Isotalatizidine, a C-diterpenoid Alkaloid, Attenuates Chronic Neuropathic Pain Through Stimulating ERK/CREB Signaling Pathway-mediated Microglial Dynorphin A Expression

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2020 Jan 12

PMID 31924228

Citations 11

Authors

Shuai Shao

Huan Xia

Min Hu

Chengjuan Chen

Junmin Fu

Gaona Shi

Qinglan Guo

Yu Zhou

Wenjie Wang

Jiangong Shi

Tiantai Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Isotalatizidine is a representative C-diterpenoid alkaloid extracted from the lateral roots of Aconitum carmichaelii, which has been widely used to treat various diseases on account of its analgesic, anti-inflammatory, anti-rheumatic, and immunosuppressive properties. The aim of this study was to evaluate the analgesic effect of isotalatizidine and its underlying mechanisms against neuropathic pain.

Methods: A chronic constrictive injury (CCI)-induced model of neuropathic pain was established in mice, and the limb withdrawal was evaluated by the Von Frey filament test following isotalatizidine or placebo administration. The signaling pathways in primary or immortalized microglia cells treated with isotalatizidine were analyzed by Western blotting and immunofluorescence.

Results: Intrathecal injection of isotalatizidine attenuated the CCI-induced mechanical allodynia in a dose-dependent manner. At the molecular level, isotalatizidine selectively increased the phosphorylation of p38 and ERK1/2, in addition to activating the transcription factor CREB and increasing dynorphin A production in cultured primary microglia. However, the downstream effects of isotalatizidine were abrogated by the selective ERK1/2 inhibitor U0126-EtOH or CREB inhibitor of KG-501, but not by the p38 inhibitor SB203580. The results also were confirmed in in vivo experiments.

Conclusion: Taken together, isotalatizidine specifically activates the ERK1/2 pathway and subsequently CREB, which triggers dynorphin A release in the microglia, eventually leading to its anti-nociceptive action.

Citing Articles

5HT1R agonist alleviates presurgical prolonged sleep deprivationinduced postsurgical pain in adolescent mice.

Zhu W, Xu X, Xu R, Huang Y, Ma Z Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025; 49(10):1543-1555.

PMID: 40074303 PMC: 11897974. DOI: 10.11817/j.issn.1672-7347.2024.240499.

Electroacupuncture produces analgesic effects via cannabinoid CB1 receptor-mediated GABAergic neuronal inhibition in the rostral ventromedial medulla.

Wan K, Xu Q, Shi Y, Cui C, Lei J, Zhang K Chin Med. 2025; 20(1):30.

PMID: 40038719 PMC: 11881457. DOI: 10.1186/s13020-025-01083-4.

A comprehensive review of traditional Chinese medicine in treating neuropathic pain.

Hu N, Liu J, Luo Y, Li Y Heliyon. 2024; 10(17):e37350.

PMID: 39296122 PMC: 11407996. DOI: 10.1016/j.heliyon.2024.e37350.

Neuropharmacological Potential of Diterpenoid Alkaloids.

Salehi A, Ghanadian M, Zolfaghari B, Jassbi A, Fattahian M, Reisi P Pharmaceuticals (Basel). 2023; 16(5).

PMID: 37242531 PMC: 10223254. DOI: 10.3390/ph16050747.

Epiisopiloturine, an Alkaloid from , Attenuates LPS-Induced Neuroinflammation by Interfering in the TLR4/NF-B-MAPK Signaling Pathway in Microglial Cells.

de Sousa J, Azul F, de Araujo A, Tome R, Silva F, de Vasconcelos S Oxid Med Cell Longev. 2023; 2023:4752502.

PMID: 37151606 PMC: 10162877. DOI: 10.1155/2023/4752502.

References

Frank D, Greenberg M . CREB: a mediator of long-term memory from mollusks to mammals. Cell. 1994; 79(1):5-8. DOI: 10.1016/0092-8674(94)90394-8. View

Canon E, Cosgaya J, Scsucova S, Aranda A . Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells. Mol Biol Cell. 2004; 15(12):5583-92. PMC: 532036. DOI: 10.1091/mbc.e04-05-0439. View

Kawasaki Y, Zhang L, Cheng J, Ji R . Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci. 2008; 28(20):5189-94. PMC: 2408767. DOI: 10.1523/JNEUROSCI.3338-07.2008. View

Stein C, Machelska H . Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacol Rev. 2011; 63(4):860-81. DOI: 10.1124/pr.110.003145. View

