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SCIENCE CHINA Life Sciences, Volume 62 , Issue 10 : 1332-1367(2019) https://doi.org/10.1007/s11427-019-9587-y

Nature brings new avenues to the therapy of central nervous system diseases—an overview of possible treatments derived from natural products

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  • ReceivedMay 24, 2019
  • AcceptedJul 1, 2019
  • PublishedAug 22, 2019

Abstract

Natural products (NPs), including traditional Chinese medicine (TCM), have been long and widely used in the prevention and treatment of central nervous system (CNS) diseases by virtue of their abundant sources, diverse structures, and novel activities. In this review article, we intend to summarize and discuss the situation or status of the clinical employments or trials of the NPs and their derivatives with CNS activities. NPs that have been extensively studied in preclinical research in recent years are also included. The compounds presented in this review are classified according to their indications and followed by details such as natural sources, possible biological mechanisms, and development status, while a considerable proportion of them are found in TCM. In addition, some drug combinations with synergistic effects are also mentioned. According to their impressive therapeutic effects and novel chemical structures, NPs are not only effective therapeutic remedies in clinic, but also lead compounds for structural modification, which indicate that nature brings new avenues to the therapy of CNS diseases.


Funded by

Special Foundation of Chinese Academy of Sciences for strategic pilot technology(XDA12040105)

National Science Foundation for Young Scientists of China(81703338)


Acknowledgment

This work was supported by Special Foundation of Chinese Academy of Sciences for strategic pilot technology (XDA12040105) and National Science Foundation for Young Scientists of China (81703338). The authors thank Dongye Shen for his contribution to English editing and polishing of this manuscript.


Interest statement

The author(s) declare that they have no conflict of interest.


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  • Figure 1

    Natural products and their derivatives for the treatment of AD.

  • Figure 2

    Natural products and their derivatives for the treatment of anxiety.

  • Figure 3

    Natural products and their derivatives for the treatment of depression.

  • Figure 4

    Natural products and their derivatives for the treatment of epilepsy.

  • Figure 5

    Natural products and their derivatives for the treatment of insomnia.

  • Figure 6

    Natural products and their derivatives for the treatment of pain.

  • Figure 7

    Natural products and their derivatives for the treatment of PD.

  • Figure 8

    Natural products and their derivatives for the treatment of ALS.

  • Figure 9

    The structure of (–)-Lobeline.

  • Figure 10

    The structure of sulforaphane.

  • Figure 11

    Natural products and their derivatives for the treatment of HD.

  • Figure 12

    Natural products and their derivatives for the treatment of MS.

  • Figure 13

    Natural products and their derivatives for the treatment of schizophrenia.

  • Table 1   Natural products and their derivatives for the treatment of AD

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Galantamine (1)

    Alkaloid/

    Amaryllidaceae

    AChE inhibitor

    Launched

    (Erkinjuntti et al., 2002)

    2

    Huperzine A (2)

    Alkaloid/

    Huperzia serrata

    AChE inhibitor

    Launched

    (Howes et al., 2017)

    3

    (–)-Clausenamide (3)

    Alkaloid/

    Clausena lansium

    Increases synaptic function and structural plasticity

    Phase II

    (Chu et al., 2016)

    4

    Arecoline (4)

    Alkaloid/

    Areca catechu

    Muscarinic receptor agonist

    Phase I (Discontinued)

    (Yang et al., 2000)

    5

    Betaine (5)

    Alkaloid/

    Beta vulgaris

    BACE1 inhibitor;

    α-secretase activator;

    GSK-3β inhibitor

    Preclinical

    (Liu et al., 2014; Sun et al., 2017)

    6

    Fascaplysin (6)

    Alkaloid/

    Fascaplysinopsis

    P-gp inducer;

    AChE inhibitor

    Preclinical

    (Manda et al., 2016)

    7

    Berberine (7)

    Alkaloid/

    Berberis

    β/γ-secretase inhibitor;

    α-secretase activator;

    Preclinical

    (Cai et al., 2018)

    8

    Resveratrol (8)

    Polyphenol/

    Polygonum cuspidatum

    BACE1 inhibitor;

    antioxidant;

    anti-inflammatory

    Phase II (Discontinued)

    (Lange and Li, 2018)

    9

    EGCG (9)

    Polyphenol/

    Green tea

    α secretase activator;

    β secretase inhibitor;

