Celastrol is extracted from the traditional Chinese medicine Tripterygium wilfordii Hook. f.. It is a kind of traditional Chinese medicine monomer with extensive pharmacological activity and has anti-tumor, anti-inflammation, anti-oxidation and neuroprotective effects. Studies have found that celastrol is not only closely related to obesity, tumor and cardiovascular diseases, but also plays a neuroprotective role in the cerebrovascular system by regulating various signaling pathways. At present, effective drugs for stroke are still limited, but with the deepening of the research on celastrol, its therapeutic potential in stroke has received more and more attention, especially in ischemic and hemorrhagic stroke, which has shown good therapeutic effects. Therefore, this is the first time to systematically summarize the therapeutic effects of celastrol on stroke and the underlying mechanisms involved, in order to provide further directions and references for the neuroprotective effects of celastrol.

1.Wang Y, Li C, Gu J, et al. Celastrol exerts anti-inflammatory effect in liver fibrosis via activation of AMPK-SIRT3 signalling[J]. J Cell Mol Med, 2020, 24(1): 941-953. DOI: 10.1111/jcmm.14805.

2.Cao F, Wang Y, Song Y, et al. Celastrol treatment ameliorated acute ischemic stroke-induced brain injury by microglial injury inhibition and Nrf2/HO-1 pathway activations[J]. Biomed Res Int, 2023, 2023: 1076522. DOI: 10.1155/2023/1076522.

3.Yang X, Chen A, Liang Q, et al. Up-regulation of heme oxygenase-1 by celastrol alleviates oxidative stress and vascular calcification in chronic kidney disease[J]. Free Radic Biol Med, 2021, 172: 530-540. DOI: 10.1016/j.freeradbiomed.2021.06.020.

4.Xu H, Zhao H, Ding C, et al. Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1[J]. Signal Transduct Target Ther, 2023, 8(1): 51. DOI: 10.1038/s41392-022-01231-4.

5.Zhang T, Zhao Q, Xiao X, et al. Modulation of lipid metabolism by celastrol[J]. J Proteome Res, 2019, 18(3): 1133-1144. DOI: 10.1021/acs.jproteome.8b00797.

6.虞莉莎, 刘新靓, 宋康, 等. 中国脑卒中环境危险因素的系统评价[J]. 医学新知, 2023, 33(3): 173-208. [Yu LS, Liu XL, Song K, et al. Environmental risk factors for stroke in China: a systematic review[J]. Yixue Xinzhi Zazhi, 2023, 33(3): 173-208.] DOI: 10.12173/j.issn.1004- 5511.202209017.

7.Katan M, Luft A. Global burden of stroke[J]. Semin Neurol, 2018, 38: 208-211. DOI: 10.1055/s-0038-1649503.

8.Hu X, De Silva TM, Chen J, et al. Cerebral vascular disease and neurovascular injury in ischemic stroke[J]. Circ Res, 2017, 120(3): 449-471. DOI: 10.1161/CIRCRESAHA.116.308427.

9.Saini V, Guada L, Yavagal DR. Global epidemiology of stroke and access to acute ischemic stroke interventions[J]. Neurology, 2021, 97(20 Suppl 2): S6-S16. DOI: 10.1212/WNL.0000000000012781.

10.周莎莎, 陈向凡, 陈霞. 依达拉奉右莰醇治疗急性缺血性脑卒中的成本-效用分析[J]. 药物流行病学杂志, 2024, 33(1): 68-74. [Zhou SS, Chend XF, Chen X. Cost-utility analysis of edaravone dexborneol for acute ischemic stroke[J]. Chinese Journal of Pharmacoepidemiology, 2024, 33(1): 68-74.] DOI: 10.12173/j.issn. 1005-0698.202305025.

11.郭年凤, 费菲, 李佳丹. 丁苯酞联合尤瑞克林治疗急性心源性脑卒中患者的有效性和安全性研究[J]. 中国药师, 2023, 26(12): 420-427. [Guo NF, Fei F, Li JD. Study on the efficacy and safety of butylphthalide in combination with eureklin in the treatment of patients with acute cardioembolic stroke[J]. China Pharmacist, 2023, 26(12): 420-427.] DOI: 10.12173/j.issn.1008-049X.202311097.

12.de Angelis M, Schriever SC, Kyriakou E, et al. Detection and quantification of the anti-obesity drug celastrol in murine liver and brain[J]. Neurochem Int, 2020, 136: 104713. DOI: 10.1016/j.neuint.2020.104713.

13.Zhao Y, Zhang X, Chen X, et al. Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment (Review)[J]. Int J Mol Med, 2022, 49(2): 15. DOI: 10.3892/ijmm.2021.5070.

14.Oo TT. Ischemic stroke and diabetes: a TLR4-mediated neuroinflammatory perspective[J]. J Mol Med (Berl), 2024-03-28. DOI: 10.1007/s00109-024-02441-9.

15.Zhao J, Liu S, Li K, et al. RBM3 promotes anti-inflammatory responses in microglia and serves as a neuroprotective target of ischemic stroke[J]. Mol Neurobiol, 2024-02-22. DOI: 10.1007/s12035-024-04052-4.

