Effects and Challenges of Pharmacology and Toxicology of Aconitum Diterpenoid Alkaloids

doi:10.19803/j.1672-8629.20250195

Abstract

Abstract: Objective To summarize the pharmacological effects, toxicological mechanisms, and research progress related to Aconitum diterpenoid alkaloids so as to provide a reference for safe applications and development. Methods Based on a literature review and data integration, the molecular mechanisms, pharmacology, and toxicity of Aconitum diterpenoid alkaloids were analyzed. Results Aconitum diterpenoid alkaloids exhibited significant cardiovascular protective, neuroregulatory, anti-inflammatory, anticancer, and antimicrobial properties. The mechanisms involved the regulation of signaling pathways such as PI3K/Akt, MAPK, and NF-κB. However, their cardiotoxicity (through mitochondrial apoptosis pathways) and hepatotoxicity (mediated by PI3K/Akt/mTOR pathway-driven autophagy) deserved more attention. Conclusion There are relatively few research reports on the structure-activity relationship of Aconitum diterpenoid alkaloids. Most of the literature currently available is concerned with the pharmacological effects and toxic reactions studied through pharmacological experiments. Aconitum diterpenoid alkaloids promise good applications, but the toxicity remains an urgent issue.

Key words: Aconitum, Diterpenoid Alkaloids, Cardiovascular Protection, Neuroregulatory, Cardiotoxicity, Hepatotoxicity, Pharmacology, Toxicology

CLC Number:

R961
R994.11

SUN Yinghao, ZANG Shuangyao, YU Wenhui, GUO Shuai, LI Tingting, ZHANG Yi, ZHANG Tingjian, MENG Fanhao. Effects and Challenges of Pharmacology and Toxicology of Aconitum Diterpenoid Alkaloids[J]. Chinese Journal of Pharmacovigilance, 2025, 22(6): 601-607.

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https://zgywjj.magtechjournal.com/EN/Y2025/V22/I6/601

