Sanjivni Amrit Regimen — How it work ? and the Dead have a tale to tell…..
By Prithu Nath
Role of Herbs and Spice Antioxidants
An alternative to using only supplements such as vitamin C, D and Zinc etc., a much more effective and more likely effective antioxidant strategy for protection against oxidative stress and related diseases caused by a reaction by the Immune system to Covid 19 would be to add the potential beneficial effects of antioxidant-rich foods, since such foods typically contain a large combination of different antioxidants that are selected, through plant evolution, to protect every part of the plant cells against oxidative damage Plus Ancient Indian herbs and spices that are both Anti Oxidants but also protect us from Free Radicals and are thereupatic thereby assisting the Immune system by Providing support and by reducing inflamation and help in killing of the invading pathogens.
Oxidative stress is the result of an imbalance between oxidant production and antioxidant mechanisms that leads to oxidative damage, including lipid peroxidation and DNA oxidation. In addition to the neutrophil infiltration and release of reactive oxygen species (ROS), viral infections are associated with a decrease in antioxidant defences.
Based on the complex nature of antioxidants and ROS, it would thus be extremely unlikely that a magic bullet with a high dose of one or a few particular antioxidants such as vitamin C, vitamin E, or β-carotene would protect all parts of the cells, organs, and tissues against oxidative damage and oxidative stress, at the same time without destroying any of the numerous normal and beneficial functions of ROS. A number of dietary antioxidants exist in herbal sources that are collectively known as phyto-antioxidants. Many plants consumed either as regular diet or as medicinal herbs reasons contain phyto-antioxidants. Many plants contain large amounts of polyphenols that can play an important role in adsorbing and neutralizing free radicals, quenching singlet and triplet oxygen, and decomposing peroxides. The majority of the antioxidant compounds belong to the family of flavonoids, lignans, and catechins. Due to the inefficiency of the endogenous defense system, in some physiopathological situations, increasing the amounts of dietary antioxidants is useful to diminish the cumulative effects of oxidative damage (Sun et al., 2002). In addition to the above compounds found in natural foods, vitamin C, vitamin E, carotene, and tocopherol, found in dietary sources are known to possess significant antioxidant potential (Cai et al., 2004; Tsao and Akhtar, 2005).
Sanjivni Amrit Regime Balances ROS with Herbal Anti-oxidants and Food
Sanjivni Amrit Regime uses close to 45 different herbs together with food and other supplements to collectively combat Free Radicals generated due to the Immune response to Covid 19 and helps to balance the resulting ROS and Inflamation and at the same time provides thereupatic benefits for healing using Herbs that collectively and Wholistically work.
All modern allopathic medications can be used in conjuntion with Sanjivni Amrit Regimen.
The Dead have Left some Clues
The high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS), which promote a cascade of biological events that drive pathological host responses. ROS induce tissue damage, thrombosis and red blood cell dysfunction, which contribute to COVID-19 disease severity. We suggest that free radical scavengers could be beneficial for the most vulnerable patients.
COVID-19 is caused by the betacoronavirus SARS-CoV-2 and has several unique features compared with other coronavirus infections. In the most vulnerable individuals (for example, older, obese or diabetic individuals), the virus sometimes triggers a cascade of acute biological events that can, unfortunately, lead to patients being ventilated and even dying. A far from negligible number of patients require intensive care, and although most hospital stays are short in duration, this places a huge strain on health systems. It is therefore urgent to gain an in-depth understanding of the critical activators of disease severity in order to reduce mortality and hospitalization rates.
The high neutrophil to lymphocyte ratio reported in critically ill patients with COVID-19 has been found to predict in-hospital mortality1. Lung autopsies of deceased patients have revealed neutrophil infiltration in pulmonary capillaries, their extravasation into the alveolar spaces and neutrophilic mucositis2. Increased levels of circulating neutrophil extracellular traps (NETs), which are indicative of neutrophil activation, have also been described in patients3. Oxidative stress is the result of an imbalance between oxidant production and antioxidant mechanisms that leads to oxidative damage, including lipid peroxidation and DNA oxidation. In addition to the neutrophil infiltration and release of reactive oxygen species (ROS), viral infections are associated with a decrease in antioxidant defences. Exposure to pro-oxidants usually leads to nuclear translocation of the master redox-sensitive transcription factor NRF2, which activates antioxidant defences; however, respiratory viral infections have been associated with inhibition of NRF2-mediated pathways and NF-κB signalling activation, which can promote inflammation and oxidative damage during these infections4. Furthermore, there is evidence of a link between decreased expression of the antioxidant enzyme superoxide dismutase 3 (SOD3) in the lungs of elderly patients with COVID-19 and disease severity5. Interestingly, children — whose neutrophils are less reactive and adherent, with no alteration of redox balance — are less prone to developing severe forms of COVID-19. The cascade of events triggered by the oxidative stress state in SARS-CoV-2 infection undoubtedly contributes to the severity of host disease and needs to be further explored.
We postulate that, particularly in vulnerable individuals, neutrophilia generates an excess of ROS that exacerbates the host immunopathological response, resulting in more severe disease (Fig. 1). The deleterious action of ROS on the functions of both pulmonary cells and red blood cells (RBCs) can be seen as a major contributor to the hypoxic respiratory failure observed in the most severe cases of COVID-19. Thus, in addition to its damaging effects on alveolar epithelial and endothelial cells with pro-coagulative endotheliitis6, an excess of ROS can also affect the RBC membrane and haeme group functionality.
a | In not at-risk individuals, an excess of reactive oxygen species (ROS) is counterbalanced by an increase in antioxidant defences. b | In subjects with impaired redox balance, ROS production is not properly controlled, leading to red blood cell (RBC) membrane peroxidation, which in turn perpetuates neutrophil activation. Excessive oxidative stress might be responsible for the alveolar damage, thrombosis and RBC dysregulation seen in COVID-19. Anti-oxidants and elastase inhibitors may have therapeutic potential.
