Caffeic acid is phenolic phytochemical belonging to the hydroxycinnamates group. Caffeic acid is a key metabolic intermediate in the synthesis of lignin in plants. As lignin is required by all plants as a structural component, caffeic acid is present to some degree in all plant material. However, some plants bioaccumulate caffeic acid, and therefore higher levels of the compound are found in certain plants. Caffeic acid is main present in plants in its ester form as chlorogenic acid, but lower amounts of the parent compound caffeic acid are found in the human diet. A number of herbs contain reasonable concentrations of caffeic acid include thyme, lemon balm, rosemary, spearmint and sage. Coffee is an important dietary source because coffee consumed in large amounts by some. Caffeic acid, and its derivatives including its ester chlorogenic acid are bioavailable in humans and other animals. Caffeic acid is known to function as an antioxidant in humans, where it may contribute significantly to the antioxidant defences in tissues.
Another way that caffeic acid could improve mood is through regulation of the brain-derived neurotrophic factor (BDNF). When animals and humans are exposed to stress, brain levels of BDNF fall. This decrease in the levels of BDNF is a biomarker for depression and anxiety and many antidepressant drugs may work through elevations in levels of BDNF. Caffeic acid has been shown to elevate depressed levels of BDNF in mice exposed to experimental stress, suggesting that the mood elevating effects of the compound may occur through similar mechanisms to antidepressant drugs. The regulation of BDNF by caffeic acid may occur through a downregulation of the lipoxygenase enzyme. This enzyme is part of the eicosanoid system of metabolising enzymes, and it can synthesise pro-inflammatory leukotrienes that may cause oxidative stress and inflammation in tissues. One of the effects of high levels of leukotrienes may be the downregulation of BDNF. Image is Salvia guaranitica (anise-scented sage or hummingbird sage) Image from : Stan Shebs [GFDL (http://www.gnu.org/ copyleft/ fdl.html), CC BY-SA 3.0 (https://creativecommons.org/ licenses /by-sa/3.0) or CC BY-SA 2.5 (https://creativecommons.org/ licenses / by-sa/2.5)], via Wikimedia Commons.
Caffeic acid is present in a number of plants that are used medicinally for their mood elevating effects including perilla (Perilla Frutescens), Echinacea purpurea and Echinacea angustifolia. For example, studies show that caffeic acid from the herb perilla can significantly decrease the depression experienced by mice exposed to stress. The same group of researchers also investigated the behavioural effects of caffeic acid and found that the behavioural changes exhibited by mice exposed to stress were reversed if the mice were administered caffeic acid, confirming that caffeic acid may have mood elevating effects. The neuropharmacological effects of caffeic acid have been shown to involve the inhibition of damaging hydrogen peroxide-induced oxidative damage in the the brains of rats. Rats exposed to stress exhibited significant improvements in mood from the caffeic acid.
A caffeic acid metabolite extracted from Salvia guaranitica (anise-scented sage or hummingbird sage) has been shown to bind to the benzodiazepine receptor. This suggests that the mood elevating effects of caffeic acid may relate to activation of the GABA system, and the induction of a calming effect through the raising of brain levels of GABA. Evidence for this was provided when researchers demonstrated that similar Salvia guaranitica extracts also produced sedative and hypnotic effects, the types of physiological effects that would be expected from activation of the GABA system. However, some evidence also suggests that caffeic acid may bind to the α1A-adrenoceptor. For example, in one study, administration of caffeic acid significantly reduce the symptoms of anxiety and depression exhibited by mice exposed to fear stress, and these effects were reversed when the mice were also given a drug to block the α1A-adrenoceptor, suggesting that activation of this receptor may have provided the mood elevating effects.
Caffeic acid is present in coffee in high amounts. Caffeic acid has been shown to protect the mammalian brain from damage from metal toxicity. For example, in one study, administration of caffeic acid to mice, significantly inhibited the damage cause by experimental application of aluminium. This damage was likely caused by increased oxidative stress in the brains of the mice. In particular the caffeic acid protected the mice from memory loss, detrimental behavioural changes, oxidative damage to brain tissue and neuronal damage. Therefore caffeic acid may also have a general effect at preventing neuronal damage and dysfunction induced by oxidative stress from aluminium poisoning.
