Advances in the mechanisms of Uncaria rhynchophylla and its monomeric compounds against central nervous system diseases

doi:10.12092/j.issn.1009-2501.2026.08.012

Abstract

Abstract:

Central nervous system diseases (CNSDs) have garnered global attention as a major category of illnesses, significantly impacting worldwide health and imposing a substantial economic burden. Traditional Chinese Medicine (TCM) demonstrates both theoretical and clinical advantages in treating CNSDs. Uncaria rhynchophylla (Gouteng), a herb used for millennia to pacify the liver and extinguish wind, plays an important role in the treatment of CNSDs through multiple pathways and targets. Research indicates that indole alkaloids are its primary active constituents, with rhynchophylline and isorhynchophylline serving as the main material basis for its therapeutic effects against CNSDs. These active components exert their actions through mechanisms such as anti-inflammatory and antioxidant effects, inhibition of apoptosis, promotion of autophagy, suppression of β-amyloid peptide deposition, and prevention of abnormal Tau protein phosphorylation. This article systematically reviews the mechanisms by which Uncaria rhynchophylla and its monomeric compounds intervene in four common CNSDs—Alzheimer^,s disease, Parkinson^,s disease, epilepsy, and depression—with the aim of providing a reference for further research and clinical application of Uncaria rhynchophylla in CNSDs, and to assist researchers in understanding both the progress and limitations of current studies on its therapeutic use.

Key words: uncaria rhynchophylla, rhynchophylline, isorhynchophylline, central nervous system diseases, Alzheimer^,s disease

CLC Number:

R285
R277.7

Jingxi YAO, Yushu WEI, Wenjun YUAN, Xing WEI, Kexin SUN, Jing SHANG, Zhenggang SHI. Advances in the mechanisms of Uncaria rhynchophylla and its monomeric compounds against central nervous system diseases[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(8): 1112-1126.