Neutrophils usually initiate aggressive responses upon encountering danger signals, which leads to their rapid migration to the targeted tissue, release of NETs, and their production and release of ROS in an oxidative burst. It had been assumed that neutrophil migration from the vascular lumen into extravascular tissues is unidirectional, but recent studies have demonstrated that neutrophils can migrate back into the bloodstream, in a process referred to as neutrophil reverse transendothelial migration (rTEM)7. rTEM neutrophils are relatively rigid cells, and this physical characteristic may delay their passage through the tissue’s microvasculature and prolong contact with the sinusoids. They may become mechanically entrapped in the microvasculature of major organs, thus contributing to distant organ damage and multiorgan failure. By producing excessive ROS, deregulated neutrophils can spread a local inflammatory response so that it becomes systemic, which explains why they have been involved in whole-body processes such as atherosclerosis and thrombosis8. Improper activation of neutrophils is also a potential explanation for the diffuse microvascular thrombosis and capillary leak syndrome observed in critically ill patients with COVID-19 (ref.9). In addition, excessive ROS production may affect membrane lipids, integrins and cytoplasmic proteins in various circulating cells. These effects are particularly critical for RBCs, which may become dysfunctional. First, excess ROS can cause oxidation of polyunsaturated fatty acids in the RBC membrane, bringing about a profound modification of the membrane lipids’ lateral and transversal distribution and organization at the nanoscale level. This results in biophysical and biomechanical changes in the RBC membrane that affect both the diffusion of oxygen and carbon dioxide and the deformability capability of RBCs in the capillary vessels, thereby favouring thrombosis. Reactivation of neutrophils in response to modification of the RBC membrane further fuels this vicious circle. In addition, this modification affects the release of ATP and nitric oxide, both necessary for adequate oxygen transport and vasodilatation between metabolizing tissues and respiratory surfaces. Second, ROS excess may upset the Fe2+/Fe3+ balance and disturb iron homeostasis for which iron must be kept in the Fe2+ state to bind oxygen. The protonation of superoxide ion associated to Fe3+ within the haemoglobin haeme keeps the iron in its higher oxidation state and incapable of binding oxygen, resulting in less efficient oxygen transport despite a high oxygen supply.
In conclusion, the presence of oxidative stress markers (for example, lipid peroxidation, rTEM and a high neutrophil to lymphocyte ratio) in patients with COVID-19 may help to identify high-risk individuals early in the course of the disease and prevent their sudden deterioration. This approach may also pave the way to new therapeutic approaches. We propose that antioxidants such as N-acetyl-L-cysteine in combination with elastase inhibitors (for instance, sivelestat)10 could be used to target rTEM neutrophils in patients with severe COVID-19.
https://www.nature.com/articles/s41577-020-0407-1
Reactive oxygen species
Reactive oxygen species (ROS) is a term that describes oxygen-derived free radical and non-radical species. While many ROS are produced via aerobic respiration and normal metabolic processes, ROS accumulation due to certain diseases-like covid-19 or diabetes-can lead to oxidative stress. This oxidative stress can damage cells and lead to other diseases, like cardiovascular disease. Hyperglycemia, a common symptom of type 2 diabetes, can cause ROS accumulation, particularly when the body has minimal antioxidant protection. Accumulation of ROS is a driving factor behind endothelial dysfunction in diabetes and hyperglycemia.
Based on the complex nature of antioxidants and ROS, it would thus be extremely unlikely that a magic bullet with a high dose of one or a few particular antioxidants such as vitamin C, vitamin E, or β-carotene would protect all parts of the cells, organs, and tissues against oxidative damage and oxidative stress, at the same time without destroying any of the numerous normal and beneficial functions of ROS. Indeed, supplementation with antioxidants has often resulted in no effect or even adverse disease outcomes. Recently, several reviews and meta-analyses have concluded that there is now a strong body of evidence indicating that there is no beneficial effect for supplemental vitamin C, vitamin E, or β-carotene (Vivekananthan et al. 2003; Eidelman et al. 2004; Bjelakovic et al. 2007; Bjelakovic et al. 2008). An alternative and much more likely antioxidant strategy to test protection against oxidative stress and related diseases would be to test the potential beneficial effects of antioxidant-rich foods, since such foods typically contain a large combination of different antioxidants that are selected, through plant evolution, to protect every part of the plant cells against oxidative damage. This is especially relevant for herbs and spices.
https://www.ncbi.nlm.nih.gov/books/NBK92763/
A number of dietary antioxidants exist in herbal sources that are collectively known as phyto-antioxidants. Many plants consumed either as regular diet or as medicinal herbs reasons contain phyto-antioxidants. Various epidemiological studies have demonstrated the beneficial effects of high intake of fruits and vegetables in combating oxidative damage and other aging related problems (Eastwood, 1999). It is not obvious that whether this effect is achieved due to passive antioxidants or by boosting bodily antioxidant responses.
