Download PDF
Planta Med 2019; 85(17): 1304-1315
DOI: 10.1055/a-0953-6738
Biological and Pharmacological Activity
Reviews
Georg Thieme Verlag KG Stuttgart · New York

Molecular Targets Involved in the Neuroprotection Mediated by Terpenoids

Laura González-Cofrade
1   Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, University Complutense of Madrid, Ciudad Universitaria s/n, Madrid, Spain
,
Beatriz de las Heras
1   Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, University Complutense of Madrid, Ciudad Universitaria s/n, Madrid, Spain
,
Luis Apaza Ticona
1   Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, University Complutense of Madrid, Ciudad Universitaria s/n, Madrid, Spain
2   Department of Chemistry, Faculty of Sciences, University Autonoma of Madrid, Cantoblanco, Madrid, Spain
,
Olga M. Palomino
1   Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, University Complutense of Madrid, Ciudad Universitaria s/n, Madrid, Spain
› Author Affiliations
Further Information

Publication History

received 10 April 2019
revised 29 May 2019

accepted 06 June 2019

Publication Date:
24 June 2019 (online)

   Permissions and Reprints

Abstract

Natural products and their derivatives represent the most consistently successful source of drug leads. Terpenoids, a structurally diverse group, are secondary metabolites widely distributed in nature, endowed with a wide range of biological activities such as antibacterial, anti-inflammatory, antitumoral, or neuroprotective effects, which consolidate their therapeutic value. During the last decades, and taking into consideration the prevalence of aging-related diseases, research activity into the neuroprotective effects of these types of compounds has increased enormously. Several signaling pathways involved in neuroprotection are targets of their mechanism of action and mediate their pleiotropic protective activity in neuronal cell damage. In the present review, molecular basis of the neuroprotection exerted by terpenoids is presented, focusing on preclinical evidence of the therapeutic potential of diterpenoids and triterpenoids on neurodegenerative disorders. By acting on diverse mechanisms simultaneously, terpenoids have been emphasized as promising multitarget agents.

Key words

antioxidant - radical scavenging - diterpenoids - triterpenoids - neuroprotection - molecular targets - activities
 

  • References

  • 1 Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimerʼs disease: Past, present and future. Neuropharmacology 2014; 76 Pt A: 27-50
    CrossrefPubMedGoogle Scholar
  • 2 Alzheimerʼs Association. 2016 Alzheimerʼs disease facts and figures. Alzheimers Dement 2016; 12: 459-509
    CrossrefPubMedGoogle Scholar
  • 3 Elbaz A, Carcaillon L, Kab S, Moisan F. Epidemiology of Parkinsonʼs disease. Rev Neurol (Paris) 2016; 172: 14-26
    CrossrefPubMedGoogle Scholar
  • 4 Gandhi S, Vaarmann A, Yao Z, Duchen MR, Wood NW, Abramov AY. Dopamine induced neurodegeneration in a PINK1 model of Parkinsonʼs disease. PLoS One 2012; 7: e37564
    CrossrefPubMedGoogle Scholar
  • 5 Han MH, Lee EH, Koh SH. Current opinion on the role of neurogenesis in the therapeutic strategies for Alzheimer disease, Parkinson disease, and ischemic stroke; considering neuronal voiding function. Int Neurourol J 2016; 20: 276-287
    CrossrefPubMedGoogle Scholar
  • 6 Almasieh M, Levin LA. Neuroprotection in glaucoma: animal models and clinical trials. Annu Rev Vis Sci 2017; 3: 91-120
    CrossrefPubMedGoogle Scholar
  • 7 Levin LA, Crowe ME, Quigley HA. Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants. Neuroprotection for glaucoma: Requirements for clinical translation. Exp Eye Res 2017; 157: 34-37
    CrossrefPubMedGoogle Scholar
  • 8 Bagli E, Goussia A, Moschos MM, Agnantis N, Kitsos G. Natural compounds and neuroprotection: mechanisms of action and novel delivery systems. In Vivo 2016; 30: 535-547
    PubMedGoogle Scholar
  • 9 Choi DY, Choi H. Natural products from marine organisms with neuroprotective activity in the experimental models of Alzheimerʼs disease, Parkinsonʼs disease and ischemic brain stroke: their molecular targets and action mechanisms. Arch Pharm Res 2015; 38: 139-170
    CrossrefPubMedGoogle Scholar
  • 10 Shal B, Ding W, Ali H, Kim YS, Khan S. Anti-neuroinflammatory potential of natural products in attenuation of Alzheimerʼs disease. Front Pharmacol 2018; 9: 548
    CrossrefPubMedGoogle Scholar
  • 11 Velmurugan BK, Rathinasamy B, Lohanathan BP, Thiyagarajan V, Weng CF. Neuroprotective role of phytochemicals. Molecules 2018; 23: E2485
    CrossrefPubMedGoogle Scholar
  • 12 Wenzel TJ, Klegeris A. Novel multi-target directed ligand-based strategies for reducing neuroinflammation in Alzheimerʼs disease. Life Sci 2018; 207: 314-322
    CrossrefPubMedGoogle Scholar
  • 13 Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science 2016; 353: 777-783