Figures/Tables 6

References 86

1	唐德才, 吴庆光. 中药学 [M]. 北京: 人民卫生出版社, 2024: 291-292.
2	Jin M, Wang C, Xu Y, et al. Pharmacological effects of salidroside on central nervous system diseases[J]. Biomed Pharmacother, 2022, 156, 113746. doi: 10.1016/j.biopha.2022.113746
3	张雯昕, 张春霞, 韩凌飞, 等. 钩藤网络药理学多靶点效应价值研究进展[J]. 中国药科大学学报, 2025, 56 (3): 376- 381.
4	余俊, 黄宗雯. 钩藤属化学成分研究进展[J]. 中药材, 2021, 44 (1): 233- 239. doi: 10.3969/j.issn.1008-021X.2022.22.031
5	Cao R, Wang Y, Zhou Y, et al. Advanced researches of traditional uses, phytochemistry, pharmacology, and toxicology of medical uncariae ramulus cum uncis[J]. J Ethnopharmacol, 2024, 325, 117848. doi: 10.1016/j.jep.2024.117848
6	周泽琴, 刘方敏, 蔡延渠. 《中国药典》2020年版一部方剂中含“后下”中药的水提取工艺问题分析[J]. 广东药科大学学报, 2025, 41 (1): 136- 141. doi: 10.16809/j.cnki.2096-3653.2024101002
7	Khan AU, Nazir S, El-Keblawy A, et al. Uncaria rhynchophylla mediated Ag/NiO nanocomposites: a new insight for the evaluation of cytotoxicity, antibacterial and photocatalytic applications[J]. Photodiagnosis Photodyn Ther, 2022, 37, 102681. doi: 10.1016/j.pdpdt.2021.102681
8	Li H, Wei W, Li Z, et al. An enhanced strategy integrating offline two-dimensional separation with data independent acquisition mode and deconvolution: characterization of metabolites of uncaria rhynchophylla in rat plasma as a case[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2021, 1181, 122917. doi: 10.1016/j.jchromb.2021.122917
9	Zhang X, Wang S, Shu L, et al. Rapid screening of hepatotoxic components in uncariae ramulus cum uncis based on “component-target-pathway” network[J]. J Pharm Biomed Anal, 2022, 219, 114968. doi: 10.1016/j.jpba.2022.114968
10	Wang M, Li H, Zhao Y, et al. Rhynchophylline attenuates allergic bronchial asthma by inhibiting transforming growth factor-β1-mediated smad and mitogen-activated protein kinase signaling transductions in vivo and in vitro[J]. Exp Ther Med, 2019, 17 (1): 251- 259.
11	Lv C, Li H, Cui H, et al. Solid lipid nanoparticle delivery of rhynchophylline enhanced the efficiency of allergic asthma treatment via the upregulation of suppressor of cytokine signaling 1 by repressing the p38 signaling pathway[J]. Bioengineered, 2021, 12 (1): 8635- 8649. doi: 10.1080/21655979.2021.1988364
12	王瑞欣, 刘莉, 邹国良, 等. 基于国家专利中药复方治疗高血压病的用药规律研究[J]. 现代中药研究与实践, 2024, 38 (1): 78- 82. doi: 10.13728/j.1673-6427.2024.01.014
13	Shi FD, Yong VW. Neuroinflammation across neurological diseases[J]. Science, 2025, 388 (6753): eadx0043. doi: 10.1126/science.adx0043
14	Ravizza T, Scheper M, Di Sapia R, et al. mTOR and neuroinflammation in epilepsy: implications for disease progression and treatment[J]. Nat Rev Neurosci, 2024, 25 (5): 334- 350. doi: 10.1038/s41583-024-00805-1
15	Zhang W, Xiao D, Mao Q, et al. Role of neuroinflammation in neurodegeneration development[J]. Signal Transduct Target Ther, 2023, 8, 267. doi: 10.1038/s41392-023-01486-5
16	常承天, 刘志华, 程率芳, 等. 中药单体靶向阿尔茨海默病相关通路的药理机制研究进展[J]. 中国临床药理学与治疗学, 2025, 30 (10): 1417- 1428. doi: 10.12092/j.issn.1009-2501.2025.10.014
17	Heneka MT, Van Der Flier WM, Jessen F, et al. Neuroinflammation in alzheimer disease[J]. Nat Rev Immunol, 2025, 25 (5): 321- 352. doi: 10.1038/s41577-024-01104-7
18	Shin SJ, Jeong Y, Jeon SG, et al. Uncaria rhynchophylla ameliorates amyloid beta deposition and amyloid beta-mediated pathology in 5XFAD mice[J]. Neurochem Int, 2018, 121, 114- 124. doi: 10.1016/j.neuint.2018.10.003
19	Xian Y, Ip S, Li H, et al. Isorhynchophylline exerts antidepressant‐like effects in mice via modulating neuroinflammation and neurotrophins: involvement of the PI3K/akt/GSK‐3β signaling pathway[J]. FASEB J, 2019, 33 (9): 10393- 10408. doi: 10.1096/fj.201802743RR
20	Chen L, Huang Y, Yu X, et al. Corynoxine protects dopaminergic neurons through inducing autophagy and diminishing neuroinflammation in rotenone-induced animal models of parkinson’s disease[J]. Front Pharmacol, 2021, 12, 642900. doi: 10.3389/fphar.2021.642900
21	雷琦, 朱婷鸽, 何进伟, 等. 异钩藤碱对癫痫大鼠SIRT1/p53/caspase-3通路及海马神经元凋亡的影响[J]. 中国免疫学杂志, 2022, 38 (18): 2205- 2208. doi: 10.3969/j.issn.1000-484X.2022.18.006
22	徐利, 李莹莹, 张锦军, 等. 毛钩藤碱对6-羟基多巴胺诱导的帕金森病模型大鼠神经保护作用及机制研究[J]. 沈阳药科大学学报, 2023, 40 (5): 613- 619. doi: 10.14066/j.cnki.cn21-1349/r.2021.0836
23	Kuang Y, Zhu M, Gu H, et al. Alkaloids in uncaria rhynchophylla improves AD pathology by restraining CD4+ T cell-mediated neuroinflammation via inhibition of glycolysis in APP/PS1 mice[J]. J Ethnopharmacol, 2024, 331, 118273. doi: 10.1016/j.jep.2024.118273