    AChE inhibitor;

    GSK-3β inhibitor

    Phase II/III

    (Baptista et al., 2014; Singh et al., 2016)

    10

    Pinitol (10)

    Polyphenol/

    pine

    γ secretase inhibitor;

    antioxidant;

    anti-inflammatory

    Phase II

    (López-Domènech et al., 2018)

    11

    Gastrodin (11)

    Phenolic glycoside/

    Rhizoma Gastrodiae

    Inhibits Aβ accumulation;

    neuroprotective effects

    Preclinical

    (Liu et al., 2018b)

    12

    Protocatechuic acid (12)

    Polyphenol/

    Salvia

    Inhibits Aβ accumulation and tau phosphorylation;

    anti-inflammatory;

    Preclinical

    (Krzysztoforska et al., 2019)

    13

    Salvianolic acid B (13)

    Polyphenol/

    Salvia

    GSK-3β inhibitor;

    BACE1 inhibitor;

    inhibits Aβ accumulation

    Preclinical

    (Tang et al., 2016)

    14

    α-Mangostin (14)

    Polyphenol/

    Garcinia

    β/γ-secretase inhibitor

    Preclinical

    (Zhao et al., 2017b)

    15

    Echinacoside (15)

    Polyphenol/

    Echinacea angustifolia

    Neuroprotective effect;

    apoptosis inhibitor;

    free radical scavenger

    Preclinical

    (Liu et al., 2018a)

    16

    Puerarin (16)

    Flavone/

    Radix puerariae

    Anti-inflammatory;

    GSK-3β inhibitor;

    inhibits tau phosphorylation

    Preclinical

    (Yao et al., 2017; Zhao et al., 2015)

    17

    Liquiritin (17)

    Flavone/

    Glycyrrhiza

    Inhibits oxidative stress and neural apoptosis

    Preclinical

    (Jia et al., 2016)

    18

    Luteolin (18)

    Flavone/

    Mignonette

    Antioxidant;

    anti-inflammatory;

    Preclinical

    (Kwon, 2017)

    19

    Myricetin (19)

    Flavone/

    Mignonette

    Inhibits Aβ accumulation;

    AChE inhibitor

    Preclinical

    (Wang et al., 2017a)

    20

    Wogonin (20)

    Flavone/

    Scutellaria baicalensis

    Promotes Aβ clearance; decreases tau phosphorylation

    Preclinical

    (Zhu and Wang, 2015)

    21

    GV-971 (21)

    Oligosaccharide/

    algae

    Aβ aggregation inhibitor

    Pre-Registered

    (Jiang et al., 2013)

    22

    Dronabinol (Δ9-THC, 22)

    Cannabinoid/

    Cannabis sative

    Cannabinoid receptors agonist

    Phase II

    (Liu et al., 2015a)

    23

    Smilagenin (23)

    Steroid/

    Anemarrhena

    Neurotrophic factor enhancer

    Phase II (Discontinued)

    (Zhang et al., 2012b)

    24

    Timosaponin B-II (24)

    Steroid/

    Anemarrhena

    AChE inhibitor;

    Preclinical

    (Zhao et al., 2016b)

    25

    Tramiprosate (25)

    Sulfamic acid/

    algae

    Aβ aggregation inhibitor

    Phase III (Discontinued)

    (Caltagirone et al., 2012)

    26

    ALZ-801 (26)

    Sulfamic acid/

    Aβ aggregation inhibitor

    Phase III

    (Hey et al., 2018)

    27

    Taraxerol (27)

    Terpenoid/

    Carthamus

    AChE inhibitor;

    antioxidant

    Preclinical

    (Berté et al., 2018)

    28

    Geniposide (28)

    Terpenoid/

    Gardenia

    Regulates tau phosphorylation; inhibits Aβ accumulation; attenuates the cholinergic defect

    Preclinical

    (Cui et al., 2018; Zhao et al., 2017a)

    29

    Hyperforin-

    DCHA (29)

    Terpenoid/

    Hypericum perforatum

    Transient receptor potential canonical 6 agonist; antioxidant and anti-inflammatory

    Preclinical

    (Jiang et al., 2018; Lu et al., 2018)

    30

    Ostol (30)

    Phenylpropanoid/

    Cnidiummonnieri

    Up-regulates Micro-RNA-9 expression;

    inhibits apoptosis

    Preclinical

    (Li et al., 2016; Yao et al., 2015)

