slight inhibitory potential.[43]
Geissoschizine methyl ether appears to have very high affinity for the D2 receptor, but is only a partial agonist of this receptor (half as potent as dopamine itself) and may be weakly suppressive at higher doses; it seems selective, and again is similar to the antipsychotic Aripiprazole
When looking at the overall plant extract, uncaria rhynchophylline appears to be neuroprotective against NMDA-mediated excitotoxicity[33] at concentrations as low as 20µg/mL of the water extract[32] or 1ug/mL of the methanolic extract;[34] Yokukansan overall is neuroprotective[51] and this is thought to be primary due to uncaria rhynchophylline and (licorice) since the protection from atractylodis lanceae is weak and the others inactive.[32]
5-10µM of a few alkaloids (Hirsuteine, hirsutine, geissoschizine methyl ether, and rhynchophylline) in primary neurons is able to attenuate glutamate-induced neuronal death by about half at the higher concentration; this was not associated with inhibiting NMDA receptors in these primary neruons.[32] This study noted that the potency at 20µg/mL was comparable between uncaria rhynchophylline and glycyrrhiza uralensis (licorice),[32] and elsewhere in PC12 cells (not expressing the main NMDA receptor subunits) 200μg/mL of uncaria rhynchophylline were found to be more protective associated with a preservation of glutathione.[52] Corynoxeine has been twice found to not be neuroprotective[18][32] while other alkaloids (rhynchophylline, isorhynchophylline, isocorynoxeine) are only significantly neuroprotective against glutamate in the 100-1,000µM range[18] and despite protection occurring at 10µM in primary neurons[32] hirsutine and hirsuteine have failed to reduce glutamate toxicity in cerebellar granule cells.[18]
The indole alkaloids (but not oxyindole alkaloids) appear to be neuroprotective against glutamate, and it seems that this may be independent of possibly blocking the receptors (but associated with preserving glutathione in the cells)
When looking at individual alkaloids, hirsutine is able to suppress the inflammatory response in the hippocampus from LPS as assessed by nitric oxide and IL-1β production.[53] In primary microglial cultures, LPS stimulation is also inhibited by rhynchophylline in the range of 3-30µM in a concentration dependent manner (as assessed by nitrite and PGE2; COX2 induction required 10µM) and attenuated inflammatory changes in NF-kB, TNF-α, and IL-1β levels.[54] Corynoxeine and isocorynoxeine, as well as vinctoside lactam, are in ths above concentration range as well (IC50 13.7-19µM) while 18,19-dehydrocoynoxeine and its epimer are not (IC50 greater than 100µM).[10]
In N9 micrglia, rhynchophylline and isorhynchophylline can suppress LPS activation of these glial cells in the concentration range of 0.3-30μM (16.6-58.7% for rhynchophylline and 18.9-63.2% for its isomer), with 1-3μM being as effective as 10μM resveratrol as reference.[55] IC50 values were attained for inhibiting the secretion of TNF-α (12.1 and 2.3μM, respectively) and IL-1β secretion (6.1 and 3.3μM) associated with inhibiting ERK and p38 phosphorylation.[55]
The alkaloids appear to have general antiinflammatory properties against LPS stimulation of microglia, with the effective concentrations perhaps low enough to be effective following oral ingestion
The microglial inflammation (assessed via immunoreactivity) in response to kainate induced seizures in rats appears to be reduced with oral ingestion of 500-1,000mg/kg uncaria rhynchophylline (7.86:1 concentrated water extract) for three days, with both doses being equally effective and neither dose being significantly different than the control group (ie. full statistical prevention of neuroinflammation from kainate).[56] Expression of nNOS and iNOS were also fully prevented with both doses relative to kainate control, being comparable to the group not given kainate,[56] and elsewhere other inflammatory biomarkers (AP-1 and NF-kB activity) were significantly decreased by both uncaria rhynchophylline and isolated rhynchophylline in response to kainate while MAPKs are unaffected (by both kainate and uncaria rhynchophylline).[57]
This is thought to underlie the anti-epileptic effects of uncaria rhynchophylline since biomarker proteins, S100B proteins (released from damaged astrocytres and involved in the pathology of seizures[58]) are not increased in rats given both kainate and uncaria rhynchophylline,[39] suggesting the astrocytes (mediators of neuroinflammation) are not being damaged.