24	Guo Q, Jin Y, Chen X, et al. NF-κB in biology and targeted therapy: New insights and translational implications[J]. Signal Transduct Target Ther, 2024, 9, 53. doi: 10.1038/s41392-024-01757-9
25	Mao H, Zhao X, Sun SC. NF-κB in inflammation and cancer[J]. Cell Mol Immunol, 2025, 22 (8): 811- 839. doi: 10.1038/s41423-025-01310-w
26	Yuan D, Ma B, Yang JY, et al. Anti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanism[J]. Int Immunopharmacol, 2009, 9 (13/14): 1549- 1554. doi: 10.1016/j.intimp.2009.09.010
27	Song Y, Qu R, Zhu S, et al. Rhynchophylline attenuates LPS‐induced pro‐inflammatory responses through down‐regulation of MAPK/NF‐κB signaling pathways in primary microglia[J]. Phytother Res, 2012, 26 (10): 1528- 1533. doi: 10.1002/ptr.4614
28	Deng Y, Tan R, Li F, et al. Isorhynchophylline ameliorates cerebral ischemia/reperfusion injury by inhibiting CX3CR1-mediated microglial activation and neuroinflammation[J]. Front Pharmacol, 2021, 12, 574793. doi: 10.3389/fphar.2021.574793
29	Hsieh CL, Ho TY, Su SY, et al. Uncaria rhynchophylla and rhynchophylline inhibit c-jun N-terminal kinase phosphorylation and nuclear factor-κκB activity in kainic acid-treated rats[J]. Am J Chin Med, 2009, 37 (2): 351- 360. doi: 10.1142/S0192415X09006898
30	Tang NY, Liu CH, Su SY, et al. Uncaria rhynchophylla (miq) jack plays a role in neuronal protection in kainic acid-treated rats[J]. Am J Chin Med, 2010, 38 (2): 251- 263. doi: 10.1142/S0192415X10007828
31	Lo WY, Tsai FJ, Liu CH, et al. Uncaria rhynchophylla upregulates the expression of MIF and cyclophilin a in kainic acid-induced epilepsy rats: a proteomic analysis[J]. Am J Chin Med, 2010, 38 (4): 745- 759. doi: 10.1142/S0192415X10008214
32	Hsu HC, Tang NY, Liu CH, et al. Antiepileptic effect of uncaria rhynchophylla and rhynchophylline involved in the initiation of c-jun N-terminal kinase phosphorylation of MAPK signal pathways in acute seizures of kainic acid-treated rats[J]. Evid Based Complement Alternat Med, 2013, 2013, 961289.
33	Jadhav VS, Khatri DK. Understanding the influence of TLR-mediated immune system on necroptosis-induced neurodegeneration in parkinson’s disease[J]. Ageing Res Rev, 2025, 112, 102872. doi: 10.1016/j.arr.2025.102872
34	林艺燕, 吴月莹, 严锐, 等. 槲皮素防治急性肺损伤作用机制的研究进展[J]. 中国临床药理学与治疗学, 2025, 30 (9): 1272- 1280. doi: 10.12092/j.issn.1009-2501.2025.09.014
35	Ho TY, Tang NY, Hsiang CY, et al. Uncaria rhynchophylla and rhynchophylline improved kainic acid-induced epileptic seizures via IL-1β and brain-derived neurotrophic factor[J]. Phytomedicine, 2014, 21 (6): 893- 900. doi: 10.1016/j.phymed.2014.01.011
36	Zhang C, Zhou J, Zhuo L, et al. The TLR4/NF-κB/NLRP3 and Nrf2/HO-1 pathways mediate the neuroprotective effects of alkaloids extracted from uncaria rhynchophylla in parkinson’s disease[J]. J Ethnopharmacol, 2024, 333, 118391. doi: 10.1016/j.jep.2024.118391
37	Hassan D, Menges CW, Testa JR, et al. AKT kinases as therapeutic targets[J]. J Exp Clin Cancer Res, 2024, 43 (1): 313. doi: 10.1186/s13046-024-03207-4
38	Xu QQ, Shaw PC, Hu Z, et al. Comparison of the chemical constituents and anti-alzheimer’s disease effects of uncaria rhynchophylla and uncaria tomentosa[J]. Chin Med, 2021, 16, 110. doi: 10.1186/s13020-021-00514-2
39	Li HR, Liu Q, Zhu CL, et al. β-nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice[J]. Redox Biol, 2023, 63, 102745. doi: 10.1016/j.redox.2023.102745
40	Zhang Z, Zhang C. Regulation of cGAS–STING signalling and its diversity of cellular outcomes[J]. Nat Rev Immunol, 2025, 25 (6): 425- 444. doi: 10.1038/s41577-024-01112-7
41	那丽莎, 陈毅超, 张凯, 等. 异钩藤碱对急性脑梗死大鼠认知障碍的影响及机制研究[J]. 中国脑血管病杂志, 2024, 21 (7): 444- 454. doi: 10.3969/j.issn.1672-5921.2024.07.002
42	Wang X, Xue Y, Yao Y, et al. PINK1 regulates mitochondrial fission/fusion and neuroinflammation in β-amyloid-induced alzheimer’s disease models[J]. Neurochem Int, 2022, 154, 105298. doi: 10.1016/j.neuint.2022.105298
43	Qi Y, Zhu H, Chen Y, et al. 4-hydroxydictyolactone alleviates cerebral ischemia injury by regulating neuroinflammation and autophagy via AMPK signaling pathway[J]. Phytomedicine, 2024, 135, 156157. doi: 10.1016/j.phymed.2024.156157
44	Zhong M, Xu QQ, Huang MQ, et al. Rhynchophylline alleviates cognitive deficits in multiple transgenic mouse models of alzheimer’s disease via modulating neuropathology and gut microbiota[J]. Acta Pharmacol Sin, 2025, 46 (7): 1813- 1833. doi: 10.1038/s41401-025-01475-0
