Santacruzamate A Alleviates Pain and Pain-Related Adverse Emotions Through the Inhibition of Microglial Activation in the Anterior Cingulate Cortex

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2024 Apr 18

PMID 38633586

Authors

Yan Qin

Qingqing Liu

Saiying Wang

Qinhui Wang

Yaya Du

Jingyue Yao

Yue Chen

Qi Yang

Yumei Wu

Shuibing Liu

Minggao Zhao

Gaofei Wei

Le Yang

Affiliations

Soon will be listed here.

Abstract

Chronic pain is a complex disease. It seriously affects patients' quality of life and imposes a significant economic burden on society. Santacruzamate A (SCA) is a natural product isolated from marine cyanobacteria in Panama. In this study, we first demonstrated that SCA could alleviate chronic inflammatory pain, pain-related anxiety, and depression emotions induced by complete Freund's adjuvant in mice while inhibiting microglial activation in the anterior cingulate cortex. Moreover, SCA treatment attenuated lipopolysaccharide (LPS)-induced inflammatory response by downregulating interleukin 1β and 6 (IL-1β and IL-6) and tumor necrosis factor-α (TNF-α) levels in BV2 cells. Furthermore, we found that SCA could bind to soluble epoxide hydrolase (sEH) through molecular docking technology, and the thermal stability of sEH was enhanced after binding of SCA to the sEH protein. Meanwhile, we identified that SCA could reduce the sEH enzyme activity and inhibit sEH protein overexpression in the LPS stimulation model. The results indicated that SCA could alleviate the development of inflammation by inhibiting the enzyme activity and expression of sEH to further reduce chronic inflammatory pain. Our study suggested that SCA could be a potential drug for treating chronic inflammatory pain.

References

Long J, Liu H, Qiu Z, Xiao Z, Lu Z . Glabridin Therapy Reduces Chronic Allodynia, Spinal Microgliosis, and Dendritic Spine Generation by Inhibiting Fractalkine-CX3CR1 Signaling in a Mouse Model of Tibial Fractures. Brain Sci. 2023; 13(5). PMC: 10216346. DOI: 10.3390/brainsci13050739. View

Zarriello S, Tuazon J, Corey S, Schimmel S, Rajani M, Gorsky A . Humble beginnings with big goals: Small molecule soluble epoxide hydrolase inhibitors for treating CNS disorders. Prog Neurobiol. 2018; 172:23-39. PMC: 6993804. DOI: 10.1016/j.pneurobio.2018.11.001. View

Krebs E, Gravely A, Nugent S, Jensen A, DeRonne B, Goldsmith E . Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA. 2018; 319(9):872-882. PMC: 5885909. DOI: 10.1001/jama.2018.0899. View

Bedene A, Dahan A, Rosendaal F, van Dorp E . Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids. Expert Rev Clin Pharmacol. 2022; 15(9):1081-1094. DOI: 10.1080/17512433.2022.2114898. View

Nguyen T, Nguyen N, Cochran A, Smith J, Al-Juboori M, Brumett A . Repeated closed-head mild traumatic brain injury-induced inflammation is associated with nociceptive sensitization. J Neuroinflammation. 2023; 20(1):196. PMC: 10464478. DOI: 10.1186/s12974-023-02871-1. View

Deng J, Han J, Chen J, Zhang Y, Huang Q, Wang Y . Comparison of analgesic activities of aconitine in different mice pain models. PLoS One. 2021; 16(4):e0249276. PMC: 8016268. DOI: 10.1371/journal.pone.0249276. View

van der Vlist M, Raoof R, Willemen H, Prado J, Versteeg S, Martin Gil C . Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain. Neuron. 2021; 110(4):613-626.e9. DOI: 10.1016/j.neuron.2021.11.020. View

Chen L, Liu Y, Tan H, Zhang Y, Xu J, Liu W . Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR and . Front Cell Neurosci. 2019; 13:61. PMC: 6409322. DOI: 10.3389/fncel.2019.00061. View

Barry D, Liu X, Liu B, Liu X, Gao F, Zeng X . Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors. Nat Commun. 2020; 11(1):1397. PMC: 7070094. DOI: 10.1038/s41467-020-15230-y. View

10.

Wu C, Shyue S, Hung T, Wen S, Lin C, Chang C . Genetic deletion or pharmacological inhibition of soluble epoxide hydrolase reduces brain damage and attenuates neuroinflammation after intracerebral hemorrhage. J Neuroinflammation. 2017; 14(1):230. PMC: 5702198. DOI: 10.1186/s12974-017-1005-4. View

11.

Munro G, Hansen R, Erichsen H, Timmermann D, Christensen J, Hansen H . The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat. Br J Pharmacol. 2012; 167(2):421-35. PMC: 3481048. DOI: 10.1111/j.1476-5381.2012.02003.x. View

12.

Zhou H, Cai Y, Liu D, Li M, Sha Y, Zhang W . Pharmacological or transcriptional inhibition of both HDAC1 and 2 leads to cell cycle blockage and apoptosis via p21 and p19 upregulation in hepatocellular carcinoma. Cell Prolif. 2018; 51(3):e12447. PMC: 6528930. DOI: 10.1111/cpr.12447. View

13.

Morisseau C, Goodrow M, Dowdy D, Zheng J, Greene J, Sanborn J . Potent urea and carbamate inhibitors of soluble epoxide hydrolases. Proc Natl Acad Sci U S A. 1999; 96(16):8849-54. PMC: 17696. DOI: 10.1073/pnas.96.16.8849. View

14.

. Protein Data Bank: the single global archive for 3D macromolecular structure data. Nucleic Acids Res. 2018; 47(D1):D520-D528. PMC: 6324056. DOI: 10.1093/nar/gky949. View

15.

Tu Y, Tan L, Tao H, Li Y, Liu H . CETSA and thermal proteome profiling strategies for target identification and drug discovery of natural products. Phytomedicine. 2023; 116:154862. DOI: 10.1016/j.phymed.2023.154862. View

16.

Vidal-Itriago A, Radford R, Aramideh J, Maurel C, Scherer N, Don E . Microglia morphophysiological diversity and its implications for the CNS. Front Immunol. 2022; 13:997786. PMC: 9627549. DOI: 10.3389/fimmu.2022.997786. View

17.

Hnasko T, Hnasko R . The Western Blot. Methods Mol Biol. 2015; 1318:87-96. DOI: 10.1007/978-1-4939-2742-5_9. View

18.

Damaskos C, Garmpis N, Valsami S, Kontos M, Spartalis E, Kalampokas T . Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer. Anticancer Res. 2016; 37(1):35-46. DOI: 10.21873/anticanres.11286. View

19.

Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y . TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest. 2005; 115(9):2393-401. PMC: 1187934. DOI: 10.1172/JCI25437. View

20.

Friedman T, La Caprara O, Zhang C, Lee K, May J, Faig C . Sex differences in peripheral immune cell activation: Implications for pain and pain resolution. Brain Behav Immun. 2023; 114:80-93. DOI: 10.1016/j.bbi.2023.07.029. View