Many plants contain large amounts of polyphenols that can play an important role in adsorbing and neutralizing free radicals, quenching singlet and triplet oxygen, and decomposing peroxides. The majority of the antioxidant compounds belong to the family of flavonoids, lignans, and catechins. Due to the inefficiency of the endogenous defense system, in some physiopathological situations, increasing the amounts of dietary antioxidants is useful to diminish the cumulative effects of oxidative damage (Sun et al., 2002). In addition to the above compounds found in natural foods, vitamin C, vitamin E, carotene, and tocopherol, found in dietary sources are known to possess significant antioxidant potential (Cai et al., 2004; Tsao and Akhtar, 2005). While consumption of fruits and raw vegetables has been found to be very beneficial, passive antioxidant therapies have largely yielded mixed results, with some studies also showing significant negative impact on human health (Bjelakovic et al., 2004). This negative effect could be due to the global down-regulation of ROS pathways that are required for our immune system, many intracellular signaling pathways and the maintenance of hormesis effect that might be crucial in maintaining the intrinsic antioxidant response of our bodies in balance (Poljsak, 2011). Additional problems can include poor bioavailability of many passive antioxidants (Siow and Mann, 2010; Patel et al., 2011; Wallace, 2011). Given these problems with passive dietary antioxidants two possible approaches are likely going to be fruitful: regulation of ROS production and selective stimulation of specific intrinsic antioxidant pathways. In recent years NADPH oxidases have been targeted for their therapeutic potential in regulation of ROS production (Drummond et al., 2011). In this review we will focus on the stimulation of bodily enzymatic antioxidant pathways but it is also possible that the plant sources that we discuss may in future be found to even help regulate the production of ROS and not just have antioxidant responses.
Ayurvedic Plants with Potential of Providing Novel Antioxidant Stimulants
In the following text, we mention plants used in Indian pharmacopeia with their scientific name but we also provide English and Hindi names in parenthesis. Names in parenthesis, before the semi-colon are the English names and ones after, are the Hindi ones. Apart from the strictly dietary sources, many medicinal plants also provide antioxidants. Some such plants fall in both dietary and medicinal groups as they are used for both purposes. Few examples of plants used for both dietary and medicinal use that are rich in antioxidant effects are as follows: Allium cepa (onion; pyaaz), A. sativum (garlic; lahsuna), Aloe vera (Indian aloe, true aloe, medicinal aloe, Chinese aloe; ghritkumari), Camellia sinensis (green tea; chai), Cinnamomum verum (cinnamon; dal chini), C. tamala (Malabar leaf; tejpat), Curcuma longa (turmeric; haridra, haldar, haldi), Emblica officinalis (Indian gooseberry; amlaki), Glycyrrhiza glabra (liquorice; yashtimadhu, mulethi), Ocimum sanctum (holy basil; tulsi), Terminalia bellerica (beleric, bastard myrobalank; behda), Tinospora cordifolia (heart-leaved moonseed; guduchi), Trigonella foenum-graecum (fenugreek; methi), and Zingiber officinalis (ginger; adarak).
Apart from these dietary plants with medicinal value, ayurveda details strict medicinal plants that show strong antioxidant activities. “Rasayan Chikitsa” (Rasa = vital + Ayana = nourishment; chikitsa = treatment) is an important branch of ayurveda that deals with revitalization and rejuvenation in a holistic manner to slow aging and also to cure certain diseases. Sharangdhar in sixteenth century AD described Rasayanas as “Jaravyadhi Vinasanam” which literal means checking the advancement of age (Jara = age) as well as destroyer (Vinasanam = destruction) of disease (Vyadhi = disease; Rastogi, 2010). The modern scientific evaluation of some of the major Vayahsthapan (anti-aging) rasayanas and Jeevaniya (life-promoting) rasayanas shows that most of these anti-aging drugs have antioxidant properties, besides several other pharmacological actions (Rastogi et al., 1998; Anekonda and Reddy, 2005). Many passive antioxidants are already extracted and commercialized from dietary sources in addition to the synthetic compounds (Shahidi, 1997), so we have not cataloged over hundreds of plants that are generally rich in phyto-antioxidants. The examples we discuss are either known to have or have a good chance to have compounds that stimulate intrinsic antioxidant machinery of the human body. These plants also happen to have passive antioxidant compounds in large quantities that we mention in chemical constituents. The ultimate goal of this review is to emphasize the need of curing oxidative damage related problems by stimulating the intrinsic antioxidant machinery of the body, instead of just treating the symptoms using passive dietary antioxidants. Following are some select Auyrvedic plants with description of their sources, traditional uses, modern verification of some of their uses, and their antioxidant potential. A summary of these plants is presented in Table Table11.
Table 1
Plants with known or likely antioxidant stimulating effects.