45	Wen P, Sun Z, Gou F, et al. Oxidative stress and mitochondrial impairment: key drivers in neurodegenerative disorders[J]. Ageing Res Rev, 2025, 104, 102667. doi: 10.1016/j.arr.2025.102667
46	He Z, Li X, Wang Z, et al. Protective effects of luteolin against amyloid beta-induced oxidative stress and mitochondrial impairments through peroxisome proliferator-activated receptor γ-dependent mechanism in alzheimer’s disease[J]. Redox Biol, 2023, 66, 102848. doi: 10.1016/j.redox.2023.102848
47	Kalyanaraman B, Cheng G, Hardy M. Gut microbiome, short-chain fatty acids, alpha-synuclein, neuroinflammation, and ROS/RNS: relevance to parkinson’s disease and therapeutic implications[J]. Redox Biol, 2024, 71, 103092. doi: 10.1016/j.redox.2024.103092
48	Xian YF, Lin ZX, Zhao M, et al. Uncaria rhynchophylla ameliorates cognitive deficits induced by D-galactose in mice[J]. Planta Med, 2011, 77 (18): 1977- 1983.
49	Xian YF, Lin ZX, Mao QQ, et al. Protective effect of isorhynchophylline against β-amyloid-induced neurotoxicity in PC12 cells[J]. Cell Mol Neurobiol, 2012, 32 (3): 353- 360. doi: 10.1007/s10571-011-9763-5
50	Chen H, Dong M, He H, et al. Ginsenoside re prevents depression-like behaviors via inhibition of inflammation, oxidative stress, and activating BDNF/TrkB/ERK/CREB signaling: an in vivo and in vitro study[J]. J Agric Food Chem, 2024, 72 (36): 19838- 19851. doi: 10.1021/acs.jafc.4c04394
51	Yang YC, Chien Y, Yarmishyn AA, et al. Inhibition of oxidative stress-induced epithelial-mesenchymal transition in retinal pigment epithelial cells of age-related macular degeneration model by suppressing ERK activation[J]. J Adv Res, 2024, 60, 141- 157. doi: 10.1016/j.jare.2023.06.004
52	Hu S, Yang L, Ma Y, et al. Protection against H2O2-evoked toxicity in HT22 hippocampal neuronal cells by geissoschizine methyl ether via inhibiting ERK pathway[J]. Transl Neurosci, 2022, 13 (1): 369- 378. doi: 10.1515/tnsci-2022-0243
53	Liu H, Zhou Y, Wang Z, et al. Heat shock protein family a member 1A attenuates apoptosis and oxidative stress via ERK/JNK pathway in hyperplastic prostate[J]. Med Comm, 2025, 6 (3): e70129. doi: 10.1002/mco2.70129
54	张学, 黄红英, 赵顺程, 等. 异钩藤碱对抑郁小鼠海马神经细胞凋亡和氧化应激的影响及其作用机制[J]. 中西医结合心脑血管病杂志, 2023, 21 (1): 69- 73. doi: 10.12102/j.issn.1672-1349.2023.01.011
55	Shen B, Wang Y, Cheng J, et al. Pterostilbene alleviated NAFLD via AMPK/mTOR signaling pathways and autophagy by promoting Nrf2[J]. Phytomedicine, 2023, 109, 154561. doi: 10.1016/j.phymed.2022.154561
56	Li C, Cai Y, Chen Y, et al. ABCG2 shields against epilepsy, relieves oxidative stress and apoptosis via inhibiting the ISGylation of STAT1 and mTOR[J]. Redox Biol, 2024, 75, 103262. doi: 10.1016/j.redox.2024.103262
57	安畅, 张颖, 马阮昕, 等. 钩藤中钩藤碱对肿瘤坏死因子-α诱导人星型胶质细胞炎症模型作用机制研究[J]. 河南师范大学学报(自然科学版), 2019, 47 (2): 98- 104. doi: 10.16366/j.cnki.1000-2367.2019.02.015
58	Newton K, Strasser A, Kayagaki N, et al. Cell death[J]. Cell, 2024, 187 (2): 235- 256. doi: 10.1016/j.cell.2023.11.044
59	Yuan J, Ofengeim D. A guide to cell death pathways[J]. Nat Rev Mol Cell Biol, 2024, 25 (5): 379- 395. doi: 10.1038/s41580-023-00689-6
60	Kumari S, Dhapola R, Reddy DH. Apoptosis in alzheimer’s disease: insight into the signaling pathways and therapeutic avenues[J]. Apoptosis, 2023, 28 (7/8): 943- 957. doi: 10.1007/s10495-023-01848-y
61	Saadh MJ, Faisal A, Adil M, et al. Parkinson’s disease and microRNAs: a duel between inhibition and stimulation of apoptosis in neuronal cells[J]. Mol Neurobiol, 2024, 61 (11): 8552- 8574. doi: 10.1007/s12035-024-04111-w
62	Shen S, Liang L, Shi T, et al. Microglia‐derived interleukin‐6 triggers astrocyte apoptosis in the hippocampus and mediates depression‐like behavior[J]. Adv Sci, 2025, 12 (11): 2412556. doi: 10.1002/advs.202412556
63	Lee YG, Yang N, Chun I, et al. Apoptosis: a janus bifrons in T-cell immunotherapy[J]. J Immunother Cancer, 2023, 11 (4): e005967. doi: 10.1136/jitc-2022-005967
64	Lee J, Son D, Lee P, et al. Alkaloid fraction of uncaria rhynchophylla protects against N-methyl-d-aspartate-induced apoptosis in rat hippocampal slices[J]. Neurosci Lett, 2003, 348 (1): 51- 55. doi: 10.1016/S0304-3940(03)00613-X
65	Wang W, Liu M, Fu X, et al. Hydroxysafflor yellow a ameliorates alcohol-induced liver injury through PI3K/AKT and STAT3/NF-κB signaling pathways[J]. Phytomedicine, 2024, 132, 155814. doi: 10.1016/j.phymed.2024.155814