Caffeic acid may also improve memory and this may occur through interaction with the acetylcholine system. For example, rats administered caffeic acid had modified levels of acetylcholinesterase in parts of their brains, In some regions the acetylcholinesterase activity increased, in other areas it decreased. As acetylcholinesterase is responsible for the breakdown of the neurotransmitter acetylcholine, this suggests that caffeic acid may modify levels of acetylcholine differently in various parts of the brain. As acetylcholine is involved in the function of memory, this may explain the memory enhancing effects of the phytochemical. Caffeic acid has also been shown to prevent the chronic fatigue that can develop in experimental animals exposed to high levels of chronic stress such as forced physical activity Caffeic acid can also reverse the anxiety such animals develop as a result of the stress. Caffeic acid may therefore possess a number of neurochemical effects that cause elevations in cognitive function.
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Perilla (Perilla frutescens) is an annual plant that belongs to the Lamiaceae or mint family of plants. Common names for Perilla frutescens include perilla or Korean perilla. Perilla is found growing in parts of Asia including Korea, China and India where it is often cultivated and used for its medicinal properties. One traditional use for perilla is in the treatment of mood disorders such as anxiety and depression. A number of studies have investigated the mood elevating effects of the herb. For example, in one study, the essential oil of perilla was shown to possess a significant antidepressant effect against chronic and unpredictable stress in mice. The stress was shown to reduce levels of serotonin in the brains of the animals and also increased pro-inflammatory markers. However, the essential oil of perilla administered orally, was able to reverse these changes. Perilla essential oils may therefore modulate inflammation and serotonin levels in the brain, and this may produce antidepressant effects.
Perilla (Perilla frutescens) (pictured) confers anti-anxiety effects to mammals. A number of phenolic compounds have been isolated from the leaves of perilla. These include caffeic acid-3-O-glucoside, rosmarinic acid-3-O-glucoside, rosmarinic acid, luteolin, and apigenin. Any of these compounds may explain the mood elevating effects of perilla. In particular, apigenin, rosmarinic acid and caffeic acid have all been shown to possess anxiolytic effects in mammals. Image from: By Dalgial (Own work) [CC BY-SA 3.0 (https://creativecommons.org/ licenses/by-sa/3.0)], via Wikimedia Commons.
The leaves of perilla contain a number of flavonoids from the flavone subclass of compounds. Two of these flavones, apigenin and luteolin, may possess anxiolytic effects. For example, in one study apigenin from perilla leaves was administered to mice who were exposed to stress. The stress induced anxiety in the mice and changed their behaviour, but apigenin significantly reduced the anxious behaviors exhibited by the animals, suggesting a significant anti-anxiety effect for apigenin. In other experiments, luteolin has also been shown to possess mood elevating effects in experiments on animals. Perilla leaves have also been shown to possess a number of terpene compounds. Terpenes have been researched for their anti-anxiety, anti-stress and antidepressant effects. The presence of terpenes in the leaf extracts of perilla could therefore explain the mood elevating effects of the herb. One way that terpenes could exert anti-anxiety effects is through interaction with the cannabinoid receptors CB1 or CB2.
Brain derived neurotrophic factor (BDNF) is a neurotrophin found in the brain of mammals. Brain derived neurotrophic factor is thought to promote neuronal survival, function, repair and plasticity. Decreases in BDNF are thought to be involved in the development of depression, and evidence suggests that some drugs that are used to treat depression are able to normalise levels of BDNF. Studies that have exposed mice to stress have measured BDNF levels and shown it to decline as a result of the stress. However, the essential oil from perilla has been shown to normalise these BDNF levels, and therefore the antidepressant effects of the essential oils observed in the mice may be due to its ability to modulate BDNF. Perilla leaves are often used in cuisine. Here (pictured) is a perilla leaf with some skinned plums.
The anti-anxiety effects of perilla may be due to the presence of hydroxycinnamates such as caffeic acid and its derivatives. Leaves of perilla contain the caffeic acid metabolite rosmarinic acid which has been shown to have anti-anxiety effects. Some studies have shown that only extracts of perilla containing rosmarinic acid are able to exert anti-anxiety effects. The parent compound of rosmarinic acid, caffeic acid, has also been shown to possess anti-anxiety effect, which may contribute to the mood elevating effects of perilla. Neither rosmarinic acid nor caffeic acid appear to cause changes to the monoamine neurotransmitter system, and so they may exert their effects through mechanisms not used by classic antidepressant drugs. Caffeic acid for example may exert its antidepressant effects through normalisation of brain derived neurotrophic factor (BDNF). In another study, the hydroxycinnamate 2,4,5-trimethoxycinnamic acid was shown to significantly reduce anxiety in mice exposed to stress.