    CrossrefPubMedGoogle Scholar
  • 14 Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders – a review. Curr Neurol Neurosci Rep 2017; 17: 25
    CrossrefPubMedGoogle Scholar
  • 15 Williams PA, Marsh-Armstrong N, Howell GR. Neuroinflammation in glaucoma: a new opportunity. Exp Eye Res 2017; 157: 20-27
    CrossrefPubMedGoogle Scholar
  • 16 Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 2016; 13: 3391-3396
    CrossrefPubMedGoogle Scholar
  • 17 Camandola S, Mattson MP. NF-kappa B as a therapeutic target in neurodegenerative diseases. Expert Opin Ther Targets 2007; 11: 123-132
    CrossrefPubMedGoogle Scholar
  • 18 Churchward MA, Tchir DR, Todd KG. Microglial function during glucose deprivation: inflammatory and neuropsychiatric implications. Mol Neurobiol 2018; 55: 1477-1487
    CrossrefPubMedGoogle Scholar
  • 19 Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 2016; 53: 1181-1194
    CrossrefPubMedGoogle Scholar
  • 20 Kim EK, Choi EJ. Compromised MAPK signaling in human diseases: an update. Arch Toxicol 2015; 89: 867-882
    CrossrefPubMedGoogle Scholar
  • 21 Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, OʼHare E, Esler WP, Maggio JE, Mantyh PW. Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo . J Neurosci 1998; 18: 2161-2173
    CrossrefPubMedGoogle Scholar
  • 22 Dal Pra I, Chiarini A, Gui L, Chakravarthy B, Pacchiana R, Gardenal E, Whitfield JF, Armato U. Do astrocytes collaborate with neurons in spreading the “infectious” aβ and Tau drivers of Alzheimerʼs disease?. Neuroscientist 2015; 21: 9-29
    CrossrefPubMedGoogle Scholar
  • 23 Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004; 1: 14
    CrossrefPubMedGoogle Scholar
  • 24 Boissiere F, Hunot S, Faucheux B, Duyckaerts C, Hauw JJ, Agid Y, Hirsch EC. Nuclear translocation of NF-kappaB in cholinergic neurons of patients with Alzheimerʼs disease. Neuroreport 1997; 8: 2849-2852
    CrossrefPubMedGoogle Scholar
  • 25 Valerio A, Boroni F, Benarese M, Sarnico I, Ghisi V, Bresciani LG, Ferrario M, Borsani G, Spano P, Pizzi M. NF-kappaB pathway: a target for preventing beta-amyloid (Abeta)-induced neuronal damage and Abeta42 production. Eur J Neurosci 2006; 23: 1711-1720
    CrossrefPubMedGoogle Scholar
  • 26 Maino B, Paparone S, Severini C, Ciotti MT, DʼAgata V, Calissano P, Cavallaro S. Drug target identification at the crossroad of neuronal apoptosis and survival. Expert Opin Drug Discov 2017; 12: 249-259
    CrossrefPubMedGoogle Scholar
  • 27 Radi E, Formichi P, Battisti C, Federico A. Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis 2014; 42 (Suppl. 03) S125-S152
    CrossrefPubMedGoogle Scholar
  • 28 Kiraz Y, Adan A, Kartal Yandim M, Baran Y. Major apoptotic mechanisms and genes involved in apoptosis. Tumour Biol 2016; 37: 8471-8486
    CrossrefPubMedGoogle Scholar
  • 29 Obulesu M, Lakshmi MJ. Apoptosis in Alzheimerʼs disease: an understanding of the physiology, pathology and therapeutic avenues. Neurochem Res 2014; 39: 2301-2312
    CrossrefPubMedGoogle Scholar
  • 30 Ghavami S, Shojaei S, Yeganeh B, Ande SR, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA, Los MJ. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014; 112: 24-49
    CrossrefPubMedGoogle Scholar
  • 31 Burstein E, Duckett CS. Dying for NF-κB? Control of cell death by transcriptional regulation of the apoptotic machinery. Curr Opin Cell Biol 2003; 15: 732-737
    CrossrefPubMedGoogle Scholar
  • 32 Kuwana T, Newmeyer DD. Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 2003; 15: 691-699
    CrossrefPubMedGoogle Scholar
  • 33 Mettang M, Reichel SN, Lattke M, Palmer A, Abaei A, Rasche V, Huber-Lang M, Baumann B, Wirth T. IKK2/NF-kappaB signaling protects neurons after traumatic brain injury. FASEB J 2018; 32: 1916-1932
    CrossrefPubMedGoogle Scholar
  • 34 Yu HJ, Koh SH. The role of PI3K/AKT pathway and its therapeutic possibility in Alzheimerʼs disease. Hanyang Med Rev 2017; 37: 18-24
    CrossrefPubMedGoogle Scholar
  • 35 Heras-Sandoval D, Perez-Rojas JM, Hernandez-Damian J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 2014; 26: 2694-2701
    CrossrefPubMedGoogle Scholar
  • 36 Caccamo A, Maldonado MA, Majumder S, Medina DX, Holbein W, Magri A, Oddo S. Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. J Biol Chem 2011; 286: 8924-8932
    CrossrefPubMedGoogle Scholar
  • 37 Leidal AM, Levine B, Debnath J. Autophagy and the cell biology of age-related disease. Nat Cell Biol 2018; 20: 1338-1348
    CrossrefPubMedGoogle Scholar
  • 38 Yue Z, Friedman L, Komatsu M, Tanaka K. The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases. Biochim Biophys Acta 2009; 1793: 1496-1507
    PubMedGoogle Scholar
  • 39 Gerónimo-Olvera C, Massieu L. Autophagy as a homeostatic mechanism in response to stress conditions in the central nervous system. Mol Neurobiol 2019; DOI: 10.1007/s12035-019-1546-x.