66	Hu S, Mak S, Zuo X, et al. Neuroprotection against MPP+-induced cytotoxicity through the activation of PI3-K/akt/GSK3β/MEF2D signaling pathway by rhynchophylline, the major tetracyclic oxindole alkaloid isolated from uncaria rhynchophylla[J]. Front Pharmacol, 2018, 9, 768. doi: 10.3389/fphar.2018.00768
67	Zheng M, Chen M, Wang W, et al. Protection by rhynchophylline against MPTP/MPP+-induced neurotoxicity via regulating PI3K/AKT pathway[J]. J Ethnopharmacol, 2021, 268, 113568. doi: 10.1016/j.jep.2020.113568
68	Zheng M, Chen M, Liu C, et al. Alkaloids extracted from uncaria rhynchophylla demonstrate neuroprotective effects in MPTP-induced experimental parkinsonism by regulating the PI3K/akt/mTOR signaling pathway[J]. J Ethnopharmacol, 2021, 266, 113451. doi: 10.1016/j.jep.2020.113451
69	李旭, 徐天娇, 刘立琨, 等. 天麻素联合异钩藤碱抑制MPP+诱导的PC12细胞凋亡的抗氧化机制[J]. 中国中药杂志, 2021, 46 (2): 420- 425.
70	Xian YF, Mao QQ, Wu JC, et al. Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation[J]. J Alzheimers Dis, 2014, 39 (2): 331- 346. doi: 10.3233/jad-131457
71	Nechushtai L, Frenkel D, Pinkas-Kramarski R. Autophagy in parkinson’s disease[J]. Biomolecules, 2023, 13 (10): 1435. doi: 10.3390/biom13101435
72	Lu JH, Tan JQ, Durairajan SSK, et al. Isorhynchophylline, a natural alkaloid, promotes the degradation of alpha-synuclein in neuronal cells via inducing autophagy[J]. Autophagy, 2012, 8 (1): 98- 108. doi: 10.4161/auto.8.1.18313
73	Chen LL, Song JX, Lu JH, et al. Corynoxine, a natural autophagy enhancer, promotes the clearance of alpha-synuclein via AKT/mTOR pathway[J]. J Neuroimmune Pharmacol, 2014, 9 (3): 380- 387. doi: 10.1007/s11481-014-9528-2
74	Zhu Q, Song J, Chen JY, et al. Corynoxine B targets at HMGB1/2 to enhance autophagy for α-synuclein clearance in fly and rodent models of parkinson’s disease[J]. Acta Pharm Sin B, 2023, 13 (6): 2701- 2714. doi: 10.1016/j.apsb.2023.03.011
75	Hou X, Liang X, Zhao X, et al. Uncaria rhynchophylla alkaloid extract exerts neuroprotective activity against parkinson’s disease via activating mitophagy with the involvement of UCHL1[J]. J Ethnopharmacol, 2025, 338, 119009. doi: 10.1016/j.jep.2024.119009
76	Yang Y, Ji WG, Zhu ZR, et al. Rhynchophylline suppresses soluble Aβ1-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors[J]. Neuropharmacology, 2018, 135, 100- 112. doi: 10.1016/j.neuropharm.2018.03.007
77	Jiang S, Borjigin G, Sun J, et al. Identification of uncaria rhynchophylla in the potential treatment of alzheimer’s disease by integrating virtual screening and in vitro validation[J]. Int J Mol Sci, 2023, 24 (20): 15457. doi: 10.3390/ijms242015457
78	Bod R, Tóth K, Essam N, et al. Synaptic alterations and neuronal firing in human epileptic neocortical excitatory networks[J]. Front Synaptic Neurosci, 2023, 15, 1233569. doi: 10.3389/fnsyn.2023.1233569
79	Zhong J, Zhang M, Huang S, et al. Traditional Chinese medicine treatment for epilepsy: focusing on voltage-gated ion channels[J]. J Ethnopharmacol, 2025, 351, 120129. doi: 10.1016/j.jep.2025.120129
80	Lin YW, Hsieh CL. Oral uncaria rhynchophylla (UR) reduces kainic acid-induced epileptic seizures and neuronal death accompanied by attenuating glial cell proliferation and S100B proteins in rats[J]. J Ethnopharmacol, 2011, 135 (2): 313- 320. doi: 10.1016/j.jep.2011.03.018
81	Shao H, Yang Y, Mi Z, et al. Anticonvulsant effect of rhynchophylline involved in the inhibition of persistent sodium current and NMDA receptor current in the pilocarpine rat model of temporal lobe epilepsy[J]. Neuroscience, 2016, 337, 355- 369. doi: 10.1016/j.neuroscience.2016.09.029
82	Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments[J]. Neuron, 2019, 102 (1): 75- 90. doi: 10.1016/j.neuron.2019.03.013
83	Xian YF, Fan D, Ip SP, et al. Antidepressant-like effect of isorhynchophylline in mice[J]. Neurochem Res, 2017, 42 (2): 678- 685. doi: 10.1007/s11064-016-2124-5
84	Qiao YL, Zhou JJ, Liang JH, et al. Uncaria rhynchophylla ameliorates unpredictable chronic mild stress-induced depression in mice via activating 5-HT1A receptor: insights from transcriptomics[J]. Phytomedicine, 2021, 81, 153436. doi: 10.1016/j.phymed.2020.153436
85	Wang C, Zhu MH, Sun N, et al. Isorhynchophylline ameliorates stress-induced emotional disorder and cognitive impairment with modulation of NMDA receptors[J]. Front Neurosci, 2022, 16, 1071068. doi: 10.3389/fnins.2022.1071068
86	Geng CA, Yang TH, Huang XY, et al. Antidepressant potential of uncaria rhynchophylla and its active flavanol, catechin, targeting melatonin receptors[J]. J Ethnopharmacol, 2019, 232, 39- 46. doi: 10.1016/j.jep.2018.12.013