The neuroinflammation indued by kainate is essentially fully prevented with oral dosing of uncaria rhynchophylla, which is thought to be due to the antiinflammatory effects since the kainate receptor is not blocked (see the glutaminergic neurotransmission section)
75-300µg/kg of isolated geissoschizine methyl ether acutely or daily for two weeks does not seem to alter locomotion or physical symptoms of otherwise healty rats[6] although higher doses has been noted to suppress spontaneous motor activity (30mg/kg),[42][59] convulsion,[60] and head twitching (10-30mg/kg);[42] the lack of activity is thought to be more relevant since the 75-300mg/kg dosage correlates to 9-36mg/kg uncaria rhynchopylla,[6] and in mice oral ingestion of 500-2,000mg/kg of the water extract of the plant failed to significantly modify locomotion.[59]
The water extract of uncaria rhychnophylla at 100-200mg/kg orally for one week prior to an elevated maze plus test in rats caused anxiolytic effects either comparable or nonsignificantly greater than the reference drug (buspirone at 1mg/kg) in a manner that is wholly mediated via 5-HT1A receptors (fully blocked by WAY 100635; flumazenil ineffective);[61] the comparable efficacy was noted after a week of ingestion, although a single dose appeared to also be effective.[61]
The 5-HT1A activation (from geissoschizine methyl ether) appears to confer anxiolytic properties of potency comparable to the reference drug of buspirone (Buspar)
In rats given the amnesiac drug scopolamine, 250mg/kg of the ethyl acetate extract can preserve 78.2% of amnesia as assessed by a passive avoidance task;[13] this was thought to be related to trans-anethole which was similar in potency to tacrine (both at 2.5mg/kg oral intake) despite trans-anethole being much weaker at inhibiting acetylcholinesterase.[13]
200-400mg/kg of the 70% aqueous ethanolic extract of uncaria rhynchophylline, but not 100mg/kg, is able to preserve cognition in a rat model of Alzheimer's disease (galactosamine induced cognitive dysfunction) when consumed over eight weeks;[41] this is associated with a preservation in glutathione and acetylcholine concentrations.[41]
The neuroprotective effects may confer some anti-amnesiac effects
One of the foremost usages of uncaria rhynchophylline in traditional medicines is for treating convulsions and epilepsy. Kainic acid injections (caused temporal lobe seizures in rats and mice with a similar phenotype to epileptic seizures in humans,[62] and thus is a research model for epileptic seizures), and the process of epileptic seizures tends to be associated with glial cell (astrocyte) proliferation,[63] neuronal losses (hippocampal),[64] and a phenomena known as mosst fiber sprouting[65] where unmyelinated axons in the hippocampus being hyperexcited and is vital to the pathophysiology of epileptic seizures.
Injections of uncaria rhynchophylline are known to significantly attenuate kainic acid induced seizures (250-1,000mg/kg of the hook extract) when given 15 minutes prior to seizure induction[66][67] and three days injections with the last dose preceding kainic acid by 30 minutes appears to be able to reduce epileptic (facial myoclonia, wet dog shakes, paw tremor) by 54-65% (uncaria rhynchophylline at 1,000mg/kg) or 65-70% (rhynchophylline at 250µg/kg), the former of which was comparable in potency to the reference drug valproate (250mg/kg) while rhynchophylline was more protective.[57] 1,000mg/kg of a 70% ethanolic extract fed to rats for two weeks prior to seizures was able to statistically normalize wet dog shakes induced by kainic acid[39] and efficacy has been noted elsewhere with oral ingestion of uncaria rhynchophylla (1,000mg/kg of the ethanolic extract) for six weeks in rats.[40]
Oral ingestion of uncaria rhynchophylline has been confirmed to reduce seizures in rats, and it appears to be quite effective as it significantly attenuates physical symptoms (potency similar to valproate) and nearly normalizes biochemical markers of inflammation associated with kainic acid
Intraperitoneal injections of the plant (1,000mg/kg of a water extract) to rats 15 minutes prior to an injection of kainic acid (to induce a seizure) noted that, when measured three hours after seizure induction, in both the frontal cortex and hippocampus the seizure reduced levels of two proteins (MIF and cyclophilin A) while administration of the herb or isolated rhynchophylline (250µg/kg) was able to increase them both beyond control levels.[68] It also seems that while S100B proteins (their induction from astrocytes, when damaged, mediates epileptic changes in the brain[58]) are increased during seizures and greatly reduced with oral intake of uncaria rhynchophylline (1,000mg/kg oral intake) in the hippocampus by 63.5% (CA1), 77% (CA3), and 85.5% (Hilus area) relative to kainic acid control.[39][40]
Oral intake of the 70% ethanolic extract (1,000mg/kg for two weeks) is able to abolish the kainic acid induced spikes in activity, and significantly attenuated cell death and glial cell proliferation in the hippocampus[40][39] associated with a reduction of mossy fiber sprouting (49.8+/-2.7% increase in kainic acid control; 17.3+/-1.1% in the group fed uncaria).[40]
There appears to be reduced signalling magnitudes in the hippocampus and less mossy fiber activation, and due to there also being no proliferation of glial cells nor release of proteins from these glial cells (which are involved in the pathology of seizures) it suggests that antiinflammatory effects on the level of the microglia may underlie the antiepileptic effects
Intraperitoneal injections of uncaria rhychnophylla at 250-1,000mg/kg (70% methanolic extract; 0.074% rhychnophylline) at the time of cerebral ischemia and again 90 minutes later appeared to cause 70.5-75.6% neuronal preservation in the hippocampus with no dose dependence and associated with less inflammatory biomarkers (PGE2, TNF-α, COX2 induction).[69] There was no dose-dependence noted, but the lowest dose (100mg/kg) was ineffective.