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Rosmarinic acid is a phytochemical with important medicinal properties. Rosmarinic acid is an ester derivative of the hydroxycinnamic acid, caffeic acid. Rosmarinic acid is found in a large number of herbs and spices including rosemary (Rosmarinus officinalis), basil (Ocimum basilicum), lemon balm (Melissa officinalis), sage (Salvia officinalis), thyme (Thymus vulgaris), borage (Heliotropium foertherianum), Koren perilla (Perilla frutescens) and peppermint (Mentha piperita). Rosmarinic acid may explain the anxiolytic effects of some of these and other herbs. Rosmarinic acid is thought to exert its anxiolytic effects is through the GABA neurotransmitter system. In particular rosmarinic acid may increase levels of GABA in the brain, through inhibition of the metabolising enzyme 4-aminobutyrate transaminase. As GABA levels rise, a feeling of calmness ensues. Rosmarinic acid may also inhibit the indoleamine 2,3-dioxygenase enzyme, and in doing so may modulate the immune system and the inflammatory response.
The mood elevating effects of rosmarinic acid have been investigated in a number of studies. For example, in one study, the neurochemical effects of rosmarinic acid were investigated in mice exposed to stressful conditions. Rosmarinic acid and its parent compound caffeic acid, both exerted significant antidepressant effects in the mice. The researchers noted that neither compound was able to alter the metabolism of monoamine neurotransmitters in mice brains, indicating that the antidepressant effect was via a different route. In another similar study, experimental stress was again induced in mice to cause behavioural changes. The behavioural changes were reversed, and there was a significant anti-stress effect exerted by both caffeic acid and rosmarinic acid. In another study, the anxiolytic effects of the herb Korean perilla (Perilla frutescens) were investigated using a number of different extracts,. However, only those herb extracts containing rosmarinic acid possessed the anxiolytic effects.
Rosmarinic acid has also been shown to be effective at ameliorating more severe forms of anxiety such as post-traumatic stress disorder. For example, in one study, rats were exposed to a stressful environment in order to experimentally induce post-traumatic stress disorder. The symptoms exhibited by the rats were however alleviated with coadministration of rosmarinic acid. Rats exposed to chronic stress have also been shown to have reductions in depression-like symptoms with coadministration of rosmarinic acid. In both of these studies, it was shown that rosmarinic acid improved extracellular-regulated kinase (ERK) signalling, something which often becomes inhibited in depression. The antidepressant drug venlafaxine is through to work primarily by increasing ERK expression. Rosmarinic acid may therefore share this mechanism of action.
Evidence from animal studies suggests that even at low doses, rosmarinic acid is effective at reducing anxiety. Incorporating a range of rosmarinic acid containing herbs into the diet should therefore be an effective strategy to elevate mood. Some evidence also suggests that rosmarinic acid have some cognitive enhancing effects. For example, in one study rosmarinic acid was shown to increase the cognition of rats undergoing an experimental learning test. The authors of the study also demonstrated that rosmarinic acid was able to inhibit the protease enzyme propyl oligopeptide. Propyl oligopeptide is able to cleave a number of proteins in the brain of mammals including arginine-vasopressin, substance P, oxytocin and angiotensin IV. These peptides are thought to be involved in memory formation, and by cleaving them propyl oligopeptide may inhibit memory formation. Rosmarinic acid may improve the formation of memories by inhibiting propyl oligopeptide and thus raise brain levels of the memory forming peptide.
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It has been known since the 1920’s that ketogenic diets have beneficial effects on patients who have seizures. Epilepsy, particularly in children, responds well to a ketogenic diet. It is unclear why ketosis is beneficial at reducing the frequency of seizures, but it is known that levels of ketones (acetoacetate and β-hydroxybutyrate) are elevated during ketosis, and these ketones can have neuroprotective effects. Another possible benefit from ketogenic diets is their ability to lower blood glucose and blood insulin levels. Insulin plays a central role in memory through the regulation of pro-inflammatory cytokines in the brain. As blood levels of insulin rise, insulin in the central nervous system can become reduced and this may negatively affect memory. Lowering blood insulin levels concomitantly raises levels of insulin in the central nervous system, returning metabolic regulation to normal, and improving cognition. Therefore the blood insulin lowering and ketone raising effect of ketogenic diets may benefit cognition.
Ketogenic diets may have memory enhancing effects. Eating lower carbohydrate foods such as fish, meat and eggs may therefore provide significant health benefits with regard cognition.