  • Table 2   Natural products and their derivatives for the treatment of anxiety

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Koumine (31)

    Alkaloid/

    Gelsemium

    Unclear

    Preclinical

    (Chen et al., 2017)

    2

    Dihydro-β-erythroidine (DHβE, 32)

    Alkaloid/

    Erythrina

    Nicotinic α4β2 receptor antagonist

    Preclinical

    (Anderson and Brunzell, 2015)

    3

    Magnolol (33)

    Polyphenol/

    Magnolia officinalis

    GABAA receptor agonist

    Preclinical

    (Alexeev et al., 2012)

    4

    Honokiol (34)

    Polyphenol/

    Magnolia officinalis

    GABAA receptor agonist

    Preclinical

    (Sulakhiya et al., 2015)

    5

    Isovitexin (35)

    Flavone/

    Belamcanda chinensis

    GABAA receptor modulator

    Preclinical

    (Oliveira et al., 2018)

    6

    6-C-Glycoside-diosmetin (36)

    Flavone/

    Erythrina

    GABAA receptor modulator

    Preclinical

    (Oliveira et al., 2018)

    7

    Gastrodin (11)

    Phenolic glycoside/

    Rhizoma Gastrodiae

    Modulates inflammatory

    factors and iNOS/p38 cascades

    Preclinical

    (Liu et al., 2018b)

    8

    Apigenin (37)

    Flavone/

    Apium graveolens

    Unclear

    Preclinical

    (Kumar and Bhat, 2014)

    9

    Apigenin 7-glucoside (38)

    Flavone/

    Apium graveolens

    Unclear

    Preclinical

    (Kumar and Bhat, 2014)

    10

    Buagafuran (AF-05, 39)

    Terpenoid/

    Agarofuran derivative

    Modulates monoamine neurotransmitters and inhibits sodium and calcium channels

    Phase II

    (Yang et al., 2017)

    11

    (-)-β-Caryophyllene (40)

    Terpenoid/

    Cannabis sative

    CB2R agonist

    Preclinical

    (Bahi et al., 2014)

    12

    Phytol (41)

    Terpenoid/

    Tilia

    GABAA receptor agonist

    Preclinical

    (Costa et al., 2014)

    13

    Carvacryl acetate (42)

    Terpenoid/

    Stachys corsica

    Stimulates the GABAergic system

    Preclinical

    (Pires et al., 2013)

  • Table 3   Natural products and their derivatives for the treatment of depression

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Psilocybin (43)

    Alkaloid/

    Psilocybe

    5-HT2A receptor agonist

    5-HT1A receptor agonist

    Phase II

    (Hendricks et al., 2015; Thomas et al., 2017)

    2

    O-Methy

    Lcorypalline (44)

    Alkaloid/

    Nelumbo nucifera

    Nicotinic α4β2 receptor antagonist

    Preclinical

    (Crestey et al., 2013)

    3

    DHβE (32)

    Alkaloid/

    Erythrina

    Nicotinic α4β2 receptor antagonist

    Preclinical

    (Andreasen et al., 2009)

    4

    Cytisine (45)

    Alkaloid/

    Laburnum anagyroides

    Nicotinic α4β2 receptor partial agonist

    Preclinical

    (Han et al., 2016)

    5

    (+)-Laburnamine (46)

    Alkaloid/

    Laburnum anagyroides

    Nicotinic α4β2 receptor partial agonist

    Preclinical

    (Tasso et al., 2013)

    6

    Piperine (47)

    Alkaloid/

    Piper nigrum

    5-HT1A and 5-HT1B receptors agonist

    Preclinical

    (Li et al., 2015; Xu et al., 2016)

    7

    Orcinoside (48)

    Polyphenols/

    Curculigo orchioides

    Modulates the glutamate system

    Phase II

    (Wang et al., 2013b)

    8

    Helicid (49)

    Phenolic glycoside/

    Helicid nilgirica Bedd

    Activates the serotonergic system

    Preclinical

    (Tong et al., 2019)

    9

    Gastrodin (11)

    Phenolic glycoside /

    Rhizoma Gastrodiae

    Modulates the serotonergic system

    Preclinical

    (Liu et al., 2018b)

    10

    Dihydrocaffeic acid (DHCA, 50)

    Polyphenol/

    Grape, etc.