    CrossrefPubMedGoogle Scholar
  • 40 Singh AK, Kashyap MP, Tripathi VK, Singh S, Garg G, Rizvi SI. Neuroprotection through rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB signaling against amyloid-beta-induced oxidative stress, synaptic/neurotransmission dysfunction, and neurodegeneration in adult rats. Mol Neurobiol 2017; 54: 5815-5828
    CrossrefPubMedGoogle Scholar
  • 41 Xu J, Huai Y, Meng N, Dong Y, Liu Z, Qi Q, Hu M, Fan M, Jin W, Lv P. L-3-n-Butylphthalide activates Akt/mTOR signaling, inhibits neuronal apoptosis and autophagy and improves cognitive impairment in mice with repeated cerebral ischemia-reperfusion injury. Neurochem Res 2017; 42: 2968-2981
    CrossrefPubMedGoogle Scholar
  • 42 Arthur JSC, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 2013; 13: 679-692
    CrossrefPubMedGoogle Scholar
  • 43 Peti W, Page R. Molecular basis of MAP kinase regulation. Protein Sci 2013; 22: 1698-1710
    CrossrefPubMedGoogle Scholar
  • 44 Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ʼtwo hitʼ hypothesis. Mech Ageing Dev 2001; 123: 39-46
    CrossrefPubMedGoogle Scholar
  • 45 Franco R, Martinez-Pinilla E, Navarro G, Zamarbide M. Potential of GPCRs to modulate MAPK and mTOR pathways in Alzheimerʼs disease. Prog Neurobiol 2017; 149 – 150: 21-38
    PubMedGoogle Scholar
  • 46 Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 2012; 5: 14
    CrossrefPubMedGoogle Scholar
  • 47 Yuste JE, Tarragon E, Campuzano CM, Ros-Bernal F. Implications of glial nitric oxide in neurodegenerative diseases. Front Cell Neurosci 2015; 9: 322
    PubMedGoogle Scholar
  • 48 Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 2016; 73: 3221-3247
    CrossrefPubMedGoogle Scholar
  • 49 Kerr F, Sofola-Adesakin O, Ivanov DK, Gatliff J, Gomez Perez-Nievas B, Bertrand HC, Martinez P, Callard R, Snoeren I, Cocheme HM, Adcott J, Khericha M, Castillo-Quan JI, Wells G, Noble W, Thornton J, Partridge L. Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimerʼs disease. PLoS Genet 2017; 13: e1006593
    CrossrefPubMedGoogle Scholar
  • 50 Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimerʼs disease and amyotrophic lateral sclerosis. EMBO J 2007; 26: 3169-3179
    CrossrefPubMedGoogle Scholar
  • 51 Bankston AN, Mandler MD, Feng Y. Oligodendroglia and neurotrophic factors in neurodegeneration. Neurosci Bull 2013; 29: 216-228
    CrossrefPubMedGoogle Scholar
  • 52 Longo FM, Massa SM. Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov 2013; 12: 507-525
    CrossrefPubMedGoogle Scholar
  • 53 Mariga A, Mitre M, Chao MV. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease. Neurobiol Dis 2017; 97: 73-79
    CrossrefPubMedGoogle Scholar
  • 54 LʼEpiscopo F, Tirolo C, Caniglia S, Testa N, Morale MC, Serapide MF, Pluchino S, Marchetti B. Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotection/repair in Parkinsonʼs disease. J Mol Cell Biol 2014; 6: 13-26
    CrossrefPubMedGoogle Scholar
  • 55 Chen SR, Dai Y, Zhao J, Lin L, Wang Y, Wang Y. A mechanistic overview of triptolide and celastrol, natural products from Tripterygium wilfordii Hook F. Front Pharmacol 2018; 9: 104
    CrossrefPubMedGoogle Scholar
  • 56 Zheng Y, Zhang WJ, Wang XM. Triptolide with potential medicinal value for diseases of the central nervous system. CNS Neurosci Ther 2013; 19: 76-82
    CrossrefPubMedGoogle Scholar
  • 57 Zhou ZL, Yang YX, Ding J, Li YC, Miao ZH. Triptolide: structural modifications, structure-activity relationships, bioactivities, clinical development and mechanisms. Nat Prod Rep 2012; 29: 457-475
