in stress induced and ageing related disorders

Definition

Adaptogens are natural stress-protective compounds or plant extracts that increase adaptability, resilience and survival of organisms.  First definition of adaptogens is dated of 1958. Tremendous progress in biology and medicine during last 60 years have a great impact on the research of adaptogens. Consequently, better understanding how they work in the organisms resulted in evolution of definition of adaptogens.

Year              Definition
1958             Adaptogens are compounds that increase the “state of non-specific resistance” in stress (Lazarev, 1958).
1968             Adaptogens are innocuous agents, nonspecifically increasing resistance against physically, chemically, biologically, and psychologically                                 noxious factors (“stressors”), normalizing effect independent of the nature of pathologic state (Brekhman, 1968).
1984             The adaptogens are nontoxic compounds with polyvalent mechanisms of action and pharmacological effects related to adaptability and                                 survival. (Farnsworth et al., 1984)
1994             Adaptogens are substances which elicit in an organism a state of nonspecifically raised resistance, allowing them to counteract stressor                                 signals and to adapt to exceptional strain (Wagner et al., 1994).
1999             Plant adaptogens are agents which reduce damaging effects of various stressors due to reduction of the reactivity of host defense system.                             They adapt organism to stress and have curative effect in stress induced disorders (Panossian et al., 1999).
1999             Adaptogens are metabolic regulators, which increase the ability of an organism to adapt to environmental factors and to avoid damage from                         such factors (Panossian et al., 1999).
2007             Adaptogenic substances have the capacity to normalize body functions and strengthen systems compromised by stress. They have a                                   protective effect on health against a wide variety of environmental assaults and emotional conditions (EMEA/HMPC/102655/2007).
2009             Adaptogens comprise a pharmacotherapeutic group of herbal preparations used to: increase attention and endurance in fatigue and                                     prevent/mitigate/reduce stress-induced impairments and disorders related to neuro-endocrine and immune systems [Panossian and Wikman, 2009].
2017             Botanical adaptogens are plant extracts, or specific constituents of plant extracts, which function to increase survival in animals and                                   humans by stimulating their adaptability to stress by inducing adaptive responses (Panossian and Amsterdam, 2017).
2017             Adaptogens are stress-response modifiers that increase an organism’s nonspecific resistance to stress by increasing its ability to adapt and                         survive. (Panossian, 2017).
2017             Botanical adaptogens are metabolic regulators that increase survival by increasing adaptability in stress. (Panossian, 2017).
2018             Adaptogens are natural compounds or plant extracts that increase adaptability and survival of living organisms to stress                                                       (Panossian et al., 2018).
???                Adaptogen – any of various natural substances used in herbal medicine to normalize and regulate the systems of the body.                                                       https://www.dictionary.com/browse/adaptogen.

Chemical class

The principal active constituents of adaptogenic plants (as investigated thus far, table 1) can be divided into two main chemical groups (1):

  1. Terpenoids, with a tetracyclic skeleton such as cortisol and testosterone: ginsenosides, sitoindosides, cucurbitacines, and withanolides.
  2. Aromatic compounds, that are structurally like catecholamines or tyrosine, including:
  • lignans: e.g. eleutheroside E (Eleutherococcus senticosus), schizandrin B (Schizandra chinensis)
  • phenylpropane derivatives: e.g. syringin (Eleutherococcus senticosus), rosavin (Rhodiola rosea)
  • phenylethane derivatives: e.g. salidroside, tyrosol (Rhodiola rosea).                                                                                                                        

Many studies indicate direct interactions between tetracyclic terpenoids and corticosteroid and estrogenic receptors (1).   