There may be some anti-ischemic properties pending future research; potency and practical significance is currently unknown
Oral ingestion of Yokukansan (850mg/kg), uncaria rhynchophylla 150mg/kg), or isolated geissoschizine methyl ether (150μg/kg) appears to attenaute physical symptoms of morphine withdrawal; while active, licorice sourced from glycyrrhiza uralensis and its bioactive (glycyrrhizin at 9.6mg/kg) appeared to be slightly more bioactive (suggesting both herbs contribute to the effects of Yokukansan).[50]
The above effects were thought to be due to interactions with α2-adrenergic signalling, since Yokukansan (12.5-200μg/mL) showed binding affinity and antagonism on this receptor (and both α1 nor β-adrenergic receptors) and specifically the α2A subset (no influence on α2B or α2C).[50] The antagonism was traced back to glycyrrhiza uralensis (IC50 36.3μg/mL) and uncaria rhynchophylla (IC50 131μg/mL) with most potency from 18β-glycyrrhetinic acid (47μg/mL) and geissomethyl ether (2.4μg/mL) respectively.[50]
In isolated RAW264.7 macrophages, uncaria rhynchophylla is able to suppress NF-kB activation (Akt and all three MAPKs were also suppressed) from LPS stimulation in the concentration range of 500-2,000µg/mL with near full reduction in nitrite production at the highest concentration but more modest inhibition of IL-1β secretion.[70]
Possible antiinflammatory effects at the level of the macrophage, although nothing remarkable was noted (moderate to low potency and higher than ideal concentrations required)
In isolated dendritic cells, Uncarinic acid C (URC) is able to enhance the expression of a wide variety of receptors (CD1a, CD38, CD40, CD54, CD80, CD83, CD86, HLA-DR and DC-Lamp) in the concentration range of 0.1-10µM, and in mature dendritic cells 100nM of URC can enhance the production of IL-12p70 to near six-fold of control (10nM inactive and 1µM less active) while blocking TLR4 signalling suppressed this by 65-80% (blocking TLR2 slightly suppressed signalling).[15]
Monocytes and immature dendritic cells tend to express the TLR2 and TLR4 receptors to high levels, but this is reduced following maturation; the reduction seen with URC (100-500nM) is less than that with LPS, causing a relatively higher level of TLR4 mRNA in matured dendritic cells.[15] This activation of dendritic cells via TLR2/TLR4 receptors has been noted with ursolic acid[14] and uncarinic acid D[16] as well, and in a manner that is synergistic with IFN-γ.[71]
This promotion of Th1 cell production is said to be IL-12 dependent[16] and blocking IL-12p70 (downstream of TLR2/TLR4) prevents the above from occurring.[15][14]
It seems that the triterpenoids in this plant can act on the surface receptors on the dendritic cells (TLR4 and a bit of TLR2) to stimulate their activity, which causes a shift in the T-cell profile form Th2 towards Th1. This is IL-12 dependent, and it appears to be very potent (occurring to a comparable level to LPS in the nanomolar range)
In dendritic cells which were primed with URC during the maturation process, there is a promotion of Th1 cell production with nonsignificant increases in IFNγ production relative to LPS control[15] but the cytotoxicity of these T-cells (CD8+) towards T2 tumor cells was enhanced.[15] This increase in Th1 cell population has been noted with ursolic acid as well, when it primed dendritic cells.[14]
The T-cells that are primed by the actions of uncarinic acids on dendritic cells appear to have enhanced cytotoxicity towards tumor cells; characteristic of Th1 cells
Atopic dermatitis (an eczematous skin disorder with dry and itchy skin) is known to be influenced by T-cells, with Th1 cells positively mediating the allergic response to chronic dermatitis while Th2 cells mediate the acute response (usually referred to as allergic dermatitis or contact dermatitis).[72]
In a mouse model of atopic dermatitis (DNFB induced contact hypersensitivity in NC/Nga mice[73]), a water extract of uncaria rhynchophylla (2.35% yield) at 100-300mg/kg orally for six weeks following sensitization with DNFB was able to attenuate the formation of skin lesions relative to control (48-53% after 3 weeks and 53-55% after 5) with no apparent dose dependence and a potency nonsignificantly greater than 3mg/kg prednisone (24% and 32% at the two time points).[74] Uncaria rhynchophylla failed to reduce the increase in IgE and IL-4 seen with sensitization, but prevented the increase in IFN-γ (and adding IFN-γ itself to DNFB mice was sufficient to cause a response), suggesting that it suppressed Th1 mediated allergic responses but not Th2.[74]
It appears that uncaria rhynchophylla may have a role in the treatment and prevention of chronic atopic dermatitis due to suppressing the hyperactivity of Th1 cells, although preliminary evidence suggests that contact dermatitis is not affected
In a DPPH asasy, uncaria rhynchophylla appears to have antioxidant effects with an IC50 of 14.3µg/mL; it was more efficient than Yokukansan (206.2µg/mL) and Yokukansan with uncaria rhynchophylla removed (244.3µg/mL) and appeared to outperform the reference of Vitamin E (IC50 24.5µM).[75]
Appears to, in general, be a potent antioxidant compound via directly reducing other molecules