    Modulates brain synaptic plasticity and peripheral inflammation

    Preclinical

    (Wang et al., 2018)

    11

    Malvidin-3′-O-glucoside (Mal-gluc, 51)

    12

    Longistyline C (52)

    Polyphenol/

    Cajanuscajan (L.) Millsp

    Regulates NMDAR

    /NR2B-ERK1/2 related

    signaling pathway

    Preclinical

    (Liu et al., 2017a)

    13

    Butyrolactone (53)

    Polyphenol/

    Aspergillus terreus

    Cdk5 inhibitor

    Preclinical

    (Li et al., 2014)

    14

    Riparin III (54)

    Polyphenol/

    Aniba riparia

    BDNF enhancer

    Preclinical

    (Vasconcelos et al., 2015)

    15

    Riparin II (55)

    Polyphenol/

    Aniba riparia

    Antioxidant;

    BDNF enhancer

    Preclinical

    (Lopes et al., 2018)

    16

    Honokiol (34)

    Polyphenol/

    Magnolia officinalis

    Anti-inflammatory;

    antioxidant; GABAA receptor agonist

    Preclinical

    (Jangra et al., 2016)

    17

    Magnolol (33)

    Polyphenol/

    Magnolia officinalis

    Anti-inflammatory;

    antioxidant; GABAA receptor agonist

    Preclinical

    (Cheng et al., 2018)

    18

    Resveratrol (8)

    Polyphenol/

    Polygonum cuspidatum

    Activates the Akt/GSK-3β signaling pathway

    Preclinical

    (Shen et al., 2019)

    19

    Ferulic acid (56)

    Polyphenol/

    Salvia officinalis

    Anti-inflammatory;

    Antioxidant;

    Preclinical

    (Liu et al., 2017b)

    20

    Icariin (57)

    Flavone/

    Epimedii Folium

    Regulates expression of mGluR1, mGluR5 and EAAT2

    Preclinical

    (Zhang et al., 2017c)

    21

    Apigenin (37)

    Flavone/

    Apium graveolens

    MAO-A inhibitor;

    BDNF enhancer

    Preclinical

    (Weng et al., 2016)

    22

    YY-21 (58)

    Steroid/

    Rhizoma Anemarrhenae

    Enhances excitatory synaptic neurotransmission

    Preclinical

    (Guo et al., 2016)

    23

    YY-23 (59)

    Steroid/

    Rhizoma Anemarrhenae

    Non-competitive NMDA receptor antagonist

    Preclinical

    (Zhang et al., 2015)

    24

    20(S)-Protopanaxadiol (S-111, 60)

    Terpenoid /

    Ginseng

    Norepinephrine and 5-HT reuptake inhibitor

    Phase II

    (Xu et al., 2010)

    25

    Cyclopassifloside IX (61)

    Triterpenoid saponin /

    Passiflora edulis Sims

    Unclear

    Preclinical

    (Wang et al., 2013a)

    26

    Bacopaside I (62)

    Triterpenoid saponin /

    Bacopa monnieri

    Modulates HPA hyperactivity and activates BDNF signaling pathway

    Preclinical

    (Zu et al., 2017)

    27

    Bacopaside II (63)

    Triterpenoid saponin /

    Bacopa monnieri

    Unclear

    Preclinical

    (Zhou et al., 2007)

    28

    (–)-β-Caryophyllene (40)

    Terpenoid/

    Cannabis sative,

    CB2R agonist;

    Adrenalin receptors (α2, β) agonist

    Preclinical

    (de Oliveira et al., 2018)

    29

    Aquilarabietic acid A (64)

    Terpenoid/

    Chinese eaglewood

    Norepinephrine reuptake inhibitor

    Preclinical

    (Yang et al., 2013)

    30

    Andinin A (65)

    Terpenoid/

    Hypericum

    Unclear

    Preclinical

    (Ccana-Ccapatinta et al., 2014)

    31

    (+)-Sesamin (66)

    Phenylpropanoid/

    Sesamumindicum

    Neurotrophic factors(BDNF and NT3) enhancer

    Preclinical

    (Zhao et al., 2018)

  • Table 4   Natural products and their derivatives for the treatment of epilepsy

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Piperine (47)

    Alkaloid/

    Piper nigrum

    Sodium channels antagonist

    Preclinical

    (Mishra et al., 2015)