References

[1] HONG LL, DING YF, ZHANG W, et al.Chemical and Biological Diversity of New Natural Products from Marine Sponges: a Review (2009-2018)[J]. Marine Life Science & Technology, 2022, 4(3): 356-372.
[2] ZHANG L, MIAO X, LI Y, et al.Traditional Processing, Uses, Phytochemistry, Pharmacology and Toxicology of Aconitum Sinom-ontanum Nakai: a Comprehensive Review[J]. Journal of Ethnophar-macology, 2022, 293: 115317.
[3] WU CT, YUE RS, HE MM, et al.Application Rule Analysis of Synopsis of Golden Chamber Wutou Decoction Based on Data Mining of Medical Case[J]. Chinese Journal of Basic Medicine in Traditional Chinese Medicine(中国中医基础医学杂志), 2022, 28(4): 614-618.
[4] LI CY, ZHOU Z, XU T, et al.Aconitum Pendulum and Aconitum Flavum: a Narrative Review on Traditional Uses, Phytochemistry, Bioactivities and Processing Methods[J]. Journal of Ethnopharm-acology, 2022, 292: 115216.
[5] WANG Y, LIN ZJ, JIANG ZX, et al.Early Warning of Aconitum Herbs in Breast Cancer Therapy by Bibliometric and Bioinformatics[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2021, 18(7): 655-662.
[6] LIANG X, SU W, ZHANG W, et al.An Overview of the Research Progress on Aconitum carmichaelii Debx.: Active Compounds, Pharmacology, Toxicity, Detoxification, and Applications[J]. Journal of Ethnopharmacology, 2025, 337: 118832.
[7] LI L, ZHANG L, LIAO T, et al.Advances on Pharmacology and Toxicology of Aconitine[J]. Fundamental & Clinical Pharmacology, 2022, 36(4): 601-611.
[8] HE YN, ZHANG DK, LIN JZ, et al.Cardiac Function Evaluation for a Novel One-Step Detoxification Product of Aconiti Lateralis Radix Praeparata[J]. Chinese Medical Journal, 2018, 13: 62.
[9] XIE GH, MA ZC, MEI Y, et al.Evaluation of Pharmacokinetics of Aconiti Lateralis Radix of Shenfu Prescription in Rats with Heart Failure[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2021, 18(7): 632-636.
[10] ZHANG J, LI D, ZHONG D, et al.Processed lateral root of Aconitum carmichaelii Debx.: a Review of Cardiotonic Effects and Cardiotoxicity on Molecular Mechanisms[J]. Frontiers in Pharmacology, 2022, 13: 1026219.
[11] WANG L, DENG H, WANG T, et al.Investigation into the Protective Effects of Hypaconitine and Glycyrrhetinic Acid Against Chronic Heart Failure of the Rats[J]. BMC Complementary Medicine and Therapies, 2022, 22(1): 160.
[12] WEN J, LI L, OU D, et al.Higenamine Protects Against Doxorubicin-Induced Heart Failure by Attenuating Ferroptosis via Modulating the Nrf2/GPX4 Signaling Pathway[J]. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology, 2025, 141: 156670.
[13] WANG MY, LIANG JW, OLOUNFEH KM, et al.A Comprehensive in Silicon Method to Study the QSTR of the Aconitine Alkaloids for Designing the Novel Drugs[J]. Molecules, 2018, 23(9): 2385.
[14] ZENG W, YANG F, SHEN WL, et al.Interactions between Central Nervous System and Peripheral Metabolic Organs[J]. Science China. Life Sciences, 2022, 65(10): 1929-1958.
[15] ZHU X, LIU S, CAO Z, et al.Higenamine Mitigates Interleukin-1β-Induced Human Nucleus Pulposus Cell Apoptosis by ROS-Mediated PI3K/Akt Signaling[J]. Molecular and Cellular Biochemistry, 2021, 476: 3889-3897.
[16] LI D, YANG K, LI J, et al.Single-Cell Sequencing Reveals Glial Cell Involvement in Development of Neuropathic Pain via Myelin Sheath Lesion Formation in the Spinal Cord[J]. Journal of Neuroinflamm-ation, 2024, 21(1): 213.
[17] ZHU XZ, WANG JQ, WU YH.MG53 Ameliorates Nerve Injury Induced Neuropathic Pain through the Regulation of Nrf2/HO-1 Signaling in Rats[J]. Behavioural Brain Research, 2023, 449: 114489.