| Plant | Antioxidant responses | Active antioxidant effects and known or putative compounds |
|---|---|---|
| Withania somnifera | Active stimulation and passive antioxidants | Stimulation due to sitoindosides VII–X and withaferin A (glycowithanolides; Bhattacharya et al., 1997; Vimal et al., 2010) |
| Centella asiatica | Active stimulation and passive antioxidants | Enhances glutathione levels, thiols, and antioxidant defenses (Shinomol and Muralidhara, 2008; Shinomol et al., 2010). Antioxidant in three pathways: superoxide free-radical activity inhibition of linoleic acid peroxidation and 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging activity (Vimala et al., 2003; Pittella et al., 2009). Reduces monamine levels that can spontaneously auto-oxidize to free radicals (Bindoli et al., 1992). Exact compounds remain to be identified |
| Asparagus racemosus | Active stimulation and passive antioxidants | Prevents decline in GPX activity and reduction in glutathione (GSH) content and reduces membrane lipid peroxidation and protein carbonyl content (Parihar and Hemnani, 2004). Compensates reduction in the superoxide dismutase, catalase, ascorbic acid, and lactate dehydrogenase levels and lowers the heightened MDA levels (Vimal et al., 2010). Exact compounds remain to be identified |
| Acorus calamus | Active stimulation and passive antioxidants | Decrease GSH and GST and increase dopamine receptors (Shukla et al., 2002). Increases the activities of major enzymes of the antioxidant defense system, especially SOD, CAT, and GPX and the levels of GSH and decrease in the formation of MDA (Sandeep and Nair, 2010). Exact compounds remain to be identified |
| Bacopa monnieri | Active stimulation and passive antioxidants | Bacopa monnieri extracts modulate the expression of certain enzymes involved in the generation and the scavenging of reactive oxygen species in the brain (Govindarajan et al., 2005). Exact compounds remain to be identified |
| Celastrus peniculatus | Active stimulation and passive antioxidants | Causes significant decrease in the brain levels of MDA and increases in levels of glutathione and catalase (Kumar and Gupta, 2002). Superoxide dismutase activity is unaffected by extracts but catalase activity is increased and MDA levels are reduced (Godkar et al., 2006). Exact compounds remain to be identified |
| Convulvulus pleuricaulis | Known passive antioxidants only | Given the antioxidant effects it is likely that there is likely stimulation of active antioxidant responses too that yet remains to be characterized |
| Curcuma longa | Known passive antioxidants only | Given the antioxidant effects it is likely that there is likely stimulation of active antioxidant responses too that yet remains to be characterized |
Withania somnifera (dunal; aswagandha, asgandhi, asoda, and amukkira)
Geographical distribution and ethnomedical description
Withania somnifera shrub that grows wild in India, is widely distributed across Africa, Europe, and Asia. It is commonly referred to as Ashwagandha (Ashwa = horse + Gandha = smell) in Sanskrit and Hindi because of its smell. In ayurveda, W. somnifera herbal remedy consists of the use of dried roots and stem bases of the plant. In traditional system it is used as anti-inflammatory and antitumor agent, immunity booster, and aphrodisiac for both men and women, though many of these effects have yet to be evaluated by modern means.
Chemical constituents
The chemistry of W. somnifera has been extensively studied and over 35 chemical constituents have been identified, extracted, and isolated (Rastogi et al., 1998). The biologically active chemical constituents are alkaloids (isopelletierine, anaferine), steroidal lactones (withanolides, withaferins), saponins containing an additional acyl group (sitoindoside VII and VIII), and withanolides with a glucose at carbon 27 (sitoindoside IX and X; Rastogi et al., 1998).
Active antioxidant and other roles
Animal stress studies have investigated the use of this herb as an antistress agent (Dadkar et al., 1987; Dhuley, 1998; Archana and Namasivayam, 1999), therapeutic in depression (Ramanathan et al., 2003) and explored its antioxidant properties (Panda and Kar, 1997). The active principles of W. somnifera – sitoindosides VII–X and withaferin A (glycowithanolides), have been tested for their antioxidant stimulant activity by measuring the levels of major free-radical scavenging enzymes, such as SOD, CAT, and glutathione peroxidase (GPX) levels in the rat brain frontal cortex and striatum (Vimal et al., 2010). Active glycowithanolides of W. somnifera show a dose dependent increase in activity of all these enzymes, to a level similar to seen with intraperitoneal administration of deprenyl, a known antioxidant (Bhattacharya et al., 1997). While, such strong active antioxidant effects have been reported, the exact active ingredients responsible for this stimulation of the innate antioxidant machinery remain to be identified (Bhattacharya et al., 1997). While large doses of ashwagandha may possess abortifacient properties and it can act as a mild central nervous system (CNS) depressant, in most cases ashwagandha appears to be very safe, with an LD50 of a 50% alcohol extract determined to be 1 g/kg in rats (Aphale et al., 1998; Williamson, 2002). Caution should be used with patients on anticonvulsants, barbiturates, and benzodiazepines due to its GABA-nergic and sedative properties (Mehta et al., 1991; Kulkarni et al., 2008; Bhattarai et al., 2010).
Centella asiatica (Linn.) urban (Indian pennywort; brahmi, manduka parani, mandooki, divya, bhekaparni)
Geographical distribution and ethnomedical description
Centella asiatica is a small creeping herbaceous plant found in damp, shady places throughout the tropical regions of the world. C. asiatica finds mention in Shsruta samhita and is an important component of the Indian pharmacopeia (Nadkarni, 1910). In ayurveda, C. asiatica parts are considered useful in the diseases of skin, nervous system, and blood. The leaves are the only recognized part in traditional pharmacopeia of India, but many modern investigators have advocated the use of entire plant, root, twigs, leaves, and seeds in medicine (Hamid et al., 2002; Sudarshan, 2005).