    2

    Cannabidiol (CBD, 67)

    Cannabinoid/

    Cannabis sative

    Indirectly modulates the endocannabinoid system; TRPV1 agonist;

    GPR55 inhibitor

    Launched

    (Gaston and Szaflarski, 2018)

    3

    Cannabidivarin (CBDV, 68)

    Cannabinoid/

    Cannabis sative

    Unclear

    Phase II

    (dos Santos et al., 2015)

    4

    Hesperidin (69)

    Flavone/

    Citrus species

    Binds to the benzodiazepine site of the GABAA receptor

    Preclinical

    (Kumar et al., 2013)

    5

    Naringin (70)

    Flavone/

    Citrus species

    Binds to the GABAA receptor

    Preclinical

    (Kola et al., 2018; Kola et al., 2017)

    6

    Eudesmin (71)

    Phenylpropanoid/

    Acorustatarinowii

    Up-regulates GABAA and GAD65 expressions;

    anti-apoptosis

    Preclinical

    (Liu et al., 2015c)

    7

    Umbelliferone (72)

    Phenylpropanoid/

    Angelicasinensis

    Unclear

    Preclinical

    (Zagaja et al., 2015)

    8

    Decursin (73)

    Phenylpropanoid/

    Angelicasinensis

    Inhibits selective neuronal death, astrogliosis and oxidative stress

    Preclinical

    (Lee et al., 2014)

    9

    3,4,5-Trimethoxyc-innamic acid (TMCA,74)

    Phenylpropanoid/

    PolygalaeRadix

    Binds to the benzodiazepine site of GABAA receptor

    Preclinical

    (Chen et al., 2016a)

    10

    (–)-β-Caryophyllene (40)

    Terpenoid/

    Cannabis sative,

    CB2R agonist

    Preclinical

    (Liu et al., 2015b)

    11

    Saikosaponin A (75)

    Triterpenoid Saponin/

    Bupleurum chinensis(radix bupleuri)

    NMDA receptor inhibitor;

    sodium and

    potassium channels agonist

    Preclinical

    (Hong et al., 2018; Yu et al., 2012)

    12

    Borneol (76)

    Terpenoid/

    Artemisia iwayomogi

    Antioxidant

    Preclinical

    (Tambe et al., 2016)

    13

    α-asarone (77)

    Phenylpropanoid /

    Acorustatarinowii

    Sodium channels antagonist; binds to the GABAA receptor

    Preclinical

    (Wang et al., 2014)

    14

    α-asaronol (78)

    Phenylpropanoid /

    Metabolite of α-asarone

    Unclear

    Preclinical

    (He et al., 2018)

    15

    Valerenic acid (79)

    Terpenoid/

    Valeriana officinalis

    Binds to the GABAA receptor

    Preclinical

    (Torres-Hernández et al., 2015)

    16

    Kaurenoic acid (80)

    Terpenoid/

    Aralia cordata

    Unclear

    Preclinical

    (Okoye et al., 2013)

  • Table 5   Natural products and their derivatives for the treatment of insomnia

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    L-Stepholidine (l-SPD,81)

    Alkaloid/

    Corydalis yanhusuo

    D1R partial agonist;

    D2R antagonist

    Clinical

    (Qiu et al., 2009)

    2

    L-Tetrahydropalmatine

    (l-THP, 82)

    Alkaloid/

    Corydalis yanhusuo

    D1R antagonist;

    D2R antagonist

    Launched

    (Chu et al., 2008)

    4

    Helicid (49)

    Phenolic glycoside/

    Helicidnilgirica Bedd

    Modulates the GABAergicsystem

    Launched

    (Zhang et al., 2017b)

    5

    Sanjoinine A (83)

    Alkaloid/

    Ziziphus jujuba Mill

    (Rhamnaceae)

    Modulates the GABAergicsystem

    Preclinical

    (Ma et al., 2007)

    6

    Spinosin (84)

    Flavone/

    Ziziphus jujuba Mill(Rhamnaceae)

    Modulates the serotonergicsystem (affects the postsynaptic5-HT1A receptor)

    Preclinical

    (Wang et al., 2010)

    7

    Jujuboside A (JubA, 85) /JubB (86)

    Triterpenoid saponin/

    Ziziphus jujuba Mill (Rhamnaceae)

