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http://dx.doi.org/10.4062/biomolther.2021.154

Oleanolic Acid Provides Neuroprotection against Ischemic Stroke through the Inhibition of Microglial Activation and NLRP3 Inflammasome Activation  

Sapkota, Arjun (Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University)
Choi, Ji Woong (Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University)
Publication Information
Biomolecules & Therapeutics / v.30, no.1, 2022 , pp. 55-63 More about this Journal
Abstract
Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to exert protective effects against several neurological diseases through its anti-oxidative and anti-inflammatory activities. The goal of the present study was to evaluate the therapeutic potential of OA against acute and chronic brain injuries after ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO, MCAO/reperfusion). OA administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, functional neurological deficits, and neuronal apoptosis. Moreover, delayed administration of OA (at 3 h after reperfusion) attenuated brain infarction and improved functional neurological deficits during the acute phase. Such neuroprotective effects were associated with attenuation of microglial activation and lipid peroxidation in the injured brain after the tMCAO challenge. OA also attenuated NLRP3 inflammasome activation in activated microglia during the acute phase. In addition, daily administration of OA for 7 days starting from either immediately after reperfusion or 1 day after reperfusion significantly improved functional neurological deficits and attenuated brain tissue loss up to 21 days after the tMCAO challenge; these findings supported therapeutic effects of OA against ischemic stroke-induced chronic brain injury. Together, these findings showed that OA exerted neuroprotective effects against both acute and chronic brain injuries after tMCAO challenge, suggesting that OA is a potential therapeutic agent to treat ischemic stroke.
Keywords
Oleanolic acid; Ischemic stroke; Microglia; Lipid peroxidation; NLRP3 inflammasome activation;
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1 Martin, R., Carvalho-Tavares, J., Hernandez, M., Arnes, M., Ruiz-Gutierrez, V. and Nieto, M. L. (2010) Beneficial actions of oleanolic acid in an experimental model of multiple sclerosis: a potential therapeutic role. Biochem. Pharmacol. 79, 198-208.   DOI
2 Martin, R., Hernandez, M., Cordova, C. and Nieto, M. L. (2012) Natural triterpenes modulate immune-inflammatory markers of experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis. Br. J. Pharmacol. 166, 1708-1723.   DOI
3 Minutoli, L., Puzzolo, D., Rinaldi, M., Irrera, N., Marini, H., Arcoraci, V., Bitto, A., Crea, G., Pisani, A., Squadrito, F., Trichilo, V., Bruschetta, D., Micali, A. and Altavilla, D. (2016) ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxid. Med. Cell. Longev. 2016, 2183026.
4 Niu, G., Sun, L., Pei, Y. and Wang, D. (2018) Oleanolic acid inhibits colorectal cancer angiogenesis by blocking the VEGFR2 signaling pathway. Anticancer Agents Med. Chem. 18, 583-590.   DOI
5 MacManus, J. P. and Buchan, A. M. (2000) Apoptosis after experimental stroke: fact or fashion? J. Neurotrauma 17, 899-914.   DOI
6 Wang, W., Chen, K., Xia, Y., Mo, W., Wang, F., Dai, W. and Niu, P. (2018b) The hepatoprotection by oleanolic acid preconditioning: focusing on PPARalpha activation. PPAR Res. 2018, 3180396.   DOI
7 Yenari, M. A., Kauppinen, T. M. and Swanson, R. A. (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7, 378-391.   DOI
8 Pu, H., Shi, Y., Zhang, L., Lu, Z., Ye, Q., Leak, R. K., Xu, F., Ma, S., Mu, H., Wei, Z., Xu, N., Xia, Y., Hu, X., Hitchens, T. K., Bennett, M. V. L. and Chen, J. (2019) Protease-independent action of tissue plasminogen activator in brain plasticity and neurological recovery after ischemic stroke. Proc. Natl. Acad. Sci. U.S.A. 116, 9115-9124.   DOI
9 Shah, I. M., Macrae, I. M. and Di Napoli, M. (2009) Neuroinflammation and neuroprotective strategies in acute ischaemic stroke - from bench to bedside. Curr. Mol. Med. 9, 336-354.   DOI