Chemical constituents
Centella contains high concentration of metal ions potassium, calcium, phosphorus, iron, and sodium. It is low in protein, carbohydrate, fat, and crude fibers but rich in vitamin C, B1, B2, niacin, carotene, and vitamin A (Tee et al., 1997). The biologically active components of Centella plant are believed to be triterpenes and saponins (Loiseau and Mercier, 2000). The triterpenes of Centella are composed of many compounds including asiatic acid, madecassic acid, asiaticosside, madecassoside, brahmoside, brahmic acid, brahminoside, thankiniside, isothankunisode, centelloside, madasiatic acid, centic acid, and cenellic acid (Zheng and Qin, 2007). Among these triterpenes, the most important biologically active compounds are the asiatic acid and madecassic acid (Inamdar et al., 1996). C. asiatica contains triterpene glycosides such as centellasaponin, asiaticoside, madecassoside, and sceffoleoside (Matsuda et al., 2001). The content of Centella’s triterpene components can be affected by the location and diverse environmental conditions (James and Dubery, 2009). Centella also contains high total phenolic contents in the form of flavonoids such as quercetin, kaempherol, catechin, rutin, apigenin, and naringin and volatile oils such as caryophyllene, farnesol, and elemene (Qin et al., 1998).
Active antioxidant and other roles
Preliminary modern studies have demonstrated some beneficial effects in neuronal function, ulcers, liver functions, and immune responses (Warrier et al., 1996; Dash and Jounious, 1997; Frawley and Lad, 2004). Centella impedes brain aging and improves attention problems (Singh et al., 2008). Besides this, Centella is also reported to be useful in improving learning scores in young mice (Rao et al., 2005), providing protection against neurodegeneration (Ramanathan et al., 2007), neuroprotection against oxidative stress in the brain of prepubertal mice, enhancing glutathione levels, thiols, and antioxidant defenses (Shinomol and Muralidhara, 2008; Shinomol et al., 2010). C. asiatica extracts can influence the morphology of hippocampal CA3 and amygdalar neuronal dendritic arborization in neonatal rats (Rao et al., 2006, 2009) and can have anxiolytic effect in animals comparable to diazepam (Chen et al., 2006). Patients of anxiety necrosis showed reduced anxiety levels and showed improvement in the mental fatigue rate and immediate memory after a C. asiatica regimen (Bradwejn et al., 2000; Jana et al., 2010) and Centella attenuates d-galactose-induced behavioral, biochemical, and mitochondrial dysfunction by involving antioxidant and mitochondrial pathways in the senescent mice (Kumar et al., 2011). Brahminoside exhibits a CNS-depressant effect in mice and rats (Ramaswamy et al., 1970). In an old clinical study, C. asiatica regimen showed improvement in mental health of mentally challenged children (Rao and Rao, 1973). Whether these effects are predominantly due to active antioxidant stimulation, passive antioxidants, or other mechanisms is not fully known. C. asiatica extracts have been reported to increase brain GABA levels (Chatterjee et al., 1992), suggesting neuromodulation to also underlie some of its neuroactive actions. Beside the triterpenes, the antioxidant protection effect of Centella is likely contributed by its passive antioxidants in the form of enriched flavonoids and selenium content (Ponnusamy et al., 2008). Among the triterpenes isolated from Centella plant, asiaticoside is the most abundant and responsible for stimulating the antioxidant activity in the early phase of the wound healing process (Shukla et al., 1999). In vitro studies have found high antioxidant activity of leaves of Centella in three pathways: superoxide free-radical activity (86.4%), inhibition of linoleic acid peroxidation (98.2%), and 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging activity (92.7%; Vimala et al., 2003; Pittella et al., 2009). In addition to its antioxidant activity, asiaticoside has been reported as being helpful in reducing dementia and enhancing cognition (De Souza et al., 1990) and found to have therapeutic value against β-amyloid neurotoxicity (Mook-Jung et al., 1999). Protection from oxidative damage, apart from encompassing both the direct passive antioxidants and the stimulants of enzymes involved in antioxidant defense, also encompasses a reduction in monamine levels because these compounds can spontaneously auto-oxidize to free radicals (Bindoli et al., 1992). Centella is useful even in this way of monamine reduction to counter oxidative damage. There is concern that Centella might cause liver damage in some people and cause side effects like stomach upset, nausea, and itching (Jorge and Jorge, 2005).
Asparagus racemosus Wild (Asparagus; Shatavari, Shatuli, Vrishya) Geographical distribution and ethnomedical description: A. racemosus is commonly known as Shatavari in India. Romans used A. racemosus for food and medicinal purpose. It was first cultivated in England at the time of Christ and brought to America by the early colonists. Shatavari has great reputation in ayurveda for relief in uterine diseases, to increase lactation, as an antacid, and as a tonic. Chemical constituents: The major bioactive constituents of Asparagus are a group of steroidal saponins. This plant also contains vitamins A, B1, B2, C, E, and folic acid. Asparagus also contains metals like Mg, P, Ca, and Fe. Other primary chemical constituents of Asparagus are essential oils, asparagine, arginine, tyrosine, flavonoids (kaempferol, quercetin, and rutin), resin, and tannin (Bopana and Saxena, 2007). Shatavarins I–IV, major steroidal saponins are present in the roots. Five steroidal saponins, shatavarins VI–X, shatavarin V, immunoside, and schidigerasaponin D5, have been isolated from the roots of A. racemosus (Hayes et al., 2008). Other active compounds such as quercetin, rutin, and hyperoside are found in the flowers and fruits, while diosgenin and quercetin-3 glucuronide are present in the leaves (Asmari et al., 2004). Asparagus is also rich in phytoestrogens, namely the isoflavones and coumastans (Bopana and Saxena, 2007).