    Modulates the serotonergic and GABAergic system

    Preclinical

    (Cao et al., 2010; Chen et al., 2008)

    8

    Eckstolonol (87)

    Polyphenol/

    Ecklonia cava

    (a kind of brown alga)

    Modulates the benzodiazepine site of the GABAA receptor

    Preclinical

    (Cho et al., 2014)

    9

    Magnolol (33)

    Polyphenol/

    Magnolia officinalis

    Modulates the benzodiazepinesite of the GABAA receptor

    Preclinical

    (Chen et al., 2012)

    10

    Apigenin

    (37)

    Flavone/

    Apium graveolens

    Modulates the GABAergicsystem (increases the expression of GAD65)

    Preclinical

    (Kim et al., 2012)

    11

    Rosmarinic acid (88)

    Phenylpropanoid/

    Rosmarinus officinalis

    Modulates the GABAergicsystem

    Preclinical

    (Kwon et al., 2017)

    12

    Decursinol angelate (89)

    Phenylpropanoid/

    Angelicakoreana

    Modulates the GABAergicsystem

    Preclinical

    (Woo et al., 2017)

    13

    TMCA (74)

    Phenylpropanoid/

    PolygalaeRadix

    Enhances sleep and alters sleep architecture throughGABAergic system

    Preclinical

    (Lee et al., 2013)

    14

    Pachymic acid (90)

    Steroid/

    Poria cocos

    Modulates the GABAergicsystem

    Preclinical

    (Shah et al., 2014)

  • Table 6   Natural products and their derivatives for the treatment of pain

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Morphine (91)

    Alkaloid/

    Opium poppy

    μ-opioid receptor agonist

    Launched

    2

    Aspirin (92)

    Salicylic acid derivative

    COXs inhibitor

    Launched

    3

    Capsaicin (93)

    Alkaloid/

    Capsicum

    TRPV1 agonist

    Launched

    (Fernandes et al., 2016)

    4

    l-THP (82)

    Alkaloid/

    Corydalis yanhusuo

    D1R antagonist;

    D2R antagonist

    Launched

    (Chu et al., 2008)

    5

    l-SPD (81)

    Alkaloid/

    Corydalis yanhusuo

    D1R partial agonist;

    D2R antagonist

    Clinical

    (Chu et al., 2008)

    6

    Tetrodotoxin (94)

    Alkaloid/

    Takifugu

    NaV1.7, NaV1.3 channels blocker

    Phase III

    (Melnikova et al., 2018)

    7

    Neosaxitoxin (95)

    Alkaloid/

    marine dinoflagellate

    NaV1.4 channel blocker

    Phase II

    (Rathmell et al., 2015)

    8

    Psilocybin (43)

    Alkaloid/

    Psilocybe

    5-HT2A receptor agonist

    5-HT1A receptor agonist

    Phase II

    (Whelan and Johnson, 2018)

    9

    Pellitorine (96)

    Alkaloid/

    Tetradium

    TRPV1 antagonist

    Preclinical

    (Oláh et al., 2017)

    10

    Incarvillateine (97)

    Alkaloid/

    Incarvillea sinensis

    Activates the adenosine system

    Preclinical

    (Wang et al., 2015)

    11

    Oxysophocarpine (98)

    Alkaloid/

    Sophora flavescens

    Reduces inflammatory pain (inhibits expressions of prostaglandin E2 and cytokines)

    Preclinical

    (Yang et al., 2015)

    12

    Gastrodin (11)

    Phenolic glycoside/

    Rhizoma Gastrodiae

    Unclear

    Launched

    (Liu et al., 2018b)

    13

    Helicid (49)

    Phenolic glycoside/

    Helicid nilgirica Bedd

    Modulates the GABAergic system

    Launched

    (Zhang et al., 2017b)

    14

    Nabiximols

    Cannabinoid/

    Cannabis sative

    Cannabinoid receptors agonist

    Launched

    (Russo et al., 2016)

    15

    Δ9-THC (22)

    Cannabinoid/

    Cannabis sative

    Cannabinoid receptors agonist, et al.