 

Botanical origin

Table 1. Plants Mentioned in Literature as Adaptogens (1, 98)*

Ajuga turkestanica (Regel) Briq.
Alstonia scholaris (L.) R. Br.
Alstonia scholaris (L.) R. Br.
Andrographis paniculata(Burm.f.) Nees (92)
Aralia mandshurica Rupr. & Maxim
Argyreia nervosa (Burm. f.) Bojer
Argyreia speciosa (L. f.) Sweet
Asparagus racemosus Wild
Bacopa monnieri (L.) Wettst
Bergenia crassifolia (L.) Fritsch
Bryonia alba L.
Caesalpinia bonduc (L.) Roxb
Centella asiatica (L.) Urb.
Chlorophytum borivilianum Santapau & R.R.Fern.
Chrysactinia mexicana A. Gray
Cicer arietinum L.
Codonopsis pilosula (Franch.) Nannf.
Convolvulus prostratus Forssk.
Curculigo orchioides Gaertn.
Curcumin from Turmeric (Curcuma longa)
Dioscorea deltoidea Wall. ex Griseb.
Dioscorea roxburghii (Wall.) Hurus.
Echinopanax elatus Nakai
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.
Emblica officinalis Gaetrn.
Eucommia ulmoides Oliv.
Evolvulus alsinoides (L.) L.
Firmiana simplex (L.) W.Wight
Gentiana pedicellata (D.Don) Wall
Glycyrrhiza glabra L.
Heteropterys aphrodisiaca Machado
Hippophae rhamnoides L.
Holoptelea integrifolia Planch
Hoppea dichotoma Willd.
Hypericum perforatum L.
Lepidium peruvianum/ Lepidium meyenii Walp.
Ligusticum striatum DC.
Melilotus officinalis (L.) Pall.
Morus alba L.
Mucuna pruriens (L.) DC.
Nelumbo nucifera Gaertn.
Ocimum sanctum L.
Oplopanax elatus (Nakai) Nakai
Panax ginseng C.A.Meyer.
Panax pseudoginseng Wall.
Pandanus odoratissimus L.f.
Paullinia cupana Kunth
Pfaffia paniculata (Mart.) Kuntze
Piper longum L.
Potentilla alba L.
Ptychopetalum olacoides Benth.
Rhaponticum carthamoides (Willd.) Iljin
Rhodiola heterodonta (Hook. f. & Thomson) Boriss.
Rhodiola rosea L.
Rostellularia diffusa (Willd.) Nees.
Salvia miltiorrhiza Bunge
Schisandra chinensis (Turcz.) Baill.
Scutellaria baicalensis Georgi
Serratula inermis
Sida cordifolia L.
Silene italica (L.) Pers.
Sinomenium acutum (Thunb.) Rehder & E.H.Wilson
Solanum torvum SW.
Sutherlandia frutescens (L.) R.Br.
Terminalia chebula Retz.
Tinospora cordifolia (Willd.) Miers
Trichilia catigua A.Juss.
Trichopus zeylanicus Gaertn.
Turnera diffusa Willd. ex Schult.
Vitis vinifera L.
Withania somnifera (L.) Dunal

*This table is an update from the reviews Wagner et al. 1994 and Panossian and Wagner 2011.  It includes plants which do and do not meet the formal definition of adaptogen. In various countries, adaptogens are used as dietary supplements or/and conventional and traditional medicinal products (2-5).

Therapeutic category/pharmacological group: adaptogens 

Pharmacological activity: stress-protective, stimulating, tonic

Mechanism of action: multitarget effect on neuroendocrine-immune system including:

  • triggering of intracellular and extracellular adaptive signaling pathways that promote cell survival and organismal resilience in stress  

  • regulation of metabolism and homeostasis via effects on expression of stress hormones (corticotropin and gonadotropin releasing hormones, urocortin, cortisol, neuropeptide Y, heat shock proteins Hsp70) and their receptors

Indications/health claims: stress-induced fatigue, mental and behavioral disorders, aging associated disorders, infectious diseases .

What is necessary and sufficient to be considered as an adaptogenic plant?

An adaptogen activates cellular adaptive signaling pathways (e.g. MAPK and I3PK mediated pathways) that are known promotes survival in response to stress and suggests neuroprotective activity and potential benefits of adaptogens in neurodegenerative diseases. In addition to activating of multiple cytoprotecting mechanisms increasing cell survival (antioxidant, immune modulation, Hsp70 modulation), adaptogens trigger generation of hormones (e.g. CRH, GRH, urocortin, cortisol), playing key role in metabolic regulation and homeostasis. Therefore, adaptogens are active in numerous conditions and diseases associated with stress and aging related impairment of neuroendocrine – immune complex, energy, fatigue, etc.  Overall, the mechanisms of action of adaptogens are “specifically” related to stress-protective activity and increased adaptability of the organism (1, 98). 