Active antioxidant and other roles
Shatavari is used for sexual debility and infertility in both sexes in some modern studies. It has been used to ameliorate menopausal symptoms (Thakur et al., 1989). The herb is widely reported for galactagogue activity (Atal and Kapur, 1982; Thakur et al., 1989; Shah and Qadry, 1990). It is also known for its nootropic effects (Ojha et al., 2010). Further, methanolic Asparagus extract dose-dependently inhibited acetylcholinesterase enzyme in specific brain regions (prefrontal cortex, hippocampus, and hypothalamus; Ojha et al., 2010). These activities may be related to the augmentation of cholinergic transmission as methanolic Asparagus extract significantly inhibited the enzyme cholinesterase. Gindi (2011) further explored these nootropic effects by using scopolamine-induced memory deficit and AlCl3 induced cognitive deficits in rats. The nootropic effects could be in part due to the observed increase in the antioxidant activity in terms of DPPH radical and NO radical scavenging activity (Gindi, 2011).
The extracts of A. racemosus protect against kainic acid induced hippocampal and striatal neuronal damage that is accompanied by an increase in lipid peroxidation and protein carbonyl content, decline in GPX activity, and reduced glutathione (GSH) content (Parihar and Hemnani, 2004). The Asparagus extract supplemented mice show an improvement in the GPX activity and the GSH content and a reduction in the membrane lipid peroxidation and protein carbonyl content (Parihar and Hemnani, 2004). Similar to kanic acid induced insult, immobilization stress induced oxidative changes in the hippocampal subregion are also counteracted by the antioxidant effects of Asparagus extracts (Vimal et al., 2010). Treatment with the Asparagus extract compensates the immobilization stress induced decrease in the SOD, catalase, ascorbic acid, and lactate dehydrogenase levels and lowers the heightened MDA levels (Vimal et al., 2010). Renal pain, peripheral edema, exacerbation of gout, and skin allergies have been reported for a small number of patients (Chrubasik et al., 2006). Lipid transfer proteins, profilin, and glycoproteins may account for the reactions as well as for cross-sensitivities of Asparagus (Pajno et al., 2002; Rieker et al., 2004; Tabar et al., 2004; Volz et al., 2005).
Acorus calamus Linn. (sweet flag, calamus; bach, vacha)
Geographical distribution and ethnomedical description
Acorus calamus L. is a polyploidic marsh plant indigenous to Asia that is now distributed along trade routes all over the northern hemisphere. The aromatic rhizome has been widely used as an herbal remedy. Ayurvedic medicine and traditional Chinese medicine use the drug to treat CNS related diseases such as epilepsy and insomnia (Williamson, 2002; Khare, 2004). In European folk medicine, A. calamus rhizomes have been mainly used to alleviate gastrointestinal ailments such as acute and chronic dyspepsia, gastritis and gastric ulcer, intestinal colic, and anorexia.
Chemical constituents
Its extract contains monoterpenes, sesquiterpenes, phenylpropanoids, range of sesquiterpene hydrocarbons, alcohols, and ketones (e.g., acorone, acoragermacrone, calamendiol) besides eugenol, methyl isoeugenol, and phenyl propane derivatives such as α and β-asarone (Raina et al., 2003). Interestingly β-asarone content in Acorus is possibly dependent upon the genetic composition of plant as the volatile oil from the tetraploid “Indian” form of calamus contains β-asarone as a major component (up to 95%) whereas the oil from the “European” or triploid form contains less than 10% β-asarone (Lander and Schreier, 1990). A diploid form of the plant contains virtually no β-asarone (Lander and Schreier, 1990).
Active antioxidant and other roles
Several in vivo studies support a sedative and tranquilizing action of the extracts of A. calamus (Dandiya et al., 1959; Dandiya and Menon, 1963; Vohora et al., 1990). The tranquilizing effect has been suspected to be due to α-asarone and β-asarone (Dandiya and Menon, 1963; Liao et al., 1998; Zanoli et al., 1998) but up to now the underlying mechanisms of action of these compounds has not been convincingly demonstrated. The ethanolic extract of Acorus calamus has been shown in a report to prevent acrylamide-induced hind limb paralysis, decrease GSH and GST, and increase dopamine receptors in the corpus striatum (Shukla et al., 2002). Acorus is effective in attenuating the noise stress via scavenging free radicals and lowering the lipid peroxidation in many regions of the rat brain, like cerebral cortex, cerebellum, pons-medulla, midbrain, hippocampus, and hypothalamus (Manikandan et al., 2005). Acorus calamus extract exhibit radioprotection abilities in part due to antioxidant activity by increasing the activities of major enzymes of the antioxidant defense system, especially SOD, CAT, and GPX and the levels of GSH and decrease in the formation of MDA and in part due to the reduction in DNA strand breaks (Sandeep and Nair, 2010).
Bacopa monnieri (Linn) wettst. (Coastal waterhyssop; Nirbrahmi)
Geographical distribution and ethnomedical description
Bacopa monnieri is commonly found in wet marshy and damp places throughout India. Occasionally it is also referred to Brahmi, the same common Hindi name as that of C. asiatica. A disambiguating and more appropriate Hindi name is Nirbrahmi (Nir = water + Brahmi) indicating the marshy habitat of Bacopa. The ambiguity, likely introduced in the sixteenth century, still persists in the common usage due to a big overlap in the medicinal value of the two herbs. B. monnieri is a major constituent of the traditional Medhya rasayana (Medhya = intelligence, Rasayana = rejuvenators) formulations, which are considered to facilitate learning and improve memory (Garai et al., 1996). In traditional medicine, the plant is used as nervine tonic, diuretic, and to treat asthma, epilepsy, insanity, and hoarseness.