    Phase III

    (Kim and Fishman, 2017)

    16

    (–)-β-Caryophyllene (40)

    Terpenoid/

    Cannabis sative

    CB2R agonist

    Preclinical

    (Klauke et al., 2014)

    17

    Carnosol (99)

    Terpenoid/

    Salvia officinalis

    mPGES-1 inhibitor;

    5-LO inhibitor;

    COXs inhibitor

    Preclinical

    (Maione et al., 2017)

    18

    Carnosic acid (100)

    Terpenoid/

    Salvia officinalis

    mPGES-1 inhibitor;

    5-LO inhibitor;

    COXs inhibitor

    Preclinical

    (Maione et al., 2017)

    19

    Xylopic acid (101)

    Terpenoid/

    Xylopia aethiopica

    Unclear

    Preclinical

    (Woode et al., 2016)

    20

    Ligustilide (102)

    Terpenoid/

    Angelica sinensis

    Reduces Toll-like receptor 4 expression in spinal astrocytes

    Preclinical

    (Qian et al., 2016; Wang et al., 2017b)

    21

    Budlein A (103)

    Terpenoid/

    Viguiera robusta

    Reduces inflammatory pain (modulates NF-κB activation and inflammasome assembly)

    Preclinical

    (Fattori et al., 2018)

    22

    (+)-Euphol (104)

    Terpenoid /

    Euphorbia kansui

    Modulates protein kinase C epsilon (PKCε)

    Preclinical

    (Dutra et al., 2015)

    23

    α-Spinasterol (105)

    Steroid/

    Phytolacca americana

    COXs inhibitor;

    TRPV1 antagonist

    Preclinical

    (Brusco et al., 2017)

  • Table 7   Natural products and their derivatives for the treatment of PD

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    EGCG (9)

    Polyphenol/

    Green tea

    Inhibits oxidative stress;

    induces iron-chelating effects; inhibits COMT and DAT

    Phase II

    (Singh et al., 2016)

    2

    ECG (106)

    3

    Baicalein (107)

    Flavone/

    Scutellaria baicalensis

    Modulates α-synuclein fibrillation; antioxidant

    Phase I

    (Li et al., 2017)

    4

    Echinacoside (15)

    Polyphenol/

    Echinacea angustifolia

    Neuroprotective effects;

    apoptosis inhibitor;

    free radical scavenger

    Preclinical

    (Liu et al., 2018a)

    5

    γ-mangostin (108)

    Polyphenol/

    Garcinia mangostana

    Antioxidant;

    reduces apoptosis

    Preclinical

    (Jaisin et al., 2018)

    6

    Isobavachalcone (109)

    Polyphenol/

    Psoralea corylifolia

    Anti-neuroinflammatory; antioxidant

    Preclinical

    (Jing et al., 2017)

    7

    3-O-Demethylswertipunicoside (110)

    Flavone/

    Swertia punicea

    Neuroprotective effects;

    growth-promoting effects on spine density;

    Preclinical

    (Zhou et al., 2015)

    8

    Amentoflavone (111)

    Flavone/

    Selaginella tamariscina

    Activating PI3K/Akt and ERK signaling pathways and attenuating neuroinflammation

    Preclinical

    (Cao et al., 2017)

    9

    2′,3′-dihydroxy-4′,6′-dimethoxychalcone (112)

    Flavone/

    Perilla frutescens

    (leaves)

    Nuclear factor erythroid 2-related factor 2 -antioxidant response element activator

    Preclinical

    (Masaki et al., 2017)

    10

    (+)-Sesamin (66)

    Phenylpropanoid/

    Sesamumindicum

    Enhances dopamine biosynthesis and increases dopamine levels; reduces apoptosis

    Preclinical

    (Bournival et al., 2012; Zhang et al., 2012a)

    11

    (–)-Sesamin (113)

    Phenylpropanoid/

    AsiasariRadix

    Improves habit learning memory and spatial memory

    Preclinical

    (Zhao et al., 2016a)

    12

    Schisantherin A (114)

    Phenylpropanoid/

    Schisandrachinensis

    Anti-inflammatory

    Preclinical

    (Sa et al., 2015b)

    13

    Licopyranocoumarin (115)

    Phenylpropanoid/

    Glycyrrhizauralensis

    Neuroprotective effects

    Preclinical

    (Fujimaki et al., 2014)

    14

    Glycyrurol (116)

    Phenylpropanoid/

    Glycyrrhizauralensis

    Neuroprotective effects

    Preclinical

    (Fujimaki et al., 2014)

    15

    Apocynin (117)

    Essential oil/

    Paeonia suffruticosa

    NOX inhibitor

    Phase I

    (Sharma et al., 2016)