History and Background

The term adaptogens is used in alternative and complimentary medicine, pharmacognosy, phytomedicine, phytopharmacology, and phytotherapy research (6-14).  Initially, the term adaptogen was coined to describe substances that can increase the “state of non – specific resistance to stress” (15,16). Originally, the adaptogenic concept (3,7-12) was based on Hans Selye’s theory (17,18) of adaptive stress response of neuroendocrine immune complex (19,20) and long-term traditional use of some medicinal plants that are believed to promote physical and mental health, improve defense mechanisms of the body, and enhance longevity (7-14, 21-33).  It was suggested that certain compounds and herbal extracts, termed adaptogens, could diminish the magnitude of the alarm phase of adaptive stress response and prolong the duration the phase of non-specific resistance to stress (7,15). Based on evidences mainly from animal studies, adaptogens were defined as nontoxic “metabolic regulators, which increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors” (6, 9).  It should be emphasized that the term “adaptogen” is associated with a physiological process – adaptation to environmental challenges, which is a multistep process that involves diverse mechanisms of intra- and extracellular interactions.  The updated definition of adaptogens (1) is supported by results of recent studies of molecular mechanisms of action of adaptogens on a variety of regulatory systems from the cellular level to whole organism (1, 34-48).

Pharmacology and the Mechanism of Action

There are many molecular targets for stress response modifiers since stress response and adaptation to environmental challenge are multistep processes that involve intracellular and extracellular signaling pathways at all levels of stress regulation.
Stimulating and stress-protective effects are characteristic and common pharmacological effects of adaptogens (9,11,31). These have been observed in many animals and humans by testing their cognitive function and physical endurance under stressful conditions (8,9,11,39, 42,43). The main difference between adaptogens and conventional stimulants, such as caffeine, amphetamine, etc., is that after prolonged use, the later can cause the user to develop both tolerance and addiction, Table 2 (12, 43). Adaptogens exhibit polyvalent beneficial effects against chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, cancer, and other aging-related diseases (22, 27, 49, 50). All of them are associated with the metabolic regulation of homeostasis and threatened adaptability of stress system.

Table 2. The Differences in Properties Between Adaptogens and Other Stimulants.

Stimulants

Adaptogens

 

Stress protective (neuro-, hepato-, cardio-protective)

No

High

Recovery process after exhaustive physical load

Low

High

Energy depletion

Yes

No

Performance in stress

Increased

Survival in stress

Increased

Quality of arousal

Poor

Good

Addiction potential

Yes

No

Side effects

Yes

Rare

DNA/proteins synthesis

Decreased

Increased

NPY mediated activation of Hsp70

Increased

The metabolic regulation of homeostasis by adaptogens at the cellular and systemic level is associated with multiple targets (1, 34-47). Consequently, the pharmacology of adaptogens is a typical example of network pharmacology that can be approached using the systems biology concept (1). The classic reductionist model that presumes a specific receptor/drug interaction (51) is unsuitable for this scenario and insufficient when attempting to understand the mechanism of action of adaptogens. Molecular targets, signaling pathways, and networks common to adaptogens have been identified (1, 34-47). They are associated with stress hormones and key mediators of the regulation of homeostasis (molecular chaperons Hsp70, neuropeptide Y, G protein-coupled receptors, dopamine-cAMP-PKA-CERT, IP3,  PLC, DAG, PI3K, NFkB,  mediated signaling pathways, stress activated kinase JNK, FOXO3, cortisol, estrogens, nitric oxide, etc.) (1, 34-47).