[18] WU YZ, SHAO S, GUO QL, et al.Aconicatisulfonines A and B, Analgesic Zwitterionic C₂₀-Diterpenoid Alkaloids with a Rearranged Atisane Skeleton from Aconitum carmichaelii[J]. Organic Letters, 2019, 21(17): 6850-6854.
[19] TANIMURA Y, YOSHIDA M, ISHIUVHI K, et al.Neoline is the Active Ingredient of Processed Aconite Root Against Murine Peripheral Neuropathic Pain Model, and Its Pharmacokinetics in Rats[J]. Journal of Ethnopharmacology, 2019, 241: 111859.
[20] SHAO S, XIA H, HU M, et al.Isotalatizidine, a C₁₉-Diterpenoid Alkaloid, Attenuates Chronic Neuropathic Pain through Stimulating ERK/CREB Signaling Pathway-Mediated Microglial Dynorphin A Expression[J]. Journal of Neuroinflammation, 2020, 17(1): 13.
[21] SUN ML, AO JP, WANG YR, et al.Lappaconitine, a C₁₈-Diterpenoid Alkaloid, Exhibits Antihypersensitivity in Chronic Pain through Stimulation of Spinal Dynorphin A Expression[J]. Psychopharmacology (Berl), 2018, 235(9): 2559-2571.
[22] XIE MX, YANG J, PANG RP, et al.Bulleyaconitine A Attenuates Hyperexcitability of Dorsal Root Ganglion Neurons Induced by Spared Nerve Injury: the Role of Preferably Blocking Nav1.7 and Nav1.3 Channels[J]. Molecular Pain, 2018, 14: 1744806918778491.
[23] AHMAD H, AHMAD S, SHAH SAA, et al.Antioxidant and Anticholinesterase Potential of Diterpenoid Alkaloids from Aconitum heterophyllum[J]. Bioorganic & Medicinal Chemistry, 2017, 25(13): 3368-3376.
[24] SALEHI A, GHANADIAN M, ZOLFAGHARI B, et al.Neurophar-macological Potential of Diterpenoid Alkaloids[J]. Pharmaceuticals (Basel, Switzerland), 2023, 16(5): 747.
[25] BALI ZK, BRUSZT N, KOSZEGI Z, et al.Aconitum Alkaloid Songorine Exerts Potent Gamma-Aminobutyric Acid-A Receptor Agonist Action in vivo and Effectively Decreases Anxiety without Adverse Sedative or Psychomotor Effects in the Rat[J]. Pharmaceutics, 2022, 14(10): 2067.
[26] NESTEROVA YV, VSYAKIKH OV, KUL'PIN PV, et al. Comparative Study of the Anxiolytic Activity of Songorine in Elevated Plus Maze Test and by Recording Ultrasonic Vocalizations[J]. Bulletin of Experimental Biology and Medicine, 2024, 177(5): 648-652.
[27] ZANG X, CHEN S, ZHU J, et al.The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases[J]. Frontiers in Aging Neuroscience, 2022, 14: 872134.
[28] ASSOGNA M, DI LORENZO F, MARTORANA A, et al.Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders[J]. Biomolecules, 2022, 12(8): 1161.
[29] AL TAHAN MA, MARWAH MK, DHALIWAL M, et al.Novel AP39-Loaded Liposomes Sustain the Release of Hydrogen Sulphide, Enhance Blood-Brain Barrier Permeation, and Abrogate Oxidative Stress-Induced Mitochondrial Dysfunction in Brain Cells[J]. Drug Design, Development and Therapy, 2025, 19: 2067-2079.
[30] HU W, WANG M, SUN G, et al.RND3 Modulates Microglial Polarization and Alleviates Neuroinflammation in Parkinson's Disease by Suppressing NLRP3 Inflammasome Activation[J]. Experimental Cell Research, 2024, 439(1): 114088.
[31] WANG J, MENG XH, CHAI T, et al.Diterpenoid Alkaloids and one Lignan from the Roots of Aconitum pendulum Busch[J]. Natural Products and Bioprospecting, 2019, 9(6): 419-423.
[32] VAZQUEZ T, PATEL J, KODALI N, et al. Plasmacytoid Dendritic Cells Are Not Major Producers of Type 1 IFN in Cutaneous Lupus: an In-Depth Immunoprofile of Subacute and Discoid Lupus[J]. The Journal of Investigative Dermatology, 2024, 144(6): 1262-1272. e7.
[33] MASOUMI M, ALESAEIDI S, KHORRAMDELAZAD H, et al.Role of T Cells in the Pathogenesis of Rheumatoid Arthritis: Focus on Immunometabolism Dysfunctions[J]. Inflammation, 2023, 46(1): 88-102.
[34] ROTH A, BARCELLINI W, D'SA S, et al. Sustained Inhibition of Complement C1s with Sutimlimab over 2 Years in Patients with Cold Agglutinin Disease[J]. American Journal of Hematology, 2023, 98(8): 1246-1253.