10 Wang, K., Sun, W., Zhang, L., Guo, W., Xu, J., Liu, S., Zhou, Z. and Zhang, Y. (2018a) Oleanolic acid ameliorates Abeta25-35 injectioninduced memory deficit in Alzheimer's disease model rats by maintaining synaptic plasticity. CNS Neurol. Disord. Drug Targets 17, 389-399.   DOI
11 Yang, F., Wang, Z., Wei, X., Han, H., Meng, X., Zhang, Y., Shi, W., Li, F., Xin, T., Pang, Q. and Yi, F. (2014) NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J. Cereb. Blood Flow Metab. 34, 660-667.   DOI
12 Ayeleso, T. B., Matumba, M. G. and Mukwevho, E. (2017) Oleanolic acid and its derivatives: biological activities and therapeutic potential in chronic diseases. Molecules 22, 1915.   DOI
13 Ziberna, L., Samec, D., Mocan, A., Nabavi, S. F., Bishayee, A., Farooqi, A. A., Sureda, A. and Nabavi, S. M. (2017) Oleanolic acid alters multiple cell signaling pathways: implication in cancer prevention and therapy. Int. J. Mol. Sci. 18, 643.   DOI
14 Kelley, N., Jeltema, D., Duan, Y. and He, Y. (2019) The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 20, 3328.   DOI
15 Lee, C. H., Sapkota, A., Gaire, B. P. and Choi, J. W. (2020) NLRP3 Inflammasome activation is involved in LPA1-mediated brain injury after transient focal cerebral ischemia. Int. J. Mol. Sci. 21, 8595.   DOI
16 Sapkota, A., Lee, C. H., Park, S. J. and Choi, J. W. (2020) Lysophosphatidic acid receptor 5 plays a pathogenic role in brain damage after focal cerebral ischemia by modulating neuroinflammatory responses. Cells 9, 1446.   DOI
17 Shi, Y. J., Sun, L. L., Ji, X., Shi, R., Xu, F. and Gu, J. H. (2021) Neuroprotective effects of oleanolic acid against cerebral ischemiareperfusion injury in mice. Exp. Neurol. 343, 113785.   DOI
18 Sairanen, T., Karjalainen-Lindsberg, M. L., Paetau, A., Ijas, P. and Lindsberg, P. J. (2006) Apoptosis dominant in the periinfarct area of human ischaemic stroke--a possible target of antiapoptotic treatments. Brain 129, 189-199.   DOI
19 Abulafia, D. P., de Rivero Vaccari, J. P., Lozano, J. D., Lotocki, G., Keane, R. W. and Dietrich, W. D. (2009) Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J. Cereb. Blood Flow Metab. 29, 534-544.   DOI
20 An, Q., Hu, Q., Wang, B., Cui, W., Wu, F. and Ding, Y. (2017) Oleanolic acid alleviates diabetic rat carotid artery injury through the inhibition of NLRP3 inflammasome signaling pathways. Mol. Med. Rep. 16, 8413-8419.   DOI
21 Caltana, L., Rutolo, D., Nieto, M. L. and Brusco, A. (2014) Further evidence for the neuroprotective role of oleanolic acid in a model of focal brain hypoxia in rats. Neurochem. Int. 79, 79-87.   DOI
22 Castellano, J. M., Garcia-Rodriguez, S., Espinosa, J. M., Millan-Linares, M. C., Rada, M. and Perona, J. S. (2019) Oleanolic acid exerts a neuroprotective effect against microglial cell activation by modulating cytokine release and antioxidant defense systems. Biomolecules 9, 683.   DOI
23 Gaire, B. P., Sapkota, A. and Choi, J. W. (2020) BMS-986020, a specific LPA1 antagonist, provides neuroprotection against ischemic stroke in mice. Antioxidants 9, 1097.   DOI
24 Jayaraj, R. L., Azimullah, S., Beiram, R., Jalal, F. Y. and Rosenberg, G. A. (2019) Neuroinflammation: friend and foe for ischemic stroke. J. Neuroinflammation 16, 142.   DOI
25 Rong, Z. T., Gong, X. J., Sun, H. B., Li, Y. M. and Ji, H. (2011) Protective effects of oleanolic acid on cerebral ischemic damage in vivo and H(2)O(2)-induced injury in vitro. Pharm. Biol. 49, 78-85.   DOI
26 Muralikrishna Adibhatla, R. and Hatcher, J. F. (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic. Biol. Med. 40, 376-387.   DOI
27 Girard, S., Murray, K. N., Rothwell, N. J., Metz, G. A. and Allan, S. M. (2014) Long-term functional recovery and compensation after cerebral ischemia in rats. Behav. Brain. Res. 270, 18-28.   DOI
28 Gu, S. (2021) Oleanolic acid improved inflammatory response and apoptosis of PC12 cells induced by OGD/R through downregulating miR-142-5P. Nat. Prod. Commun. 16, 1934578X211018019.