Superoxide (O2-) can be nonenzymatically reduced with uncaria rhynchophylla at an IC50 value of 18.3µg/mL, and it appears to be the most potent herb in Yokukansan since the mixture has an IC50 value of 67.7µg/mL and removing uncaria rhynchophylla from the mix weakens it to 92.4µg/mL.[75] The potency of this plant is similar to Quercetin (18.7µM) but greater than both epicatechin (175.2µM) and caffeic acid (141.7µM).[75]
The plant overall appears to be comparable in antioxidant potency as quercetin ex vivo, which suggests that a bioactive is significantly more potent
As assessed by deoxyribose degradation (a model of assessing hydroxl radical antioxidative effects) in the presence of EDTA; uncaria rhynchophylla appeared to inhibit oxidation (IC50 of 2.2mg/mL; similar potency to quercetin at 1.9mM) in a manner that was enhanced with removal of EDTA (to an IC50 of 1.3mg/mL);[75] this is thought to be due to the ability of uncaria rhynchophylla to chelate minerals and prevent the complexation of ferrozine-iron with an IC50 of 1.3mg/mL..[75]
Moderate hydroxyl radical scavenging properties but also a present metal chelating property
In rat brain homogenate, assessing the anti-lipid peroxidative effects of uncaria rhynchophylla (via TBARS formation), it appears to suppress lipid peroxidation with an IC50 of 19.1µg/mL and is the causative agent of Yokukansan since the mixture had an IC50 of 124.7µg/mL and removing uncaria rhynchophylla from said mixture increaesd the IC50 to 368.6µg/mL;[75] the effects of the plant were more potent than Vitamin E as a referece (153.7µM) but not quercetin (3.1µM).[75]
Appears to also reduce lipid peroxidation when tested outside the body, which may persist to oral ingestion (see the cardiovascular health section on red blood cells)
The uncarinic acids (C-E) are able to inhibit phospholipase Cγ1 with an IC50 value in the range of 9.5−44.6μM (most potency from uncarinic acid E)[17] while A-B are comparable to the weaker ones (35.66-44.55μM[76]); inhibition of this phospholipase is thought to be a good target for antiproliferative therapy as it is elevated in cancer cells[77][78] and mediates proliferation.
The uncarinic acids (triterpenes with phenolic acid moieties) appear to be potent inhibitors of phospholipase Cγ1 which is thought to be an antiproliferative mechanism
In cancer cells that normally overexpress phospholipase Cγ1 (colonic HCT-15, breast MCF-7, lung A549, and bladder HT-1197) uncarinic acids can suppress their proliferation with an IC50 of 0.5−6.5μg/mL; the most potency (IC50 of 500nM) being uncarinic acid E on colon cancer cells.[17]
In cancer cells that overexpress phospholipase Cγ1, it appears that the triterpenes can suppress their proliferation via inhibiting phospholipase Cγ1
When looking at angiogenesis, a 70% ethanolic extract of the root in HUVEC cells noted that concentrations as low as 100ng/mL enhanced cell proliferation (21.1%) reaching up to 45.5% at 10μg/mL; this proliferative effect was blocked with antibodies against VEGF and bFGF.[79] HUVEC cell migration was also enhanced 9.7-fold to at 25μg/mL, and uncaria rhynchophylla was noted to increase VEGF and bFGF mRNA expression and secretion in the concentration range of 1-100μg/mL (bFGF influenced more potently).[79]
This angiogenic property of the 70% ethanolic extract was confirmed in mice injected with 25μg of the extract where it promoted blood vessel formation with similar potency to 100ng bFGF.[79]
Something in the plant appears to be highly angiogenic, which in theory is good for wound healing but not for proliferation of tumor cells. Practical significance of this data is not known, but the potency suggests that it is relevant to supplementation (assuming the same bioactives are in the roots as well as hooks)
A methanolic extract of uncaria rhynchophylla has been noted to have mild (15.8%) inhibitory properties against HT-29 cell proliferation at the concentration of 500μg/mL[80] although in another type of colon cancer cell (HCT-15) that overexpress Cγ1 the Uncarinic acids have reduced proliferation with IC50 values of 1.4μg/mL (Uncarinic acids A and B), 1.9μg/mL (Uncarinic acid C), 2.5μg/mL (Uncarinic acid D), and 500ng/mL (Uncarinic acid E).[17]
Potential antiproliferative effects due to the phospholipase Cγ1 inhibition, but in cells where this is not overexpressed it does not appear to by as potent. Practical significance of this data and its usage towards cancer prevention uncertain
When tested alongside protein fibrils associated with Alzheimer's disease (Aβ1-40 and Aβ1-42) at 10µg/mL, uncaria rhynchophylla is able to prevent formation of fibrils with 38.9-50.3% inhibition and can destabilize preexisting fibrils with 77.2-87.7% potency with both values referring to Aβ1-40 (Aβ1-42 slightly more resistant);[3] these effects were also noted with curcuma longa, Cinnamomum cassia, and Paeonia suffruticosa with slightly less potency.[3] When looking at Tau proteins, rhynchophylline and its isomer do not alter total concentrations of it in vitro at 100µM[81] although isorhynchophylline has once been implicated in inducing autophagy of α-synuclein (protein) in neuronal cells in a manner that is independent of mTOR but dependnet on Beclin-1.[82]