    16

    Smilagenin (23)

    Steroid/

    Rhizoma Anemarrhenae

    Neurotrophic factor enhancer

    Phase II (Discontinued)

    (Zhang et al., 2012b)

    17

    Ginsenoside-Rg1 (118)

    Triterpenoid saponin /

    Ginseng

    (Panax species)

    Anti-inflammatory antioxidant;

    anti-apoptosis

    Preclinical

    (Song et al., 2017)

    18

    Erinacine A (119)

    Terpenoid/

    Hericium erinaceus

    Anti-inflammatory

    Preclinical

    (Kuo et al., 2016)

  • Table 8   Natural products and their derivatives for the treatment of ALS

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Sarsagenin (120)

    Steroid/

    Rhizoma Anemarrhenae

    Protects against neuronal damage; increases neurite outgrowth;antioxidant

    Phase I

    (Pan et al., 2017)

    2

    n-Butylidenephthalide (121)

    Essential oil/

    Angelica sinensis

    Inhibits inflammatory, oxidative stress and autophagy

    Preclinical

    (Zhou et al., 2017)

    3

    DL-3-n-butylphthalide (122)

    Essential oil/

    Synthetic racemate ofL-3-n-butylphthalide

    Improves mitochondrial function; reduces neural apoptosis;

    Preclinical

    (Feng et al., 2012)

  • Table 9   Natural products and their derivatives for the treatment of ASD

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    CBD (67)

    Cannabinoid/

    Cannabis sative

    Unclear

    Clinical

    (Poleg et al., 2018)

    2

    CBDV (68)

    Cannabinoid/

    Cannabis sative

    Unclear

    Phase I

    (Poleg et al., 2018)

    3

    Sulforaphane (124)

    Brassica oleracea

    “Fever effect”

    Clinical

    (Singh and Zimmerman, 2016)

  • Table 10   Natural products and their derivatives for the treatment of HD

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Nabiximols

    Cannabinoid/

    Cannabis sative

    Reduces excitotoxicity andinflammation; antioxidant

    Phase II

    (Sagredo et al., 2012)

    2

    Fisetin (125)

    Flavone/

    Toxicodendronvernicifluum

    Activates ERK

    Preclinical

    (Maher et al., 2011)

    3

    T1-11 (126)

    Alkaloid/

    Gastrodia elata

    A2A receptor agonist; ENT1inhibitor

    Preclinical

    (Huang et al., 2011)

  • Table 11   Natural products and their derivatives for the treatment of MS

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    Nabiximols

    Cannabinoid/

    Cannabis sative

    Improves MS-related spasticity, pain and sleep disturbances

    Launched

    (Rice and Cameron, 2018)

    2

    Δ9-THC (22)

    Cannabinoid/

    Cannabis sative

    Improves MS-related spasticity, pain and sleep disturbances

    Phase II

    (Rice and Cameron, 2018)

    3

    EGCG (9)

    Polyphenol/

    green tea

    Anti-inflammatory;

    increases Olig1 and PLP expressions

    Phase II/III

    (Semnani et al., 2017)

    4

    (–)-β-Caryophyllene (40)

    Terpenoids/

    Cannabis sative

    CB2R agonist

    Preclinical

    (Alberti et al., 2017)

    5

    Glucomoringin isothiocyanate (127)

    Glucosinolate/

    Moringaoleifera

    Anti-inflammatory

    Preclinical

    (Galuppo et al., 2014)

    6

    Plumbagin (128)

    Phenol/

    Droseraceae

    Restricts the expression of Th1- and Th17-polarizing cytokines

    Preclinical

    (Zhang et al., 2014)

  • Table 12   Natural products and their derivatives for the treatment of schizophrenia

    No.

    Compound

    Category/source

    Mechanism of action

    Phase

    References

    1

    CBD (67)

    Cannabinoid/

    Cannabis sative

    Inhibits the reuptake of AEA

    Phase II

    (Scherma et al., 2018)

    2

    L-Theanine (129)

    Amino acid/

    Green tea

    Modulates the glutamatergic system

    Preclinical

    (Ota et al., 2015)

    3

    Maslinic acid (130)

    Terpenoid/

    Syzygium aromaticum

    Activates Akt-GSK-3β and ERK-CREB

    Preclinical

    (Jeon et al., 2017)

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