(+)-Borneol Inhibits Neuroinflammation and M1 Phenotype Polarization of Microglia in Epileptogenesis Through the TLR4-NFκB Signaling Pathway

Overview

Journal Front Neurosci

Date 2024 Nov 28

PMID 39605791

Authors

Shuo Li

Alhamdu Adamu

Yucai Ye

Fankai Gao

Rulin Mi

Guofang Xue

Zhaojun Wang

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate the effect of (+)-borneol on neuroinflammation and microglia phenotype polarization in epileptogenesis and its possible mechanism.

Methods: Based on mouse models of status epilepticus (SE) induced by pilocarpine, and treated with 15 mg/kg (+)-borneol, western-blot was used to detect the expressions of NeuN, Iba-1, TLR4, p65 and p-p65 in the hippocampus. Immunofluorescence was used to detect the expression of apoptosis-related proteins Bax and Bcl-2. To explore the effect of (+)-borneol on microglia , we used the kainic acid-induced microglia model and the concentration of (+)-borneol was 25 μM according to CCK-8 results. The levels of tumor necrosis factor- (TNF-α), interleukin-1β (IL-1β) and interleukin-10 (IL-10) in the supernatant of each group was detected by ELISA. The nitric oxide (NO) content in the supernatant was detected by Griess method. The expressions of Iba-1 and TLR4-NFκB signaling pathway-related proteins (TLR4, p65, p-p65) were detected by Western-Blot. Immunofluorescence was used to detect microglia's M1 and M2 phenotype polarization and the expression of Iba-1 and TLR4.

Results: (+)-borneol reduced hippocampal neuronal injury, apoptosis, and microglia activation by inhibiting the TLR-NFκB signaling pathway in SE mice. TLR4 agonist LPS partially reversed the neuroprotective effect of (+)-borneol. In the KA-induced microglia model, (+)-borneol inhibited microglia activation, M1 phenotype polarization, and secretion of pro-inflammatory cytokines through the TLR4-NFκB signaling pathway. LPS treatment inhibited the therapeutic effects of (+)-borneol.

Conclusion: (+)-borneol inhibits microglial neuroinflammation and M1 phenotype polarization through TLR4-NFκB signaling pathway and reduces neuronal damage and apoptosis in SE mice. Therefore, (+)-borneol may be a potential drug for epilepsy modification therapy.

References

Pracucci E, Pillai V, Lamers D, Parra R, Landi S . Neuroinflammation: A Signature or a Cause of Epilepsy?. Int J Mol Sci. 2021; 22(13). PMC: 8267969. DOI: 10.3390/ijms22136981. View

Zou L, Zhang Y, Li W, Zhang J, Wang D, Fu J . Comparison of Chemical Profiles, Anti-Inflammatory Activity, and UPLC-Q-TOF/MS-Based Metabolomics in Endotoxic Fever Rats between Synthetic Borneol and Natural Borneol. Molecules. 2017; 22(9). PMC: 6151575. DOI: 10.3390/molecules22091446. View

Thompson K . Status epilepticus and early development: Neuronal injury, neurodegeneration, and their consequences. Epilepsia Open. 2022; 8 Suppl 1:S110-S116. PMC: 10173843. DOI: 10.1002/epi4.12601. View

Patel D, Tewari B, Chaunsali L, Sontheimer H . Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci. 2019; 20(5):282-297. PMC: 8558781. DOI: 10.1038/s41583-019-0126-4. View

Zhong Y, Qi Y, Jiang Z, Hu Y, Zhang X, Wu C . Analysis of medication rules and application characteristics of Chinese patent medicine containing borneol based on data mining. Heliyon. 2023; 9(11):e21232. PMC: 10641158. DOI: 10.1016/j.heliyon.2023.e21232. View

Benson M, Manzanero S, Borges K . Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models. Epilepsia. 2015; 56(6):895-905. DOI: 10.1111/epi.12960. View

Hiragi T, Ikegaya Y, Koyama R . Microglia after Seizures and in Epilepsy. Cells. 2018; 7(4). PMC: 5946103. DOI: 10.3390/cells7040026. View

Kwon H, Koh S . Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020; 9(1):42. PMC: 7689983. DOI: 10.1186/s40035-020-00221-2. View

Vega-Garcia A, Guevara-Guzman R, Garcia-Gomez O, Feria-Romero I, Fernandez-Valverde F, Alonso-Vanegas M . Aberrant Connection Formation and Glia Involvement in the Progression of Pharmacoresistant Mesial Temporal Lobe Epilepsy. Curr Pharm Des. 2022; 28(28):2283-2297. DOI: 10.2174/1381612828666220616162739. View

10.

Paudel Y, Angelopoulou E, Akyuz E, Piperi C, Othman I, Shaikh M . Role of Innate Immune Receptor TLR4 and its endogenous ligands in epileptogenesis. Pharmacol Res. 2020; 160:105172. DOI: 10.1016/j.phrs.2020.105172. View

11.

Tian M, Wang R, Holscher C, Mi R, Yuan Z, Li D . The novel GLP-1/GIP dual receptor agonist DA3-CH is neuroprotective in the pilocarpine-induced epileptogenesis rat model. Epilepsy Res. 2019; 154:97-106. DOI: 10.1016/j.eplepsyres.2019.05.008. View

12.

Beghi E . The Epidemiology of Epilepsy. Neuroepidemiology. 2019; 54(2):185-191. DOI: 10.1159/000503831. View

13.

Henshall D, Simon R . Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab. 2005; 25(12):1557-72. DOI: 10.1038/sj.jcbfm.9600149. View

14.

Pitkanen A, Kharatishvili I, Karhunen H, Lukasiuk K, Immonen R, Nairismagi J . Epileptogenesis in experimental models. Epilepsia. 2007; 48 Suppl 2:13-20. DOI: 10.1111/j.1528-1167.2007.01063.x. View

15.

Peng J, Wang K, Xiang W, Li Y, Hao Y, Guan Y . Rosiglitazone polarizes microglia and protects against pilocarpine-induced status epilepticus. CNS Neurosci Ther. 2019; 25(12):1363-1372. PMC: 6887926. DOI: 10.1111/cns.13265. View

16.

Li W, Wu J, Zeng Y, Zheng W . Neuroinflammation in epileptogenesis: from pathophysiology to therapeutic strategies. Front Immunol. 2024; 14:1269241. PMC: 10771847. DOI: 10.3389/fimmu.2023.1269241. View

17.

Ma R, Lu D, Xie Q, Yuan J, Ren M, Li Y . l-Borneol and d-Borneol promote transdifferentiation of astrocytes into neurons in rats by regulating Wnt/Notch pathway to exert neuroprotective effect during recovery from cerebral ischaemia. Phytomedicine. 2023; 109:154583. DOI: 10.1016/j.phymed.2022.154583. View

18.

Younger D, Murugan M, Rao K, Wu L, Chandra N . Microglia Receptors in Animal Models of Traumatic Brain Injury. Mol Neurobiol. 2018; 56(7):5202-5228. DOI: 10.1007/s12035-018-1428-7. View

19.

Levesque M, Biagini G, de Curtis M, Gnatkovsky V, Pitsch J, Wang S . The pilocarpine model of mesial temporal lobe epilepsy: Over one decade later, with more rodent species and new investigative approaches. Neurosci Biobehav Rev. 2021; 130:274-291. DOI: 10.1016/j.neubiorev.2021.08.020. View

20.

Long Y, Li X, Deng J, Ye Q, Li D, Ma Y . Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases. Ageing Res Rev. 2023; 93:102160. DOI: 10.1016/j.arr.2023.102160. View