Chemical constituents
Pharmacological compounds from B. monnieri include alkaloids, saponins, and sterols. It also contains the brahmine, herpestine, saponins, monnierin, hersaponin, bacosides, four aglycones of ebelin, lactone (Kulshreshtha and Rastogi, 1973), bacogenins A1 (Kulshreshtha and Rastogi, 1973; Chandel et al., 1977), jujubogenin, and pseudojujubogenin (Kawai and Shibata, 1978), d-mannitol, betulic acid, β-sitosterol, stigmasterol and its esters, heptacosane, octacosane, non-acosane, triacontane, hentriacontane, dotriacontane, nicotine, 3-formyl-4-hydroxy-2H-pyran, and luteolin and its derivatives (Rastogi and Mehrotra, 1990).
Active antioxidant and other roles
Bacopa monnieri extract shows neuroprotective effect against neurotoxicants like aluminum and nicotine in experimental animals (Jyoti and Sharma, 2006; Vijayan and Helen, 2007). In one study, B. monnieri extract was shown to reduce the amyloid levels in a Alzheimer’s disease model mice, suggestive of its therapeutic potential (Holcomb et al., 2006) and we think further studies are needed to explore this issue further. In one study, the oral administration of 5–10 mg B. monnieri crude extract per kg body weight markedly reduced the memory deficits in rats along with a reduction in acetylcholine concentrations, choline acetylase activity, and muscuranic receptor binding in the hippocampus and the frontal cortex (Dhawan and Singh, 1996). B. monnieri also helps in coping with combined hypoxic, hypothermic, and ischemic stress that could lead to the onslaught of free radicals (Rohini et al., 2004). Studies suggest that Bacopa extracts scavenge superoxide anion and hydroxyl radical and reduce H2O2 induced cytotoxicity and DNA damage in human fibroblast cells (Tripathi et al., 1996; Rai et al., 2003). B. monnieri extracts modulate the expression of certain enzymes involved in the generation and the scavenging of ROS in the brain (Govindarajan et al., 2005). Bacosides from B. monnieri are known for their antioxidant activity (Tripathi et al., 1996; Bhattacharya et al., 2000; Deb et al., 2008), for example bacoside A has been shown to offer significant protection against chronic cigaret smoking-induced oxidative damage in rat brains (Anbarasi et al., 2006). The antioxidant activity of B. monnieri is able to explain, at least in part, the reported antistress, cognition-facilitating, and ant-aging effects produced by it in experimental animals and in clinical situations. In a study, when a preparation of the plant was evaluated for safety and tolerability it showed no serious adverse effects but there were some reports of mild gastrointestinal symptoms (Pravina et al., 2007).
Celastrus peniculatus Willd. (climbing staff tree, intellect tree; Mal-kangani)
Geographical distribution and ethnomedical description
Celastrus paniculatus is a large, woody, climbing shrub, distributed almost all over India. In traditional medicine the seeds are considered to be stimulant, intellect promoting, laxative, emetic, expectorant, appetizer, aphrodisiac, cardiotonic, anti-inflammatory, and diuretic (Chopra and Chopra, 1958; Warrier et al., 1996; Bhanumathy et al., 2010). It has also been traditionally used for healing abdominal disorders, leprosy, pruritus, skin diseases, paralysis, cephalalgia, arthralgia, asthma, leucoderma, cardiac debility, inflammation, nephropathy, amenorrhoea, dysmenorrhoea, beri-beri, and sores (Chopra and Chopra, 1958; Warrier et al., 1996; Bhanumathy et al., 2010). In traditional medicine the bark is considered to be an abortifacient, a depurative and a brain tonic and the leaves as emmenagogue and the leaf sap, a good antidote for opium poisoning (Chopra and Chopra, 1958; Warrier et al., 1996; Bhanumathy et al., 2010).
Chemical constituents
Celastrus peniculatus contains several possible active ingredients like polyalcohols, malkanguniol (Hertog et al., 1974), β-sitosterol, β-amyrin, a pentacyclic triterpene diol paniculatadiol (Hertog et al., 1973), several phytosteroids, saponins, and tannins (Joshi and Sabnis, 1989), n-triacontanol, pristimerin (Jain, 1963), celastrol, pristimerin, zeylasterone, and zeylasteral (Gamlath et al., 1990).
Active antioxidant and other roles
Celastrus peniculatus has been reported for stimulatory effects on brain (Warrier et al., 1996). In an old study it was found to enhance memory and improve the IQ of mentally retarded children (Morris et al., 1953). The seed extract of C. paniculatus demonstrate improvements in learning abilities in mice along with improvements in antioxidant activity in the form of significant decrease in the brain levels of MDA and increases in levels of glutathione and catalase (Kumar and Gupta, 2002). Celastrus extracts can attenuate hydrogen peroxide and glutamate-induced injury in embryonic rat forebrain neuronal cells, in a dose dependent manner (Godkar et al., 2006). SOD activity was unaffected after treatment, in comparison to this catalase activity was increased and MDA levels were reduced (Godkar et al., 2006).
Convulvulus pleuricaulis Choisy. (Bindweed; Kaudiali, Shankhahuli, Shankhpushpi)
Geographical distribution and ethnomedical description
Convolvulus pleuricaulis is used in traditional systems of medicine in anxiety, neurosis, insanity, epilepsy, insomnia, fatigue, low energy level, and as a brain tonic (Sethiya and Mishra, 2010). Traditionally the whole herb is used medicinally in the form of decoction with cumin and milk in nervous debility, and loss of memory (Chopra and Chopra, 1958; Warrier et al., 1996). This plant is widely distributed across Indian subcontinent.