    CrossrefPubMedGoogle Scholar
  • 58 Hao M, Li X, Feng J, Pan N. Triptolide protects against ischemic stroke in rats. Inflammation 2015; 38: 1617-1623
    CrossrefPubMedGoogle Scholar
  • 59 Zhang B, Song C, Feng B, Fan W. Neuroprotection by triptolide against cerebral ischemia/reperfusion injury through the inhibition of NF-kappaB/PUMA signal in rats. Ther Clin Risk Manag 2016; 12: 817-824
    PubMedGoogle Scholar
  • 60 Xu P, Li Z, Wang H, Zhang X, Yang Z. Triptolide inhibited cytotoxicity of differentiated PC12 cells induced by amyloid-beta25–35 via the autophagy pathway. PLoS One 2015; 10: e0142719
    CrossrefPubMedGoogle Scholar
  • 61 Bai S, Hu Z, Yang Y, Yin Y, Li W, Wu L, Fang M. Anti-inflammatory and neuroprotective effects of triptolide via the NF-kappaB signaling pathway in a rat MCAO model. Anat Rec (Hoboken) 2016; 299: 256-266
    CrossrefPubMedGoogle Scholar
  • 62 Li W, Yang Y, Hu Z, Ling S, Fang M. Neuroprotective effects of DAHP and triptolide in focal cerebral ischemia via apoptosis inhibition and PI3K/Akt/mTOR pathway activation. Front Neuroanat 2015; 9: 48
    PubMedGoogle Scholar
  • 63 Yang Y, Gao K, Hu Z, Li W, Davies H, Ling S, Rudd JA, Fang M. Autophagy upregulation and apoptosis downregulation in DAHP and triptolide treated cerebral ischemia. Mediators Inflamm 2015; 2015: 120198
    PubMedGoogle Scholar
  • 64 Lee HF, Lee TS, Kou YR. Anti-inflammatory and neuroprotective effects of triptolide on traumatic brain injury in rats. Respir Physiol Neurobiol 2012; 182: 1-8
    CrossrefPubMedGoogle Scholar
  • 65 Hu G, Gong X, Wang L, Liu M, Liu Y, Fu X, Wang W, Zhang T, Wang X. Triptolide promotes the clearance of alpha-synuclein by enhancing autophagy in neuronal cells. Mol Neurobiol 2017; 54: 2361-2372
    CrossrefPubMedGoogle Scholar
  • 66 Wan B, Hu X, Nie J, Zhou M, Yang B, Li Y, Wen W, Lu C. Effects of triptolide on degeneration of dendritic spines induced by Aβ1–40 injection in rat hippocampus. Neurol Sci 2014; 35: 35-40
    CrossrefPubMedGoogle Scholar
  • 67 Gao JP, Sun S, Li WW, Chen YP, Cai DF. Triptolide protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats: implication for immunosuppressive therapy in Parkinsonʼs disease. Neurosci Bull 2008; 24: 133-142
    CrossrefPubMedGoogle Scholar
  • 68 Yang F, Wu L, Guo X, Wang D, Li Y. Improved retinal ganglion cell survival through retinal microglia suppression by a chinese herb extract, triptolide, in the DBA/2 J mouse model of glaucoma. Ocul Immunol Inflamm 2013; 21: 378-389
    CrossrefPubMedGoogle Scholar
  • 69 Yang F, Wu L, Li Y, Wang D. Protective effects of triptolide on retinal ganglion cells in a rat model of chronic glaucoma. Drug Des Devel Ther 2015; 9: 6095-6107
    PubMedGoogle Scholar
  • 70 Xue B, Jiao J, Zhang L, Li KR, Gong YT, Xie JX, Wang XM. Triptolide upregulates NGF synthesis in rat astrocyte cultures. Neurochem Res 2007; 32: 1113-1119
    CrossrefPubMedGoogle Scholar
  • 71 Ning C, Mo L, Chen X, Tu W, Wu J, Hou S, Xu J. Triptolide derivatives as potential multifunctional anti-Alzheimer agents: synthesis and structure-activity relationship studies. Bioorg Med Chem Lett 2018; 28: 689-693
    CrossrefPubMedGoogle Scholar
  • 72 Kishore V, Yarla NS, Bishayee A, Putta S, Malla R, Neelapu NR, Challa S, Das S, Shiralgi Y, Hegde G, Dhananjaya BL. Multi-targeting andrographolide and its natural analogs as potential therapeutic agents. Curr Top Med Chem 2017; 17: 845-857
    CrossrefPubMedGoogle Scholar
  • 73 Yang CH, Yen TL, Hsu CY, Thomas PA, Sheu JR, Jayakumar T. Multi-targeting andrographolide, a novel NF-kappaB inhibitor, as a potential therapeutic agent for stroke. Int J Mol Sci 2017; 18: E1638