In neurons incubated alongside Aβ25–35 to assess the neurotoxicity in PC12 cells from said protein, coincubation with alkaloids from uncaria rhynchophylla noted that the basic extract (particularly molecules in the butanolic fraction) were protective in the 10-50µg/mL (but not 1µg/mL) range partially preserved cell viability, and pure rhynchophylline or its isomer (100µM) partially attenuated the effects.[81] Isolated isorhynchophylline also has protective effects against Aβ25–35 in PC12 cells in a concentration dependent manner between 1-50µM, and reduced the increase in oxidation (ROS) from 234% of control down to 132-186% and the increase in lipid peroxidation (MDA) from 177% of control down to 124-139% (1µM not significantly protective) while preserving glutathione concentrations and reducing apoptosis rates.[83]
There appear to be mechanisms which suggest that this herb is protective/therapeutic for Alzheimer's disease, but at this moment in time not enough information is given and the bioactives that are being investigated do not appear to accumulate in the brain to sufficient quantities. Further research is required, possibly with geissoschizine methyl ether
A hot water extract of uncaria rhynchophylla (4.07% yield) given intraorally to rats cerebrally lesioned with 6-OHDA (a dopaminergic and oxidative toxin that is a rat model for Parkinson's disease[84][85]) at the oral dose of 5mg/kg, but not 50mg/kg, was able to very mildly reduce apomorphine induced rotations and TH positive neurons.[86]
Lacklustre data on the interactions of uncaria rhynchophylla and Parkinson's disease
Geissoschizine methyl ether has been reported to have third-generation like antipsychotic effects very similar to Aripiprazole, since both drugs have an activating effect on 5-HT1A and D2L receptors and inhibitory potential on 5-HT2A, 5-HT2C, and 5-HT7 receptors; all of which are very similar potency as assessed by IC50, EC50, and Emax values.[43] Furthermore, both aripiprazole and geissoschizine methyl ester are weak partial agonist of the 5-HT2A and 5-HT2C receptors.[43]
A molecule in uncaria rhynchophylla known as geissoschizine methyl ether has similar potency and a similar pharmacological profile as the antipsycotic drug Aripiprazole, and at least in rats (assessed by aggression as a biomarker of 5-HT1A activity) it seems to be active following oral administration
2,000mg/kg of the water extract of uncaria rhychnophylla to rats for one week does not cause any apparent clinical toxicity.[61]
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- ^ a b c d e Liu CH, et al. Neuroprotective Effect of Uncaria rhynchophylla in Kainic Acid-Induced Epileptic Seizures by Modulating Hippocampal Mossy Fiber Sprouting, Neuron Survival, Astrocyte Proliferation, and S100B Expression. Evid Based Complement Alternat Med. (2012)
- ^ a b c Xian YF, et al. Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice. Planta Med. (2011)
- ^ a b c d e f g Pengsuparp T, et al. Pharmacological studies of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., in the central nervous system. Eur J Pharmacol. (2001)
- ^ a b c d e f g h i Ueda T, et al. Geissoschizine methyl ether has third-generation antipsychotic-like actions at the dopamine and serotonin receptors. Eur J Pharmacol. (2011)
- ^ a b Ueki T, et al. Effects of geissoschizine methyl ether, an indole alkaloid in Uncaria hook, a constituent of yokukansan, on human recombinant serotonin(7) receptor. Cell Mol Neurobiol. (2013)
- ^ Takahashi A, et al. Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression. Psychopharmacology (Berl). (2011)
- ^ Popova NK. From genes to aggressive behavior: the role of serotonergic system. Bioessays. (2006)
- ^ Terawaki K, et al. Partial agonistic effect of yokukansan on human recombinant serotonin 1A receptors expressed in the membranes of Chinese hamster ovary cells. J Ethnopharmacol. (2010)
- ^ Kanno H, et al. Effect of yokukansan, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected rats. J Pharm Pharmacol. (2009)
- ^ He J, et al. Prostate Cell Membrane Chromatography-Liquid Chromatography-Mass Spectrometry for Screening of Active Constituents from Uncaria rhynchophylla. J Chromatogr Sci. (2012)
- ^ a b c d Nakagawa T, et al. Yokukansan inhibits morphine tolerance and physical dependence in mice: the role of α₂A-adrenoceptor. Neuroscience. (2012)
- ^ Kawakami Z, et al. Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells. Neuroscience. (2009)
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- ^ Jung HY, et al. Hirsutine, an indole alkaloid of Uncaria rhynchophylla, inhibits inflammation-mediated neurotoxicity and microglial activation. Mol Med Rep. (2013)
- ^ Song Y, et al. Rhynchophylline attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-κB signaling pathways in primary microglia. Phytother Res. (2012)
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- ^ a b Griffin WS, et al. Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsy. J Neurochem. (1995)
- ^ a b Sakakibara I, et al. Effect on locomotion of indole alkaloids from the hooks of uncaria plants. Phytomedicine. (1999)
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- ^ Hsieh CL, et al. Anticonvulsant effect of Uncaria rhynchophylla (Miq) Jack. in rats with kainic acid-induced epileptic seizure. Am J Chin Med. (1999)
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So its winter. Now we ladies (and gentlemen) have to deal with this cold dry air and wind, and sun damage and snow. We also have that wonderful acne to fight and you have bought just about everything on the market to take care of your face.