Disease	Intervention	Model	Mechanism	References
AD	Extract of Uncaria rhynchophylla	5XFAD mice (transgenic model)	Iba-1↓	[18]
AD	Uncaria rhynchophylla alkaloid extract	APP/PS1 (transgenic model) mice; splenic lymphocytes (ConA)	Aβ, p-tau, IFN-γ, IL-17, CD4? effector T cells, HK2, GLUT1, p-PI3K, p-Akt, p-mTOR↓; IL-10, TGF-β, Treg↑	[23]
AD	RN，IRN	N9 microglial cells (LPS)	TNF-α, IL-1β, NO, iNOS, ERK, MAPKs, IκBα↓	[26]
AD	RN	Primary microglia (LPS)	NO, PEG2, MCP-1, TNF-α, IL-1β, iNOS, COX2, p-IκBα, p-MAPKs↓	[27]
AD	Extract of Uncaria rhynchophylla	SD rats (STZ)	p-tau, IL-6, IL-1β, TNF-α↓; p-Akt, p-GSK-3β↑	[38]
AD	RN	TgCRND8 mice，5×FAD mice， 3×Tg-AD mice (transgenic models); BV-2 cells (Aβ42)	p-tau, p-APP, BACE1, APH1, FL-APP, IL-6, IL-1β, TNF-α, Galectin-3, C/EBPβ, AEP, HDAC2, AMPKα1↓; IDE, PINK1↑	[44]
PD	Hirsutine	SD rats (6-OHDA)	p-IκBα, NF-κB p65, IL-6, IL-1β, TNF-α↓; DA, TH↑	[22]
PD	Uncaria rhynchophylla alkaloid extract	C57BL/6J mice (MPTP); BV-2 cells, SH-SY5Y cells (LPS)	IL-1β, TNF-α, IL-6, TLR4, NLRP3, COX2↓; TH, IL-10↑	[36]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	Superoxide anion, NF-κB, AP-1, p-JNK↓	[29]
EP	Extract of Uncaria rhynchophylla	SD rats (kainic acid)	ED1, nNOS, iNOS↓	[30]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	MIF, CypA↑	[31]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	MAPK, p-JNK↓	[32]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	IL-1β, BDNF↓	[35]
EP	IRN	SD rats (Lithium-pilocarpine)	IL-6, IL-1β, TNF-α, Acetyl-p53/p53, cleaved caspase-3/caspase-3↓; SIRT1↑	[21]
DD	IRN	ICR mice (CUMS)	TNF-α, IL-6, NF-kB p-65↓; NGF, BDNF, p-GSK-3β, p-Akt↑	[19]
Cerebral Ischemia/ Reperfusion Injury	IRN	SD rats (MCAO)	GFAP, IBA-1, TNFα, IL-1β, CX3CR1, p-NF-κB p65↓; YM-1/2, IκB-α↑	[28]
ACI	IRN	SD rats (MCAO)	IL-6, TNF-α, STING, p-TBK1, p-IRF3↓; ZO-1, occludin↑	[41]