A number of studies have investigated the effects of ketogenic diet on cognition and memory. For example, in one study, researchers randomly assigned 23 elderly individuals with mild cognitive impairment to receive either a high carbohydrate diet or a low carbohydrate diet for 6 weeks. Those subjects following the low carbohydrate diet had significant improvement in verbal memory. This improvement in memory was accompanied by reductions in weight, waist circumference, fasting glucose levels and fasting insulin levels. There was a tend for a correlation between the lowering of insulin levels and the improvements in memory seen in the subjects, suggesting that the lower blood insulin levels may have played a role in the improvements in memory. However, ketone body levels in the blood were strongly associated with improvements in memory. This supports evidence that suggests that ketogenic diets have beneficial effects on memory in human subjects mainly because of increased krone synthesis.
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Arjuna (Terminalia arjuna) is a tree that belongs to the Combretaceae family of plants. Arjuna is usually found growing along river beds and can reach heights of around 25 meters. Arjuna is native to Asian countries including Bangladesh and India and historically, the bark from the tree has been used as part of the traditional Ayurvedic Medicine system in India. The main use for arjuna is as a cardioprotective tonic, whereby it is administered as a decoction. Evidence from scientific studies suggest that decoctions of the bark improve left ventricular function, corroborating the anecdotal evidence from traditional ayurvedic medicine. Arjuna also appears to have some anticancer effects in cell culture studies. The health effects of arjuna may relate to its antioxidant capacity, which has been measured and shown to be substantial, providing similar levels of free radical scavenging as vitamin C in comparison trials. The antioxidant effects of arjuna may also explain the hepatoprotective effects that it shows.
Extracts of arjuna (Terminalia arjuna) have been shown to confer protection from liver damaging chemicals. This effect is likely due to the antioxidant effects of the herb. For example, treatment of rats with adrenaline to induce liver damage, causes elevations in a number of liver enzymes as oxidative stress depletes antioxidants in the liver. Administration of arjuna however, increases antioxidant levels in the liver, notable of glutathione peroxidase and superoxide dismutase. The improvement in antioxidant status of the liver in turn then reduces oxidative stress. As a result the elevated liver enzyme levels return to normal, and damage to the liver tissue is prevented. Image is of a arjuna tree. Image from: By Liné1 (Picture taken with my Panasonic TZ3) [GFDL (http://www.gnu.org /copyleft/fdl.html) or CC BY-SA 3.0 (https://creativecommons.org/ licenses/by-sa/3.0)], via Wikimedia Commons.
For example, in one study, and extract of arjuna was used to treat mice that had been exposed to sodium fluoride in order to induce oxidative stress in their livers. Addition of sodium fluoride significantly reduced the antioxidant defences of the mice including superoxide dismutase, catalase and glutathione peroxidase. However the addition of the arjuna extract normalised these enzymes and reduced oxidative stress. The authors suggested that the hepatoprotective effects of the arjuna extract was likely as a direct result of its antioxidative effects. In another study, researcher induced oxidative stress on the livers of rats by administering alcohol. The alcohol induce oxidative stress caused elevations in blood levels of a number of liver enzymes, in nitric oxide levels and in lipid peroxidation rates, indicating that liver tissue was undergoing oxidative stress. However, extracts of arjuna were able to normalise these values and improve the antioxidant status of the rats, suggesting a significant hepatoprotective effect for the herb.
Carbon tetrachloride is a liver poison that is able to cause significant damage to liver tissue in mammals following a single dose. This damage occurs because of a depletion of antioxidants. This depletion occurs because the cytochrome P450 enzyme system converts carbon tetrachloride into the highly reactive trichloromethyl peroxide radical, and this then bonds to the sulfhydryl group of antioxidant molecules such as glutathione, thus reducing the capacity of the antioxidant defences of the liver. Arjuna extract is able to protect rats from carbon tetrachloride induced liver dysfunction because it supplies additional exogenous antioxidants that can substitute for the endogenous antioxidants that have been inhibited. In rats arjuna extracts have been shown to reduce the hepatotoxicity associated with a single dose of carbon tetrachloride. Evidence suggests that the antioxidant effect of arjuna extracts come in part from the presence of phenolic acids and flavonoids. Image is of arjuna fruit. Image from: By J.M.Garg (Own work) [GFDL (http://www.gnu.org /copyleft/fdl.html) or CC BY-SA 3.0 (https://creativecommons.org/ licenses/by-sa/3.0)], via Wikimedia Commons.