[35] WAN ZL, ZHANG M, XIAO Y, et al.C-Diterpenoid Alkaloids from Aconitum refractum var. Circinatum[J]. Natural Product Research, 2024, 38(18): 3201-3206.
[36] DING N, WANG S, XIAO Y, et al.Four New C₁₉ -Diterpenoid Alkaloids from Aconitum nagarum Stapf[J]. Chemistry & Biodiversity, 2023, 20(5): e202300058.
[37] DUAN XY, ZHAO DK, SHEN Y.Two new bis-C₂₀-Diterpenoid Alkaloids with Anti-Inflammation Activity from Aconitum bulley-anum[J]. Journal of Asian Natural Products Research, 2019, 21(4): 323-330.
[38] ZENG XZ, HE LG, WANG S, et al.Aconine Inhibits RANKL-Induced Osteoclast Differentiation in RAW264.7 Cells by Suppressing NF-κB and NFATc1 Activation and DC-STAMP Expression[J]. Acta Pharmacologica Sinica, 2016, 37(2): 255-263.
[39] GUO C, HE L, HU N, et al.Aconiti Lateralis Radix Praeparata Lipid-Soluble Alkaloids Alleviates IL-1β-Induced Inflammation of Human Fibroblast-Like Synoviocytes in Rheumatoid Arthritis by Inhibiting NF-κB and MAPKs Signaling Pathways and Inducing Apoptosis[J]. Cytokine, 2022, 151: 155809.
[40] WU Y, LIU Y, ZHANG L, et al.Aconiti Lateralis Radix Praeparata Total Alkaloids Exert Anti-RA Effects by Regulating NF-κB and JAK/STAT Signaling Pathways and Promoting Apoptosis[J]. Frontiers in Pharmacology, 2022, 13: 980229.
[41] XIAO Y, HAN M, CHEN Y, et al.In vitro and in vivo Biological Evalu-ation of Lappaconitine Derivatives as Potential Anti-Inflammatory Agents[J]. Chemistry & Biodiversity, 2024, 21(2): e202301761.
[42] RUI Y, ZHANG X, MIN X, et al.Unlocking Renal Restoration: Mesaconine from Aconitum Plants Restore Mitochondrial Function to Halt Cell Apoptosis in Acute Kidney Injury[J]. International Immuno-pharmacology, 2024, 133: 112170.
[43] HE JB, LUAN J, LV XM, et al.Navicularines A-C: New Diterpenoid Alkaloids from Aconitum Naviculare and Their Cytotoxic Activities[J]. Fitoterapia, 2017, 120: 142-145.
[44] JIANG H, HUANG S, GAO F, et al.Diterpenoid Alkaloids from Aconitum brevicalcaratum as Autophagy Inducers[J]. Natural Product Research, 2019, 33(12): 1741-1746.
[45] LI X, HU J, TONG D, et al.Inhibitory Effect of Aconitine on Colorectal Cancer Malignancy via Inducing Apoptosis and Suppression of Cell Motion[J]. The Turkish Journal of Gastroenterology: the Official Journal of Turkish Society of Gastroenterology, 2024, 36(1): 53-60.
[46] FENG HT, ZHAO WW, LU JJ, et al.Hypaconitine Inhibits TGF-β1-Induced Epithelial-Mesenchymal Transition and Suppresses Adhesion, Migration, and Invasion of Lung Cancer A549 Cells[J]. Chinese Journal of Natural Medicines, 2017, 15(6): 427-435.
[47] QI XZ, WANG L, WANG H, et al.Aconitine Inhibits the Proliferation of Hepatocellular Carcinoma by Inducing Apoptosis[J]. International Journal of Experimental Pathology, 2018, 11(11): 5278-5289.
[48] YIN TP, CAI L, ZHOU H, et al.A new C19-Diterpenoid Alkaloid from the Roots of Aconitum duclouxii[J]. Natural Product Research, 2014, 28(19): 1649-1654.
[49] YU J, YIN TP, WANG JP, et al.A new C₂₀-Diterpenoid Alkaloid from the Lateral Roots of Aconitum carmichaeli[J]. Natural Product Research, 2017, 31(2): 228-232.
[50] HU ZX, AN Q, TANG HY, et al.Acoapetaludines A-K, C₂₀- and C₁₉-Diterpenoid Alkaloids from the Whole Plants of Aconitum apetalum (Huth) B.Fedtsch[J]. Phytochemistry, 2019, 167: 112111.
[51] ANMOL KS, KUMAR R, SINGH R, et al.Antiplasmodial Diter-penoid Alkaloid from Aconitum heterophyllum Wall. ex Royle: Isolation, Characterization, and UHPLC-DAD BASED QUANTIFICation[J]. Journal of Ethnopharmacology, 2022, 287: 114931.