Brust A, Croker D, Colless B, Ragnarsson L, Andersson A, Jain K . Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties. J Med Chem. 2016; 59(6):2381-95. DOI: 10.1021/acs.jmedchem.5b00911. View

Ji L, Chen Y, Wei H, Feng H, Chang R, Yu D . Activation of alpha7 acetylcholine receptors reduces neuropathic pain by decreasing dynorphin A release from microglia. Brain Res. 2019; 1715:57-65. DOI: 10.1016/j.brainres.2019.03.016. View

Lee C, Yan B, Yoo K, Choi J, Kwon S, Her S . Ischemia-induced changes in glucagon-like peptide-1 receptor and neuroprotective effect of its agonist, exendin-4, in experimental transient cerebral ischemia. J Neurosci Res. 2011; 89(7):1103-13. DOI: 10.1002/jnr.22596. View

Zhuang Z, Gerner P, Woolf C, Ji R . ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain. 2005; 114(1-2):149-59. DOI: 10.1016/j.pain.2004.12.022. View

Wahlert A, Funkelstein L, Fitzsimmons B, Yaksh T, Hook V . Spinal astrocytes produce and secrete dynorphin neuropeptides. Neuropeptides. 2013; 47(2):109-15. PMC: 3606903. DOI: 10.1016/j.npep.2012.10.006. View

10.

McGrath J, Lilley E . Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP. Br J Pharmacol. 2015; 172(13):3189-93. PMC: 4500358. DOI: 10.1111/bph.12955. View

11.

Taves S, Berta T, Chen G, Ji R . Microglia and spinal cord synaptic plasticity in persistent pain. Neural Plast. 2013; 2013:753656. PMC: 3759269. DOI: 10.1155/2013/753656. View

12.

Huang Q, Mao X, Wu H, Liu H, Sun M, Wang X . Cynandione A attenuates neuropathic pain through p38β MAPK-mediated spinal microglial expression of β-endorphin. Brain Behav Immun. 2017; 62:64-77. DOI: 10.1016/j.bbi.2017.02.005. View

13.

Zhou D, Zhang S, Hu L, Gu Y, Cai Y, Wu D . Inhibition of apoptosis signal-regulating kinase by paeoniflorin attenuates neuroinflammation and ameliorates neuropathic pain. J Neuroinflammation. 2019; 16(1):83. PMC: 6458750. DOI: 10.1186/s12974-019-1476-6. View

14.

Li T, Fan H, Wang Y . Aconitum-Derived Bulleyaconitine A Exhibits Antihypersensitivity Through Direct Stimulating Dynorphin A Expression in Spinal Microglia. J Pain. 2016; 17(5):530-48. DOI: 10.1016/j.jpain.2015.12.015. View

15.

Nyirimigabo E, Xu Y, Li Y, Wang Y, Agyemang K, Zhang Y . A review on phytochemistry, pharmacology and toxicology studies of Aconitum. J Pharm Pharmacol. 2014; 67(1):1-19. DOI: 10.1111/jphp.12310. View

16.

Tsuda M . Microglia in the spinal cord and neuropathic pain. J Diabetes Investig. 2016; 7(1):17-26. PMC: 4718109. DOI: 10.1111/jdi.12379. View

17.

Lv G, Sun D, Zhang J, Xie X, Wu X, Fang W . Lx2-32c, a novel semi-synthetic taxane, exerts antitumor activity against prostate cancer cells and . Acta Pharm Sin B. 2017; 7(1):52-58. PMC: 5237719. DOI: 10.1016/j.apsb.2016.06.005. View

18.

Illias A, Gist A, Zhang H, Kosturakis A, Dougherty P . Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity. Pain. 2018; 159(7):1308-1316. PMC: 6008166. DOI: 10.1097/j.pain.0000000000001212. View

19.

Tang Y, Liu L, Xu D, Zhang W, Zhang Y, Zhou J . Interaction between astrocytic colony stimulating factor and its receptor on microglia mediates central sensitization and behavioral hypersensitivity in chronic post ischemic pain model. Brain Behav Immun. 2017; 68:248-260. DOI: 10.1016/j.bbi.2017.10.023. View

20.

Jiang L, Pan C, Wang C, Liu B, Han Y, Hu L . Selective suppression of the JNK-MMP2/9 signal pathway by tetramethylpyrazine attenuates neuropathic pain in rats. J Neuroinflammation. 2017; 14(1):174. PMC: 5580313. DOI: 10.1186/s12974-017-0947-x. View