Chemical constituents
Convolvulus contains neuroactive alkaloids such as shankhpushpine, convolamine, and other likely potent compounds such as hextriacontane (Deshpande and Srivastava, 1975), scopoletin, P-sitosterol and ceryl alcohol (Deshpande and Srivastava, 1969), 20-oxodotriacontanol, tetratriacontanoic acid and 29-oxodotriacontanol, flavonoid kampferol and phytosteroids such as phytosterol and P-sitosterol (Singh and Bhandari, 2000).
Active antioxidant and other roles
Supporting the long-standing belief and extensive large-scale commercial use in India of the aqueous extract of Convolvulus, a recent rodent study showed significant improvement in learning by finding reduction in scopolamine induced increase in the transfer latency in the elevated plus maze and improvement in the impaired spatial memory in the Morris water maze (Bihaqi et al., 2011). Extract was also found to decrease acetylcholinesterase activity in the cortex and hippocampal subregion and increase the activity of glutathione reductase, SOD, and GSH (Bihaqi et al., 2011). Whether the learning boosting effects were solely due to antioxidant activity in the above-mentioned study is not obvious but the potential of this plant for finding active stimulants of antioxidant pathway seems very high. Significant antioxidant boosting and acetylcholinesterase inhibitory properties have previously been observed too (Nag and De, 2008). Extracts of convolvulus have also been shown to reduce the increased levels of MDA along with altering glutathione levels in hippocampus (Parihar and Hemnani, 2003). In summary, studies demonstrate the potential of C. pleuricaulis for being a promising source of novel stimulants of antioxidant responses.
Curcuma longa Linn. (Turmeric; Haldi)
Geographical distribution and ethnomedical description
Curcuma longa known commonly as Haldi is perennial rhizome plant grows also all over India. Its antioxidant potential is well demonstrated and many compounds commercialized. Given the ease of availability of information on this plant (Ammon and Wahl, 1991; Park and Kim, 2002; Singh et al., 2002; Basnet and Skalko-Basnet, 2011; Schaffer et al., 2011; Mythri and Bharath, 2012), we are keeping discussion of this herbal source to a minimum.
Chemical constituents
Curcuma contains phenylheptanoids, monoterpenes, ses-quiterpenes, several diphenyl alkanoids, phenyl propene derivatives of cinnamic acid type, and terpenoids, along with very active and well studied compound: curcumin (Roth et al., 1998; Park and Kim, 2002; Singh et al., 2002). The rhizomes contains curcuminoids, curcumin, demethoxy curcumin, bis-demethoxycurcumin, 5′-methoxycurcumin, and dihydrocurcumin that are known antioxidants (Ravindranath and Satyanarayana, 1980; Kiuchi et al., 1993; Nakayama et al., 1993; Park and Kim, 2002).
Active antioxidant and other roles
Methanol extract of turmeric has led to the isolation of Calebin-A and some curcumin compounds that are claimed to offer a good degree of protection to the neuronal cells against β-amyloid deposition (Park and Kim, 2002). Oral administration of curcumin to alcohol-fed rats causes a significant reversal of brain lipid peroxidation, indicating its neuroprotective role (Rajakrishnan et al., 1999). Curcuminoids have been found to be potent inhibitors of lipid peroxidation, inhibiting lipid peroxidation in rat brain homogenates, and rat liver microsomes to a higher level than alpha-tocopherol (Rao, 1994). It is not clear whether the antioxidant potential of turmeric is due to rich passive antioxidants that it contains or due to additional active antioxidant stimulating compounds. While the use of turmeric in food and monitored quantities as medicine is very safe, very high doses of C. longa (500 mg/kg) have been reported to induce chromosomal aberrations in animal models (Jain et al., 1987), suggesting need for caution when selecting the medicinal dose.
Bioavailability of Herbal Drugs and Antioxidant Property
Bioavailability has been broadly defined as “absorption and utilization of a nutrient” (Krebs, 2001). The degree and quantity of penetration of herbal drug or its active ingredient is determined by its bioavailability (Youdim et al., 2004; Reddy et al., 2005). Bioavailability of ayurvedic herbal drugs has been largely neglected and only some studies have conducted fine quantitative measurements, for example measurement of baicalein found in T. arjuna (Tilak et al., 2006). Bioavailability can depend on chemical complexity of the herb due to synergistic and antagonistic actions of the constituents in promoting absorption, hydrophobic properties determining the ability to cross luminal wall, gut microflora, and hepatic activity of the individual, and chemical modifications of the herbal constituents. Constituents in herbal drugs must cross the blood brain barrier to be effective in the CNS and there is a dearth of literature on Indian herbs, especially ones with bodily antioxidant stimulating potential on such an important topic. Synergistic interactions of herbs can play an important role in bioavailability, like capsicum can increase the availability of theophylline (Bouraoui et al., 1986) and tamarind can increase the bioavailability of Asprin (Mustapha et al., 1996). Atal et al. (1981) demonstrated that long pepper, black pepper, and ginger can increase bioavailability of some compounds. There is evidence of considerable person-to-person variation in gut microflora and hepatic activity too (Williamson and Manach, 2005). A look at turmeric extracts in the context of non-oxidative issues can bring to light the problem of a compound or an extract working in vitro failing to work in vivo because of issues of bioavailability (Basnet and Skalko-Basnet, 2011; Belkacemi et al., 2011; Irving et al., 2011)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405414/