[52] HELLER CD, ZAHEDIFARD F, DOSKOCIL I, et al.Traditional Medicinal Ranunculaceae Species from Romania and Their in vitro Antioxidant, Antiproliferative, and Antiparasitic Potential[J]. International Journal of Molecular Sciences, 2024, 25(20): 10987.
[53] LAWSON C, McCABE DJ, FELDMAN R. A Narrative Review of Aconite Poisoning and Management[J/OL]. Journal of Intensive Care Medicine, (2024-04-13)[2025-05-20]. https://pubmed.ncbi.nlm.nih.gov/38613376/.
[54] LIU F, TAN XX, HAN X, et al.Cytotoxicity of Aconitum Alkaloid and Its Interaction with Calf Thymus DNA by Multi-Spectroscopic techniques[J]. Scientific Reports, 2017, 7(1): 14509.
[55] JIANG H, ZHANG Y, ZHANG Y, et al.An Updated Meta-Analysis Based on the Preclinical Evidence of Mechanism of Aconitine-Induced Cardiotoxicity[J]. Frontiers in Pharmacology, 2022, 13: 900842.
[56] LIU X, YANG L, ZHOU R,et al.The Inhibition of PPARα Protein Degradation Alleviates the Cardiotoxicity of Tiebangchui by Regulating Fatty Acid Metabolism[J]. Journal of Ethnopharmacology, 2025, 348: 119838.
[57] GAO XT, ZANG XC, HU J, et al.Aconitine Induces Apoptosis in H9c2 Cardiac Cells via Mitochondria-Mediated Pathway[J]. Molecular Medicine Reports, 2018, 17(1): 284-292.
[58] PENG F, ZHANG N, WANG CT, et al.Aconitine Induces Cardiomyocyte Damage by Mitigating BNIP3-Dependent Mitophagy and the TNFα-NLRP3 Signalling Axis[J]. Cell Proliferation, 2020, 53(1): e12701.
[59] LIU F, HAN X, LI N, et al.Aconitum Alkaloids Induce Cardiotoxicity and Apoptosis in Embryonic Zebrafish by Influencing the Expression of Cardiovascular Relative Genes[J]. Toxicology Letters, 2019, 305: 10-18.
[60] GE YX, WANG YG, ZHANG Z, et al.Effect of Hypaconitine of Radix Aconiti Carmichaeli on hERG Channels in Cardiac Myocytes via miR-134 Regulation[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2024, 21(6): 606-610.
[61] COULSON JM, CAPARROTTA TM, THOMPSON JP.The Management of Ventricular Dysrhythmia in Aconite Poisoning[J]. Clinical Toxicology (Philadelphia, Pa.), 2017, 55(5): 313-321.
[62] HUANG R, PANG Q, ZHENG L, et al.Acute aconitine Poisoning Resulting from the Ingestion of Medicinal Liquor[J]. Journal of Forensic Sciences, 2024, 69(6): 2317-2324.
[63] YANG HQ, WANG H, LIU YB, et al.The PI3K/Akt/mTOR Signaling Pathway Plays a Role in Regulating Aconitine-Induced Autophagy in Mouse Liver[J]. Research In Veterinary Science, 2019, 124: 317-320.
[64] WANG H, LIU Y, GUO Z, et al.Aconitine Induces Cell Apoptosis via Mitochondria and Death Receptor Signaling Pathways in Hippocampus Cell Line[J]. Research in Veterinary Science, 2022, 143: 124-133.
[65] CONG JJ, RUAN YL, LYN QL, et al.A Proton-Coupled Organic Cation Antiporter is Involved in the Blood-Brain Barrier Transport of Aconitum Alkaloids[J]. Journal of Ethnopharmacology, 2020, 252: 112581.
[66] ZHANG Y, ZHANG TJ, LI XY, et al.2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one Derivatives: Simplification and Modification of Aconitine Scaffold for the Discovery of Novel Anticancer Agents[J]. European Journal of Medicinal Chemistry, 2021, 210: 112988.
[67] ZHANG N, LIAN Z, PENG X, et al.Applications of Higenamine in Pharmacology and Medicine[J]. Journal of Ethnopharmacology, 2017, 196: 242-252.
[68] ZONG XX, YAN XJ, WU JL, et al.Potentially Cardiotoxic Diterpenoid Alkaloids from the Roots of Aconitum Carmichaelii[J]. Journal of Natural Products, 2019, 82(4): 980-989.
[69] LI HC, GE YX, WANG NN, et al.Research Progress in Roles of Ginseng Combined with Radix Aconiti Carmichaeli in Reducing Toxicity and Increasing Efficiency in Myocardial Cells[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2024, 21(6): 601-605.