Disease	Intervention	Model	Mechanism	References
AD	Extract of Uncaria rhynchophylla	5XFAD mice (transgenic model)	Iba-1↓	[18]
AD	Uncaria rhynchophylla alkaloid extract	APP/PS1 (transgenic model) mice; splenic lymphocytes (ConA)	Aβ, p-tau, IFN-γ, IL-17, CD4? effector T cells, HK2, GLUT1, p-PI3K, p-Akt, p-mTOR↓; IL-10, TGF-β, Treg↑	[23]
AD	RN，IRN	N9 microglial cells (LPS)	TNF-α, IL-1β, NO, iNOS, ERK, MAPKs, IκBα↓	[26]
AD	RN	Primary microglia (LPS)	NO, PEG2, MCP-1, TNF-α, IL-1β, iNOS, COX2, p-IκBα, p-MAPKs↓	[27]
AD	Extract of Uncaria rhynchophylla	SD rats (STZ)	p-tau, IL-6, IL-1β, TNF-α↓; p-Akt, p-GSK-3β↑	[38]
AD	RN	TgCRND8 mice，5×FAD mice， 3×Tg-AD mice (transgenic models); BV-2 cells (Aβ42)	p-tau, p-APP, BACE1, APH1, FL-APP, IL-6, IL-1β, TNF-α, Galectin-3, C/EBPβ, AEP, HDAC2, AMPKα1↓; IDE, PINK1↑	[44]
PD	Hirsutine	SD rats (6-OHDA)	p-IκBα, NF-κB p65, IL-6, IL-1β, TNF-α↓; DA, TH↑	[22]
PD	Uncaria rhynchophylla alkaloid extract	C57BL/6J mice (MPTP); BV-2 cells, SH-SY5Y cells (LPS)	IL-1β, TNF-α, IL-6, TLR4, NLRP3, COX2↓; TH, IL-10↑	[36]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	Superoxide anion, NF-κB, AP-1, p-JNK↓	[29]
EP	Extract of Uncaria rhynchophylla	SD rats (kainic acid)	ED1, nNOS, iNOS↓	[30]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	MIF, CypA↑	[31]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	MAPK, p-JNK↓	[32]
EP	Extract of Uncaria rhynchophylla，RN	SD rats (kainic acid)	IL-1β, BDNF↓	[35]
EP	IRN	SD rats (Lithium-pilocarpine)	IL-6, IL-1β, TNF-α, Acetyl-p53/p53, cleaved caspase-3/caspase-3↓; SIRT1↑	[21]
DD	IRN	ICR mice (CUMS)	TNF-α, IL-6, NF-kB p-65↓; NGF, BDNF, p-GSK-3β, p-Akt↑	[19]
Cerebral Ischemia/ Reperfusion Injury	IRN	SD rats (MCAO)	GFAP, IBA-1, TNFα, IL-1β, CX3CR1, p-NF-κB p65↓; YM-1/2, IκB-α↑	[28]
ACI	IRN	SD rats (MCAO)	IL-6, TNF-α, STING, p-TBK1, p-IRF3↓; ZO-1, occludin↑	[41]