    CrossrefPubMedGoogle Scholar
  • 74 Chern CM, Liou KT, Wang YH, Liao JF, Yen JC, Shen YC. Andrographolide inhibits PI3K/AKT-dependent NOX2 and iNOS expression protecting mice against hypoxia/ischemia-induced oxidative brain injury. Planta Med 2011; 77: 1669-1679
    Article in Thieme ConnectPubMedGoogle Scholar
  • 75 Tao L, Zhang L, Gao R, Jiang F, Cao J, Liu H. Andrographolide alleviates acute brain injury in a rat model of traumatic brain injury: possible involvement of inflammatory signaling. Front Neurosci 2018; 12: 657
    CrossrefPubMedGoogle Scholar
  • 76 Chan SJ, Wong WS, Wong PT, Bian JS. Neuroprotective effects of andrographolide in a rat model of permanent cerebral ischaemia. Br J Pharmacol 2010; 161: 668-679
    CrossrefPubMedGoogle Scholar
  • 77 Yen TL, Chen RJ, Jayakumar T, Lu WJ, Hsieh CY, Hsu MJ, Yang CH, Chang CC, Lin YK, Lin KH, Sheu JR. Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats. Transl Res 2016; 170: 57-72
    CrossrefPubMedGoogle Scholar
  • 78 Wong SY, Tan MGK, Wong PTH, Herr DR, Lai MKP. Andrographolide induces Nrf2 and heme oxygenase 1 in astrocytes by activating p38 MAPK and ERK. J Neuroinflammation 2016; 13: 251
    CrossrefPubMedGoogle Scholar
  • 79 Du J, Zhang C, Na X, Li A, Zhang Q, Li K, Ding Y. Andrographolide protects mouse astrocytes against hypoxia injury by promoting autophagy and S100B expression. Braz J Med Biol Res 2018; 51: e7061
    PubMedGoogle Scholar
  • 80 Rivera DS, Lindsay C, Codocedo JF, Morel I, Pinto C, Cisternas P, Bozinovic F, Inestrosa NC. Andrographolide recovers cognitive impairment in a natural model of Alzheimerʼs disease (Octodon degus). Neurobiol Aging 2016; 46: 204-220
    CrossrefPubMedGoogle Scholar
  • 81 Serrano FG, Tapia-Rojas C, Carvajal FJ, Hancke J, Cerpa W, Inestrosa NC. Andrographolide reduces cognitive impairment in young and mature AβPPswe/PS-1 mice. Mol Neurodegener 2014; 9: 61
    CrossrefPubMedGoogle Scholar
  • 82 Wang T, Liu B, Zhang W, Wilson B, Hong JS. Andrographolide reduces inflammation-mediated dopaminergic neurodegeneration in mesencephalic neuron-glia cultures by inhibiting microglial activation. J Pharmacol Exp Ther 2004; 308: 975-983
    CrossrefPubMedGoogle Scholar
  • 83 Varela-Nallar L, Arredondo SB, Tapia-Rojas C, Hancke J, Inestrosa NC. Andrographolide stimulates neurogenesis in the adult hippocampus. Neural Plast 2015; 2015: 935403
    PubMedGoogle Scholar
  • 84 Dai Y, Chen SR, Chai L, Zhao J, Wang Y, Wang Y. Overview of pharmacological activities of Andrographis paniculata and its major compound andrographolide. Crit Rev Food Sci Nutr 2018; 59 (Suppl. 01) S17-S29
    PubMedGoogle Scholar
  • 85 Geng J, Liu W, Xiong Y, Ding H, Jiang C, Yang X, Li X, Elgehama A, Sun Y, Xu Q, Guo W, Gao J. Andrographolide sulfonate improves Alzheimer-associated phenotypes and mitochondrial dysfunction in APP/PS1 transgenic mice. Biomed Pharmacother 2018; 97: 1032-1039
    CrossrefPubMedGoogle Scholar
  • 86 Zhang Z, Lai D, Wang L, Yu P, Zhu L, Guo B, Xu L, Zhou L, Sun Y, Lee SM, Wang Y. Neuroprotective effects of the andrographolide analogue AL-1 in the MPP(+)/MPTP-induced Parkinsonʼs disease model in vitro and in mice. Pharmacol Biochem Behav 2014; 122: 191-202
    CrossrefPubMedGoogle Scholar
  • 87 Javed S, Tariq A, Ahmed T, Budzynska B, Tejada S, Daglia M, Nabavi SF, Sobarzo-Sanchez E, Nabavi SM. Tanshinones and mental diseases: from chemistry to medicine. Rev Neurosci 2016; 27: 777-791
    CrossrefPubMedGoogle Scholar