That's the problem with us today, there are so many $20+ solutions out there that we fail to realize that a cheaper option may be in sight. Like that black soap you see.
Black soap, also known as African black soap, contain various oils, like the coconut oil, palm oil, palm kernel oil, shea butter and cocoa butter. They also contain ashes from different plants, like shea tree bark, banana trees, cocoa pods, and plantain leaves. Along with these water is used as a base for producing these soaps. This is beneficial in many ways beneficial because this soap can do so much from head to toe!
- Eliminates acne
- Removes makeup
- Heals acne scars
- Removes oils from the skin
- Keeps the skin moisturized
- You can even use it to wash your hair
The biggest benefit is the moisture in my opinion. This weather has been topsy turvy in Mississippi! One day it is hot, the next day it is cold and my face is full of dry patches. Black soap is made with Glycerin. Glycerin gets on the skin and literally pulls moisture in, keeping the face moisturized and soft.
I bought this soap for $1.29 out of the (very small) African American section of the health and beauty aisle in Kroger.
Do you use black soap? Have you ever used it? How did it effect your skin or hair?

subset: commoncrawl


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BLISTERFELT, Lawrence H. 1907-1981
Posted By: S. Bell
Date: 2/3/2014 at 00:18:41
[Waterloo Courer, Tuesday, January 13, 1981, Waterloo, Iowa]
CEDAR FALLS-Services for Lawrence H. Bisterfelt, 73, of 2104 Iowa St., will be 1:30 p.m. Thursday at First Baptist Church with burial in Cedar Valley Memorial Gardens. He died Monday morning at Allen Memorial Hospital. Waterloo, of a heart attack.
He was born Nov. 28, 1907, at Waverly, son of William and Rachel Pitts Bisterfelt. He married Harriet Heuckendorf at Creston in August 1928. She preceded him in death. He then married Opal Shepherd d'Happart April 3. 1937. at Marysville, Mo. Before retiring in 1973, he was a pint contractor.
Survivors include his wife; four sons. Clarence d'Happart and Larry Bisterfelt, both of Garland. Texas, Floyd Bisterfelt of Honolulu, Hawaii, and John Bisterfelt of Van Alstyne. Texas: two daughters, Mary Ellen Nicklaus of Des Moines and Laura Rose Nicklaus of Parkersburg; and nine grandchildren and eight great-grandchildren.
Memorials may be given in his name to the Heart Fund or Cancer Society. Friends may call after 9 a.m. Wednesday at Richardson Funeral Home.
Black Hawk Obituaries maintained by Kermit Kittleson.
WebBBS 4.33 Genealogy Modification Package by WebJourneymen


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Now we're talkin' bout my generation (apologies to The Who); those people born between 1965 – 1981. We're up to our eyeballs in debt it seems, so we're looking for a bargain.
Thriftiness is an admirable trait (terrible for marketers); but it appears that we're getting this way due to other excesses. To live the dream, you have to have a nice car, a nice home – and none of these things can be bought for cash these days – for most of us anyway. Then there's the kids, etc. etc. etc. Most of us have accumlated a fair amount of debt to achieve these norms.
According to this article on Emarketer, now we've hit the credit redlines we're looking for bargains – we have the technology the experience and the tools to seek these out, whether they are locally or across the world; courtesy of the Internet. I remember needing to buy some bits a while back and it was far cheaper for me to have them sent from the USA than to buy locally.
It seems that Generation X'ers are now also suspicious of the corporate machine – and really, who can blame us – so we're not as loyal to brands as we once were. A recent example that springs to mind was a local company that produced top quality work boots; so good, I was prepared to spend extra bucks on them. They shifted their operations overseas rather quietly. That didn't bother me, but they were charging the same, so I simply chose a cheaper brand. I'm an example of Generation X Brand Loyalty Fickleness. The boots have lasted well, so I'll stick with them.. for now.
While the Emarketer reports tends to allude to cost being everything and while it is important to we X-ers, we are also somewhat sick of shoddy goods regardless of what we pay. So if you've got a higher price tag, that doesn't get you out of the game; you simply need to justify it – big time and fast; even more so now during these shakey financial times.