Adaptogens exert a polyvalent biological activity and provoke multiple effects at the transcriptional level of regulation of cellular metabolism and homeostasis. The genome-wide effects of several adaptogenic herbal extracts in brain cells culture were recently elucidated (34-36, 89-94). These data highlight the consistent activation of adaptive stress response signaling pathways (ASRSPs) by adaptogens in T98G neuroglia cells. The extracts affected many genes playing key roles in modulation of adaptive homeostasis, indicating their ability to modify gene expression to prevent stress-induced and aging-related disorders. At least 88 of the 3516 genes regulated by various adaptogens in isolated brain cells were closely associated ASRSPs, including neuronal signaling related to corticotropin-releasing hormone, cAMP-mediated, protein kinase A, and CREB; pathways related to signaling involving CXCR4, melatonin, nitric oxide synthase, GP6, Gαs, MAPK, neuroinflammation, neuropathic pain, opioids, renin–angiotensin, AMPK, calcium, and synapses; and pathways associated with dendritic cell maturation and G-coupled protein receptor–mediated nutrient sensing in enteroendocrine cells (90). All adaptogens tested showed significant effects on the expression of genes encoding neurohormones CRH, GNRH, UCN, G-protein coupled and other transmembrane receptors TLR9, PRLR, CHRNE, GP1BA, PLXNA4, a ligand-dependent nuclear receptor RORA, transmembrane channels, transcription regulators FOS, FOXO6, SCX, STAT5A, ZFPM2, ZNF396, ZNF467, protein kinases MAPK10, MAPK13, MERTK, FLT1, PRKCH, ROS1, TTN), phosphatases PTPRD, PTPRR, peptidases, metabolic enzymes, a chaperone (HSPA6), and other proteins, all of which modulate numerous life processes, playing key roles in several canonical pathways involved in defense response and regulation of homeostasis in organisms (90).

A characteristic feature of adaptogens is that they act as eustressors (i.e. “good stressors”), and as mild stress mimetics or ‘stress- vaccines’ that induce a stress-protective response (44, 47).  Adaptogens exhibit multitarget action and the shared use of several different receptors, including receptors for corticosteroid, mineralocorticoid, progestin, estrogen, serotonin, NMDA, and nicotinic acetylcholine, receptor tyrosine kinases, and many G-protein coupled receptors (1, 34-47, 50,52-72). Therefore, the possibility that numerous molecular network interactions (with feedback regulation of the neuroendocrine and immune systems) contribute to the overall pharmacological response and result in agonist-dependent antagonism is most suitable for understanding the mechanisms of action of adaptogens (1).

Molecular targets, signaling pathways, and networks common to adaptogens are associated with chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, and cancer, all of which are more common with age (14, 34,35,36).

Current and Potential Use

Current and potential uses of adaptogens are mainly related to stress-induced fatigue and cognitive function, mental illness, and behavioral disorders, infectious diseases (9, 13, 32, 42, 43, 76-85, 89-100). Their prophylactic use by healthy subjects to ameliorate stress and prevent age-related diseases appears to be justified (14, 21, 23-26, 42,43, 89-93), e.g. Rhodiola rosea, Withania somnifera and Eleutherococcus senticosus downregulate the expression of key genes (ALOX5AP, DPEP2, LTC4S) involved biosynthesis of leukotrienes A, B, C, D and E, resulting in inhibition of leukotriene signaling pathway suggesting their potential benefits in Alzheimer disease (89). Recent observations indicate on potential beneficial effects of adaptogens on neuronal functions associated with mild cognitive impairments in cancer chemotherapy (91-93, 95-97).
In a number of clinical studies, beneficial effects of adaptogens have been demonstrated on healthy subjects in stress conditions (42,43, 73-81, 95-97). This is especially true of the mental and physical performance of fatigue and mental strain (42,43, 73-81, 95-97). Furthermore, efficacy of adaptogens in mild and moderate depression has been demonstrated (32, 82-85).
Adaptogens have been used for the last decades in the official medicine of Russia and neighbor countries (Estonia, Ukraine, Armenia, Kazakhstan, etc.) as a stimulant against fatigue by patients who suffered asthenic states and by healthy people who showed asthenia during periods of high mental exertion or after intensive physical work (2, 27, 86, 87). Adaptogens are also applied in psychiatric practice.  (13, 32, 84, 85).
In Sweden, Norway and Denmark, rhodiola traditional herbal medicinal product is indicated as an adaptogen in situations of decreased performance such as fatigue and sensation of weakness.
Dietary supplements containing rhodiola, withania, ginseng, eleutherococcus, schisandra and other adaptogenic plant extracts are widely used all over the world (6).   

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