  • 88 Dai C, Liu Y, Dong Z. Tanshinone I alleviates motor and cognitive impairments via suppressing oxidative stress in the neonatal rats after hypoxic-ischemic brain damage. Mol Brain 2017; 10: 52
    CrossrefPubMedGoogle Scholar
  • 89 Park JH, Park O, Cho JH, Chen BH, Kim IH, Ahn JH, Lee JC, Yan BC, Yoo KY, Lee CH, Hwang IK, Kwon SH, Lee YL, Won MH, Choi JH. Anti-inflammatory effect of tanshinone I in neuroprotection against cerebral ischemia-reperfusion injury in the gerbil hippocampus. Neurochem Res 2014; 39: 1300-1312
    CrossrefPubMedGoogle Scholar
  • 90 Jing X, Wei X, Ren M, Wang L, Zhang X, Lou H. Neuroprotective effects of tanshinone I against 6-OHDA-induced oxidative stress in cellular and mouse model of Parkinsonʼs disease through upregulating Nrf2. Neurochem Res 2016; 41: 779-786
    CrossrefPubMedGoogle Scholar
  • 91 Wang S, Jing H, Yang H, Liu Z, Guo H, Chai L, Hu L. Tanshinone I selectively suppresses pro-inflammatory genes expression in activated microglia and prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinsonʼs disease. J Ethnopharmacol 2015; 164: 247-255
    CrossrefPubMedGoogle Scholar
  • 92 Chen Y, Wu X, Yu S, Fauzee NJ, Wu J, Li L, Zhao J, Zhao Y. Neuroprotective capabilities of Tanshinone IIA against cerebral ischemia/reperfusion injury via anti-apoptotic pathway in rats. Biol Pharm Bull 2012; 35: 164-170
    CrossrefPubMedGoogle Scholar
  • 93 Yin X, Yin Y, Cao FL, Chen YF, Peng Y, Hou WG, Sun SK, Luo ZJ. Tanshinone IIA attenuates the inflammatory response and apoptosis after traumatic injury of the spinal cord in adult rats. PLoS One 2012; 7: e38381
    CrossrefPubMedGoogle Scholar
  • 94 Zhu Y, Tang Q, Wang G, Han R. Tanshinone IIA protects hippocampal neuronal cells from reactive oxygen species through changes in autophagy and activation of phosphatidylinositol 3-kinase, protein kinas B, and mechanistic target of rapamycin pathways. Curr Neurovasc Res 2017; 14: 132-140
    PubMedGoogle Scholar
  • 95 Liu L, Zhang X, Wang L, Yang R, Cui L, Li M, Du W, Wang S. The neuroprotective effects of tanshinone IIA are associated with induced nuclear translocation of TORC1 and upregulated expression of TORC1, pCREB and BDNF in the acute stage of ischemic stroke. Brain Res Bull 2010; 82: 228-233
    CrossrefPubMedGoogle Scholar
  • 96 Cai M, Guo Y, Wang S, Wei H, Sun S, Zhao G, Dong H. Tanshinone IIA elicits neuroprotective effect through activating the nuclear factor erythroid 2-related factor-dependent antioxidant response. Rejuvenation Res 2017; 20: 286-297
    CrossrefPubMedGoogle Scholar
  • 97 Yao NW, Lu Y, Shi LQ, Xu F, Cai XH. Neuroprotective effect of combining tanshinone IIA with low-dose methylprednisolone following acute spinal cord injury in rats. Exp Ther Med 2017; 13: 2193-2202
    CrossrefPubMedGoogle Scholar
  • 98 Maione F, Piccolo M, De Vita S, Chini MG, Cristiano C, De Caro C, Lippiello P, Miniaci MC, Santamaria R, Irace C, De Feo V, Calignano A, Mascolo N, Bifulco G. Down regulation of pro-inflammatory pathways by tanshinone IIA and cryptotanshinone in a non-genetic mouse model of Alzheimerʼs disease. Pharmacol Res 2018; 129: 482-490
    CrossrefPubMedGoogle Scholar
  • 99 Ren B, Zhang YX, Zhou HX, Sun FW, Zhang ZF, Wei Z, Zhang CY, Si DW. Tanshinone IIA prevents the loss of nigrostriatal dopaminergic neurons by inhibiting NADPH oxidase and iNOS in the MPTP model of Parkinsonʼs disease. J Neurol Sci 2015; 348: 142-152
    CrossrefPubMedGoogle Scholar
  • 100 Xu J, Wold EA, Ding Y, Shen Q, Zhou J. Therapeutic potential of oridonin and its analogs: From anticancer and antiinflammation to neuroprotection. Molecules 2018; 23: E474