Creating effective landing pages
Crafting marketing copy


text:
Published on
REMAKING MADE IN CHINA (contd.)INTRODUCTIONIts a tall order, given that Chinese businesses have little experience developing thetype of brands that dominate on the global stage. Chinese brands have yet to gainenough status to earn a price premium over global counterparts. Not only that, butthey are still tainted by association with shoddy Chinese manufacturing. Consumersin developed markets are skeptical at best of Chinese products.Still, there is tremendous potential. Japan, Korea and Germany are among thenations whose brands have overcome hostile or skeptical consumer perceptions. Itwas once seen as down-market to "buy Japanese," for example, but today fewshoppers consider "Made in Japan" a negative.And in our hyper-connected, globalized, fast-moving world, the journey fromnegative to positive perceptions can be significantly shorter than it once was.Millennials already have a very different image of China than the outdatedassociations that may linger among older consumers. And the youngest consumers,Gen Z, have only known China as a rapidly modernizing economic giant.


text:
The W Factor needed a new logo and business card design and created a contest on 99designs.
A winner was selected from 248 designs submitted by 67 freelance designers.
The W Factor
The W Factor is a professional development training and publishing business. The primary focus of The W Factor is to bring woman in touch with the essence of their "Woman's Power" and their "Woman's Intelligence" - transformational work. We are primarily targeting women who are employed and who are wanted to progress their careers to the next level.
Blue, Purple and possibly a ruby red


text:
HONG KONG (MarketWatch) -- Shares of Hong Kong-listed Zijin Mining Group Co. 2899, +2.47% jumped 6.2% to HK$12.66 amid reports China's securities regulators have approved a plan by the copper and gold miner to list shares in Shanghai. The miner reportedly plans to sell 1.5 billion shares denominated in yuan, the Chinese currency, although no timetable has been set for the fund raising or the when the shares will begin trading. Zijin reportedly wants to raise up to 4.92 billion yuan to fund eight projects, including gold and copper mines and a plant to refine gold.
Zijin Mining shares rise after Shanghai-listing approval
Quote References
+0.08 +2.47%


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text:
A missing man with dementia has been located and will be returning home Saturday night, Toronto police say.
Alber Marbena, 74, from Brampton, was last seen in the area of Humberline Dr. and Finch Ave. W. at around 9:30 p.m. on Thursday.
After Toronto police and Peel Regional police informed the public of the search, a resident in the area of Kipling Ave. and Westhumber Blvd. spotted him on home security footage at around 3 p.m. on Friday.
Marbena was found on a bus by a resident he knew in the Jane and Finch area. Police say the resident saw the 74-year-old on the news and called police.
Both Toronto police and Peel Regional police called a level-three search, the highest level of importance. This status enables police to use any of their resources, including mounted units, K9s and drone aircraft in the area.
Marbena will be checked by emergency crew officials and will be going home shortly after, police say.
tigators from the 21 Division Criminal Investigation Bureau are seeking the public's assistance in locating a missing 74 year-old man.
Alber Marbena was last seen on the morning of January 10, 2019 at his residence in the area of Saintsbury Crescent and Egypt Drive in the City of Brampton.
Alber Marbena is described as male, 5'8'', tanned complexion, balding with a white mustache, and wearing a black hat and a black leather jacket.
Family and police are concerned for the health and well-being of Alber Marbena. To view a photo, please visit our website at peelpolice.ca.
Anyone with information on the whereabouts of Alber Marbena is asked to call investigators at the 21 Division Criminal Investigation Bureau at (905) 453–2121, ext. 2133. Information may also be left anonymously by calling Peel Crime Stoppers at 1-800-222-TIPS (8477), or by visiting peelcrimestoppers.ca.
Like us on Facebook and follow us on Twitter. Visit our YouTube channel and our Livestream page.
Inc. # PR190013076


text:
Ashburn, VA 20+ Home Inspectors near you
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Four men and two boys brought up in the dirty depths of braintree, along with a very
untrusted d team member, dragged them selves out of the slums to reclaim thier prize of
being THE LORDS OF THE SWORDS. Bangers were landed laughs were a plenty slams
happened but in the end we rose as warriors took our challenge and conqured.
password: lots


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For years, I volunteered as a "teacher" for Vacation Bible School at the church I was a member of. I LOVED volunteering for the 4, 5, and 6 year olds...as that is the age (in my opinion) where their personalities really start coming out.
It was one of the cutest things ever.
I'm telling you, the fifteen minutes we had for snack time were never enough. Few kids had eaten their whole snack when snack time was up. And to be clear, we're talking about 15 goldfish - at the max - per kid.
This memory hit me yesterday, as I was eating blueberries in our kitchen. I was having a snack and was eating these without really tasting them, without savoring them.
I decided to take a lesson from these kids...
I sat down. I put about a half cup of blueberries onto my napkin and picked up each berry to admire it before I popped it in my mouth. I enjoyed the whole sensation of eating them...the burst of flavor when my teeth pierced through the skin, how some were more tart than others, and how some were a bit mushier than others.
Eating one blueberry at a time sure took longer. But in the end, I was more satisfied than had I rushed through the entire experience.
I think that's what mindful eating means to me - being aware and appreciative of the food that is in your mouth. Being thankful for all of the hands that touched the food before it got to your plate...for all of the farmers, irrigation specialists, truckers, and grocers.