Disease	Intervention	Model	Mechanism	References
AD	Extract of Uncaria rhynchophylla	ICR mice(D-galactose)	ACh, GSH↑; AChE, MDA↓	[48]
AD	IRN	PC12 cells (Aβ25-35)	ROS, MDA↓; GSH↑	[49]
AD	Geissoschizine methyl ether	HT22 (H₂O₂)	ROS, p-ERK↓	[52]
AD	Extract of Uncaria rhynchophylla	SD rats (STZ)	Keap1↓; SOD, CAT, GPx, HO-1, Nrf2↑	[38]
AD	RN	Astrocytes (TNF-α)	IL-23, IL-6, MDA, p-mTOR, p-STAT3↓; NOS, NO, SOD↑	[57]
PD	Uncaria rhynchophylla alkaloid extract	C57BL/6J mice (MPTP); BV-2 cells, SH-SY5Ycells (LPS)	IL-1β, TNF-α, IL-6, LDH, MDA, TLR4, NLRP3, COX2↓; TH, IL-10, SOD, GSH, Nrf2, HO-1↑	[36]
DD	IRN	SD rats (CUMS)	MDA, p-JNK↓; SOD, GSH-Px↑	[54]

Disease	Intervention	Model	Mechanism	References
AD	Extract of Uncaria rhynchophylla	ICR mice(D-galactose)	ACh, GSH↑; AChE, MDA↓	[48]
AD	IRN	PC12 cells (Aβ25-35)	ROS, MDA↓; GSH↑	[49]
AD	Geissoschizine methyl ether	HT22 (H₂O₂)	ROS, p-ERK↓	[52]
AD	Extract of Uncaria rhynchophylla	SD rats (STZ)	Keap1↓; SOD, CAT, GPx, HO-1, Nrf2↑	[38]
AD	RN	Astrocytes (TNF-α)	IL-23, IL-6, MDA, p-mTOR, p-STAT3↓; NOS, NO, SOD↑	[57]
PD	Uncaria rhynchophylla alkaloid extract	C57BL/6J mice (MPTP); BV-2 cells, SH-SY5Ycells (LPS)	IL-1β, TNF-α, IL-6, LDH, MDA, TLR4, NLRP3, COX2↓; TH, IL-10, SOD, GSH, Nrf2, HO-1↑	[36]
DD	IRN	SD rats (CUMS)	MDA, p-JNK↓; SOD, GSH-Px↑	[54]

Disease	Intervention	Model	Mechanism	References
AD	IRN	SD rats (Aβ25-35)	caspase-3, caspase-9, GSK-3β↓; Bcl-2/Bax, Akt↑	[70]
AD	IRN	PC12 cells (Aβ25-35)	caspase-3↓; Bcl-2/Bax↑	[49]
AD	Extract of Uncaria rhynchophylla	SD rats (NMDA)	c-jun, p53, bax↓	[64]
PD	RN	Primary cerebellar granule neurons (MPP?)	Bax/Bcl-2↓; MEF2, MEF2D, p-GSK3β, p-Ser473-Akt↑	[66]
PD	RN	PC12 cells (MPP?)	LDH, Ca²⁺, ROS, caspase-3↓; Bcl-2/Bax, p-Akt↑	[67]
PD	Extract of Uncaria rhynchophylla	C57BL/6 mice (MPTP)	caspase-3↓; DA, HVA, DAT, TH, p-mTOR, p-Akt, Bcl-2/BAD↑	[68]
PD	Gastrodin, IRN	PC12 cells (MPP⁺)	caspase-3, LPO, ERK1/2, PI3K, GSK-3β↓; HO-1, NQO-1↑	[69]
DD	IRN	SD rats (CUMS)	level of apoptosis, Bax, Cleaved Caspase-3, p-JNK↓; Bcl-2↑	[54]