In another study, an extract of arjuna was administered to a group of rats who has also been administered the liver poison carbon tetrachloride. The administration of arjuna significantly increased liver concentrations of glutathione peroxidase, superoxide dismutase, significantly inhibited lipid peroxidation, and significantly reduced elevated blood levels of liver enzymes, uric acid and creatinine. Pretreatment with arjuna inhibited the inflammation, liver necrosis and degeneration associated with carbon tetrachloride administration. In a similar study, rats were exposed to isoniazid to induce liver toxicity, and this resulted in significant elevations of liver enzymes while also depleting antioxidant including glutathione and superoxide dismutase. Coadministration of arjuna extract significantly reduced the elevated levels of liver enzyme and significantly increased glutathione peroxidase and superoxide dismutase liver enzyme values. The hepatoprotective effects of the herb were therefore likely due to its antioxidant effects.
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Jiaogulan (Gynostemma pentaphyllum) is a member of the gourd or Cucurbitaceae family of plants that also contains squash, cucumbers, melons, pumpkin and zucchini. Jiaogulan is native to parts of East Asia including Vietnam, Korea, China and Japan. The plant is a creeping climbing vine, which is characterised by serrated leaves and a purple gourd (inedible fruit). Jiaogulan is used in traditional Chinese medicine for its adaptogenic properties, and in this respect can be thought of as similar in effect to other adaptogenic herbs including Panax ginseng, Withania (ashwagandha), mimosa, sour date, rhodiola, Siberian ginseng, brahmi, and gotu kola. Some of the health effects of jiaogulan include general antioxidant and anti-stress effects, which are common to most adaptogens. Studies also indicate that Jiaogulan has blood pressure normalising, cardioprotective, cholesterol normalising, and anti-diabetic effects. As with other adaptogenic herbs, jiaogulan may also have particular anti-anxiety and antidepressant effects. These effects may relate to the triterpene saponins and flavonoids contained within the plant.
For example, in one study mice were exposed to a number of forms of experimental stress. The stress caused significant changes in the behaviour of the mice, but these changes were reversed in a group of mice who were administered jiaogulan extract for 14 days. In addition, the stress caused a reduction in the dopamine and serotonin levels in the brains of the mice, and again these effects were reversed in a group of mice who were administered jiaogulan extract for 14 days. The authors observed that jiaogulan extract was able to significantly reduce the cortisol levels in the animals. Jiaogulan extract was also able to reduce elevated levels of a protein called c-fos in the brains of the mice. Elevated levels of c-fos are associated with poor cellular and health outcomes. Therefore the beneficial mood elevating effects of jiaogulan may derive from a general effect that lowers the response to stress. This normalisation of stress may then lead to normalisation of disrupted neurotransmitter levels, including dopamine and serotonin.
Jiaogulan is used as a herbal tea in China in order to combat general stress. The active phytochemicals in jiaogulan are thought to be a group of triterpene saponins called gypenosides. These include a large number of structurally similar terpene derivatives including gynosaponin TN-1, gynosaponin TN-2, gypenoside XLV, and gypenoside LXXIV. Eight of the terpene saponins in jiaogulan are the same as the panaxadiol-type of terpene saponins in Panax ginseng. This similarity in structure for some of the terpene saponins may explain the similarity in effects between jiaogulan and ginseng extracts. Jiaogulan may also contain a number of other phytochemicals including flavonoids. A number of flavonoid subclasses including flavones and flavonols have been shown to possess mood elevating effects in humans and animals. Jioagulin is known to contain the flavonol ombuin, the flavonol glycoside ombuoside, the flavonol glycoside gynopentaphylloside and the flavone glycoside vitexin. In addition, vitamins, minerals and amino acids are also present in extracts of jiaogulan. Isolated gypenosides from jiaogulan have been shown to have significant anti-stress effects in mice. The anti-stress effects of jiaogulan extracts can lower cortisol levels, and normalise levels of dopamine and serotonin. This may explain the mood elevating effects of the herb. Image (jioagulan) from: By bauty (Own work) [CC BY 2.0 de (http://creativecommons.org/licenses/by/2.0/de/deed.en)], via Wikimedia Commons.
In another study, researchers exposed experimental mice to chronic stress which increased their anxiety levels. This reduced their grip strength, the amount of movement they exhibited and increased levels of the stress hormone cortisol. However administration of jiaogulan extract significantly reduced these negative effects in the mice. Experimental evidence also suggests that jiaogulan can protect from neurotoxicity and against experimentally induced Parkinson’s disease. For example, in one study study, jiaogulan extract was shown to be protective of neurotoxicity and to normalise dopamine levels in rats. A similar study also showed that jiaogulan extract was shown to have similar neuroprotective effects in mice. In another study, jiaogulan significantly reduce the anxiety experienced by mice exposed to chronic stress and protected dopamine containing neurones from degeneration. In a further study, dopamine containing neurones were protected from stress induced cell death by administration of jiaogulan extract in rats.
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