29 Gudoityte, E., Arandarcikaite, O., Mazeikiene, I., Bendokas, V. and Liobikas, J. (2021) Ursolic and oleanolic acids: plant metabolites with neuroprotective potential. Int. J. Mol. Sci. 22, 4599.   DOI
30 Ismael, S., Zhao, L., Nasoohi, S. and Ishrat, T. (2018) Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke. Sci. Rep. 8, 5971.   DOI
31 Kim, M. S., Han, J. Y., Kim, S. H., Jeon, D., Kim, H. Y., Lee, S. W., Rho, M. C. and Lee, K. (2018) Oleanolic acid acetate attenuates polyhexamethylene guanidine phosphate-induced pulmonary inflammation and fibrosis in mice. Respir. Physiol. Neurobiol. 252-253, 1-9.   DOI
32 Lapchak, P. A. (2010) A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert. Opin. Pharmacother. 11, 1753-1763.   DOI
33 Lenart, N., Brough, D. and Denes, A. (2016) Inflammasomes link vascular disease with neuroinflammation and brain disorders. J. Cereb. Blood Flow. Metab. 36, 1668-1685.   DOI
34 Liu, J. (2005) Oleanolic acid and ursolic acid: research perspectives. J. Ethnopharmacol. 100, 92-94.   DOI
35 He, Y., Hara, H. and Nunez, G. (2016) Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41, 1012-1021.   DOI
36 Castellano, J. M., Guinda, A., Delgado, T., Rada, M. and Cayuela, J. A. (2013) Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes. Diabetes 62, 1791-1799.   DOI
37 Martin, R., Cordova, C., San Roman, J. A., Gutierrez, B., Cachofeiro, V. and Nieto, M. L. (2014) Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease. J. Mol. Cell. Cardiol. 72, 250-262.   DOI
38 Schmidt-Pogoda, A., Bonberg, N., Koecke, M. H. M., Strecker, J. K., Wellmann, J., Bruckmann, N. M., Beuker, C., Schabitz, W. R., Meuth, S. G., Wiendl, H., Minnerup, H. and Minnerup, J. (2020) Why most acute stroke studies are positive in animals but not in patients: a systematic comparison of preclinical, early phase, and phase 3 clinical trials of neuroprotective agents. Ann. Neurol. 87, 40-51.   DOI
39 Wang, J. L., Ren, C. H., Feng, J., Ou, C. H. and Liu, L. (2020) Oleanolic acid inhibits mouse spinal cord injury through suppressing inflammation and apoptosis via the blockage of p38 and JNK MAPKs. Biomed. Pharmacother. 123, 109752.   DOI
40 Xu, K., Chu, F., Li, G., Xu, X., Wang, P., Song, J., Zhou, S. and Lei, H. (2014) Oleanolic acid synthetic oligoglycosides: a review on recent progress in biological activities. Pharmazie 69, 483-495.
41 Xu, Q., Zhao, B., Ye, Y., Li, Y., Zhang, Y., Xiong, X. and Gu, L. (2021) Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke. J. Neuroinflammation 18, 123.   DOI
42 Jin, R., Yang, G. and Li, G. (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J. Leukoc. Biol. 87, 779-789.   DOI
43 Msibi, Z. N. P. and Mabandla, M. V. (2019) Oleanolic acid mitigates 6-hydroxydopamine neurotoxicity by attenuating intracellular ROS in PC12 cells and striatal microglial activation in rat brains. Front. Physiol. 10, 1059.   DOI
44 O'Collins, V. E., Macleod, M. R., Donnan, G. A., Horky, L. L., van der Worp, B. H. and Howells, D. W. (2006) 1,026 experimental treatments in acute stroke. Ann. Neurol. 59, 467-477.   DOI
45 Xu, S., Lu, J., Shao, A., Zhang, J. H. and Zhang, J. (2020) Glial cells: role of the immune response in ischemic stroke. Front. Immunol. 11, 294.   DOI
46 Ye, X., Shen, T., Hu, J., Zhang, L., Zhang, Y., Bao, L., Cui, C., Jin, G., Zan, K., Zhang, Z., Yang, X., Shi, H., Zu, J., Yu, M., Song, C., Wang, Y., Qi, S. and Cui, G. (2017) Purinergic 2X7 receptor/NLRP3 pathway triggers neuronal apoptosis after ischemic stroke in the mouse. Exp. Neurol. 292, 46-55.   DOI
47 Gladstone, D. J., Black, S. E. and Hakim, A. M. (2002) Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33, 2123-2136.   DOI