    CrossrefPubMedGoogle Scholar
  • 101 Owona BA, Schluesener HJ. Molecular insight in the multifunctional effects of oridonin. Drugs R D 2015; 15: 233-244
    CrossrefPubMedGoogle Scholar
  • 102 de Oliveira MR. The dietary components carnosic acid and carnosol as neuroprotective agents: a mechanistic view. Mol Neurobiol 2016; 53: 6155-6168
    CrossrefPubMedGoogle Scholar
  • 103 Wu CR, Tsai CW, Chang SW, Lin CY, Huang LC, Tsai CW. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinsonʼs disease: involvement of antioxidative enzymes induction. Chem Biol Interact 2015; 225: 40-46
    CrossrefPubMedGoogle Scholar
  • 104 James JT, Dubery IA. Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban. Molecules 2009; 14: 3922-3941
    CrossrefPubMedGoogle Scholar
  • 105 Nagoor Meeran MF, Goyal SN, Suchal K, Sharma C, Patil CR, Ojha SK. Pharmacological properties, molecular mechanisms, and pharmaceutical development of asiatic acid: a pentacyclic triterpenoid of therapeutic promise. Front Pharmacol 2018; 9: 892
    CrossrefPubMedGoogle Scholar
  • 106 Krishnamurthy RG, Senut MC, Zemke D, Min J, Frenkel MB, Greenberg EJ, Yu SW, Ahn N, Goudreau J, Kassab M, Panickar KS, Majid A. Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia. J Neurosci Res 2009; 87: 2541-2550
    CrossrefPubMedGoogle Scholar
  • 107 Lee KY, Bae ON, Serfozo K, Hejabian S, Moussa A, Reeves M, Rumbeiha W, Fitzgerald SD, Stein G, Baek SH, Goudreau J, Kassab M, Majid A. Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia. Stroke 2012; 43: 1632-1638
    CrossrefPubMedGoogle Scholar
  • 108 Lee KY, Bae ON, Weinstock S, Kassab M, Majid A. Neuroprotective effect of asiatic acid in rat model of focal embolic stroke. Biol Pharm Bull 2014; 37: 1397-1401
    CrossrefPubMedGoogle Scholar
  • 109 Xu MF, Xiong YY, Liu JK, Qian JJ, Zhu L, Gao J. Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells. Acta Pharmacol Sin 2012; 33: 578-587
    CrossrefPubMedGoogle Scholar
  • 110 Patil SP, Maki S, Khedkar SA, Rigby AC, Chan C. Withanolide A and asiatic acid modulate multiple targets associated with amyloid-beta precursor protein processing and amyloid-beta protein clearance. J Nat Prod 2010; 73: 1196-1202
    CrossrefPubMedGoogle Scholar
  • 111 Zhang X, Wu J, Dou Y, Xia B, Rong W, Rimbach G, Lou Y. Asiatic acid protects primary neurons against C2-ceramide-induced apoptosis. Eur J Pharmacol 2012; 679: 51-59
    CrossrefPubMedGoogle Scholar
  • 112 Ahmad Rather M, Justin Thenmozhi A, Manivasagam T, Nataraj J, Essa MM, Chidambaram SB. Asiatic acid nullified aluminium toxicity in in vitro model of Alzheimerʼs disease. Front Biosci (Elite Ed) 2018; 10: 287-299
    PubMedGoogle Scholar
  • 113 Ahmad Rather M, Justin Thenmozhi A, Manivasagam T, Dhivya Bharathi M, Essa MM, Guillemin GJ. Neuroprotective role of asiatic acid in aluminium chloride induced rat model of Alzheimerʼs disease. Front Biosci (Schol Ed) 2018; 10: 262-275
    CrossrefPubMedGoogle Scholar
  • 114 Sirichoat A, Chaijaroonkhanarak W, Prachaney P, Pannangrong W, Leksomboon R, Chaichun A, Wigmore P, Welbat JU. Effects of asiatic acid on spatial working memory and cell proliferation in the adult rat hippocampus. Nutrients 2015; 7: 8413-8423
    CrossrefPubMedGoogle Scholar
  • 115 Xiong Y, Ding H, Xu M, Gao J. Protective effects of asiatic acid on rotenone- or H2O2-induced injury in SH-SY5Y cells. Neurochem Res 2009; 34: 746-754
    CrossrefPubMedGoogle Scholar