I used to be one of those people who would say that I was fat because I really enjoyed food. I DO enjoy food. But I find that I enjoy it more when I slow down and taste all of the flavors in the food. Complex dishes are more amazing when I taste as many of the individual flavors as I can. Cheeses are creamier and more luxurious. Fresh veggies are more enjoyable. If I really love food, why not show it by reveling in the tastes, textures, and loveliness of it?
This week, you won't get any huge, complex goals out of me - sure I want to continue to lose weight, but I think I'll go back to the basics.
I want to enjoy the food I eat. I don't want to eat things that taste icky. I want to take time with my food. I want to decrease my typical frantic pace of eating and actually TASTE my food.
Just like a child.


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Bringing color into a living space isn't just about painting the walls. It's also about paying attention to the way the objects in a home relate to one another. A full spectrum of color resides on most bookshelves, but it takes a good eye to make an average shelf into a work of art.
If you're really lucky, you can find a complete set of color-coded books at a thrift store. A few collections that come in a colorful series: Wallpaper's City Guides, many of the old color-coded Penguin books, and World Book Editions. For inspiration, check out the Rainbow of Books Flickr Group.
by Chotda
How to Organize Your Bookshelves By Color
Some argue that the color-coding system isn't the best way to organize books, since it abandons alphabetical or genre ordering. But for visually-oriented people, color cataloging can be easier to use than other systems, as long as you remember a book by its cover.
by Steve Rhodes
by hinke
by dcfox
Title by hey mr glen.


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AARP Travel Center Verified Reviews
Don't miss out on a lower price on this hotel
Get an overview of this hotel3-star hotel with restaurant and seasonal outdoor pool
Popular property highlights
Situated near the airport, this hotel is within 9 mi (15 km) of Hopi House, Grand Canyon Visitor Center, and Grand Canyon National Park. Mather Point and Hopi Point are also within 9 mi (15 km).
Hotel Features
Along with a restaurant, this hotel has coffee/tea in a common area and a seasonal outdoor pool. Free WiFi in public areas and free self parking are also provided. Additionally, laundry facilities, a 24-hour front desk, and a computer station are onsite.
Room Amenities
All 229 rooms offer free WiFi, coffee makers, and flat-screen TVs with satellite channels. Phones, desks, and free toiletries are among the other amenities that guests will find.
Languages Spoken
- English
Red Feather Lodge
Hotel Amenities
Hotel Amenities
The hotel offers a restaurant. A computer station is located on site and wireless Internet access is complimentary. This business-friendly hotel also offers a seasonal outdoor pool, tour/ticket assistance, and a picnic area. Onsite self parking is complimentary.
Red Feather Lodge has designated areas for smoking.
- Safe-deposit box at front desk
- Picnic area
- Bar/lounge
- Coffee/tea in common areas
- Designated smoking areas (fines apply)
- Elevator
- ATM/banking
- Fitness facilities
- Designated smoking areas
- 24-hour front desk
- Laundry facilities
- Express check-out
- Tours/ticket assistance
- Restaurant
- Total number of rooms - 225
- Free self parking
- Number of floors - 3
- Free WiFi
- Number of buildings/towers - 2
- Computer station
- Outdoor seasonal pool
- Free newspapers in lobby
- RV, bus, truck parking
Family Friendly Amenities
- Family Hotel
- Free Wi-Fi
- Laundry facilities
Available in all rooms: Free WiFi
Available in some public areas: Free WiFi
Languages Spoken
- English
- Spanish
Free self parking, RV, bus, truck parking
Room Amenities
- Pay movies
- Air conditioning
- Phone
- Coffee/tea maker
- Daily housekeeping
- Free toiletries
- Hair dryer
- Desk
- Satellite TV service
- Flat-panel TV
- Free WiFi
- Free WiFi (limited) device count
Where to Eat
Red Feather Lodge has a restaurant on site.
Nearby Things to Do
Recreational amenities at the hotel include a seasonal outdoor pool.
If you have requests for specific accessibility needs, please note them in the special requests field on the booking page after selecting your room.
- Accessible bathroom
- Roll-in shower
- Wheelchair accessible parking
- In-room accessibility
- Assistive listening devices available
- Braille or raised signage
- Wheelchair accessible (may have limitations)
Hotel Policies
Check-in time starts at 4:00 PM
Check-in time ends at 5 AM
Minimum check-in age is: 18
Special check-in instructions:
Check-out time is noon
Payment types
Children and extra beds
- Children are welcome.
- Kids stay free! Up to 2 children stay free when using existing bedding.
- Rollaway/extra beds are available for USD 10.0 per day.
- Pets not allowed
You need to know
Extra-person charges may apply and vary depending on property policy.
- Please note that cultural norms and guest policies may differ by country and by property. The policies listed are provided by the property.
Optional extras
- Rollaway bed fee: USD 10.0 per day
Hotel Name
- Red Feather Grand Canyon
- Red Feather Lodge
- Red Feather Lodge Grand Canyon
- Red Feather
- Red Feather Lodge Hotel
- Red Feather Lodge Grand Canyon
- Red Feather Lodge Hotel Grand Canyon