  • 116 Nataraj J, Manivasagam T, Justin Thenmozhi A, Essa MM. Neuroprotective effect of asiatic acid on rotenone-induced mitochondrial dysfunction and oxidative stress-mediated apoptosis in differentiated SH-SYS5Y cells. Nutr Neurosci 2017; 20: 351-359
    CrossrefPubMedGoogle Scholar
  • 117 Chao PC, Lee HL, Yin MC. Asiatic acid attenuated apoptotic and inflammatory stress in the striatum of MPTP-treated mice. Food Funct 2016; 7: 1999-2005
    CrossrefPubMedGoogle Scholar
  • 118 Nataraj J, Manivasagam T, Justin Thenmozhi A, Essa MM. Neurotrophic effect of asiatic acid, a triterpene of Centella asiatica against chronic 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine hydrochloride/probenecid mouse model of Parkinsonʼs disease: the role of MAPK, PI3K-Akt-GSK3β and mTOR signalling pathways. Neurochem Res 2017; 42: 1354-1365
    CrossrefPubMedGoogle Scholar
  • 119 Huang W, Gao F, Hu F, Huang J, Wang M, Xu P, Zhang R, Chen J, Sun X, Zhang S, Wu J. Asiatic acid prevents retinal ganglion cell apoptosis in a rat model of glaucoma. Front Neurosci 2018; 12: 489
    CrossrefPubMedGoogle Scholar
  • 120 Rios JL, Manez S. New pharmacological opportunities for betulinic acid. Planta Med 2018; 84: 8-19
    Article in Thieme ConnectPubMedGoogle Scholar
  • 121 Zhang DM, Xu HG, Wang L, Li YJ, Sun PH, Wu XM, Wang GJ, Chen WM, Ye WC. Betulinic acid and its derivatives as potential antitumor agents. Med Res Rev 2015; 35: 1127-1155
    CrossrefPubMedGoogle Scholar
  • 122 Lu Q, Xia N, Xu H, Guo L, Wenzel P, Daiber A, Munzel T, Forstermann U, Li H. Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress. Nitric Oxide 2011; 24: 132-138
    CrossrefPubMedGoogle Scholar
  • 123 Lu P, Zhang CC, Zhang XM, Li HG, Luo AL, Tian YK, Xu H. Down-regulation of NOX4 by betulinic acid protects against cerebral ischemia-reperfusion in mice. J Huazhong Univ Sci Technolog Med Sci 2017; 37: 744-749
    PubMedGoogle Scholar
  • 124 Jiao S, Zhu H, He P, Teng J. Betulinic acid protects against cerebral ischemia/reperfusion injury by activating the PI3K/Akt signaling pathway. Biomed Pharmacother 2016; 84: 1533-1537
    CrossrefPubMedGoogle Scholar
  • 125 Kaundal M, Deshmukh R, Akhtar M. Protective effect of betulinic acid against intracerebroventricular streptozotocin induced cognitive impairment and neuronal damage in rats: Possible neurotransmitters and neuroinflammatory mechanism. Pharmacol Rep 2018; 70: 540-548
    CrossrefPubMedGoogle Scholar
  • 126 Kaundal M, Zameer S, Najmi AK, Parvez S, Akhtar M. Betulinic acid, a natural PDE inhibitor restores hippocampal cAMP/cGMP and BDNF, improve cerebral blood flow and recover memory deficits in permanent BCCAO induced vascular dementia in rats. Eur J Pharmacol 2018; 832: 56-66
    CrossrefPubMedGoogle Scholar
  • 127 Li C, Zhang C, Zhou H, Feng Y, Tang F, Hoi MPM, He C, Ma D, Zhao C, Lee SMY. Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKbeta-dependent AMPK activation. Front Mol Neurosci 2018; 11: 98
    CrossrefPubMedGoogle Scholar
  • 128 Ding H, Wang H, Zhu L, Wei W. Ursolic acid ameliorates early brain injury after experimental traumatic brain injury in mice by activating the nrf2 pathway. Neurochem Res 2017; 42: 337-346
    CrossrefPubMedGoogle Scholar
  • 129 Li L, Zhang X, Cui L, Wang L, Liu H, Ji H, Du Y. Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res 2013; 1497: 32-39
    CrossrefPubMedGoogle Scholar
  • 130 Caltana L, Rutolo D, Nieto ML, Brusco A. Further evidence for the neuroprotective role of oleanolic acid in a model of focal brain hypoxia in rats. Neurochem Int 2014; 79: 79-87
    CrossrefPubMedGoogle Scholar