16.Albaqami FF, Abdel-Rahman RF, Althurwi HN, et al. Targeting inflammation and oxidative stress for protection against ischemic brain injury in rats using cupressuflavone[J]. Saudi Pharm J, 2024, 32(1): 101933. DOI: 10.1016/j.jsps.2023.101933.

17.Li Y, He D, Zhang X, et al. Protective effect of celastrol in rat cerebral ischemia model: down-regulating p-JNK, p-c-Jun and NF-κB[J]. Brain research, 2012, 1464: 8-13. DOI: 10.1016/j.brainres.2012.04.054.

18.Wang J, Ding X, Li C, et al. Early exercise intervention promotes myelin repair in the brains of ischemic rats by inhibiting the MEK/ERK pathway[J]. Transl Neurosci, 2024, 15(1): 20220335. DOI: 10.1515/tnsci-2022-0335.

19.Wang L, Qu Z, Sun Q, et al. 4-hydroxysesamin, a modified natural compound, attenuates neuronal apoptosis after ischemic stroke via inhibiting MAPK pathway[J]. Neuropsychiatr Dis Treat, 2024, 20: 523-533. DOI: 10.2147/NDT.S444760.

20.Tao T, Liu M, Chen M, et al. Natural medicine in neuroprotection for ischemic stroke: Challenges and prospective[J]. Pharmacol Ther, 2020, 216: 107695. DOI: 10.1016/j.pharmthera.2020.107695.

21.Magid-Bernstein J, Girard R, Polster S, et al. Cerebral hemorrhage: pathophysiology, treatment, and future directions[J]. Circ Res, 2022, 130(8): 1204-1229. DOI: 10.1161/CIRCRESAHA.121.319949.

22.Wang L, Zhang X, Xiong X, et al. Nrf2 regulates oxidative stress and its role in cerebral ischemic stroke[J]. Antioxidants (Basel), 2022, 11(12): 2377. DOI: 10.3390/antiox11122377.

23.Duan C, Wang H, Jiao D, et al. Curcumin restrains oxidative stress of after intracerebral hemorrhage in rat by activating the Nrf2/HO-1 pathway[J]. Front Pharmacol, 2022, 27(13): 889226. DOI: 10.3389/fphar.2022.889226.

24.Koutsaliaris IK, Moschonas IC, Pechlivani LM, et al. Inflammation, oxidative stress, vascular aging and atherosclerotic ischemic stroke[J]. Curr Med Chem, 2022, 29(34): 5496-5509. DOI: 10.2174/0929867328666210921161711.

25.Sun Y, Zhu H, Zhao R, et al. Remote ischemic conditioning attenuates oxidative stress and inflammation via the Nrf2/HO-1 pathway in MCAO mice[J]. Redox Biol, 2023, 66: 102852. DOI: 10.1016/j.redox.2023.102852.

26.Wei C, Kong Y, Li G, et al. Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway[J]. Sci Rep, 2017, 7(1): 717. DOI: 10.1038/s41598-017-00851-z.

27.Zhang B, Zhong Q, Chen X, et al. Neuroprotective effects of celastrol on transient global cerebral ischemia rats via regulating HMGB1/NF-κB signaling pathway[J]. Front Neurosci, 2020, 14: 847. DOI: 10.3389/fnins.2020.00847.

28.Saadh MJ, Faisal A, Adil M, et al. Parkinson's disease and microRNAs: a duel between inhibition and stimulation of apoptosis in neuronal cells[J]. Mol Neurobiol, 2024-03-23. DOI: 10.1007/s12035-024-04111-w.

29.Galluzzi L, Vitale I, Abrams JM, et al. Molecular definitions of cell death subroutines: recommendations of the nomenclature committee on cell death 2012[J]. Cell Death Differ, 2012, 19(1): 107-120. DOI: 10.1038/cdd.2011.96.

30.Jiang M, Liu X, Zhang D, et al. Celastrol treatment protects against acute ischemic stroke-induced brain injury by promoting an IL-33/ST2 axis-mediated microglia/macrophage M2 polarization[J]. J Neuroinflammation, 2018, 15(1): 78. DOI: 10.1186/s12974-018-1124-6.

31.Liu C, Gu J, Yu Y. Celastrol assuages oxygen-glucose deprivation and reoxygenation-induced damage in human brain microvascular endothelial cells through the circDLGAP4/miR-6085/GDF11 pathway[J]. Metabolic brain disease, 2023, 38(1): 255-267. DOI: 10.1007/s11011-022-01106-1.

32.Xu H, Cai Y, Yu M, et al. Celastrol protects against early brain injury after subarachnoid hemorrhage in rats through alleviating blood-brain barrier disruption and blocking necroptosis[J]. Aging, 2021, 13(12): 16816-16833. DOI: 10.18632/aging.203221.

33.Barthels D, Das H. Current advances in ischemic stroke research and therapies[J]. Biochim Biophys Acta Mol Basis Dis, 2020, 1866(4): 165260. DOI: 10.1016/j.bbadis.2018.09.012.

34.乔会敏, 董梅, 陈林玉, 等. 雷公藤红素下调p-p38、p-JNK、NF-κB减轻脑梗死后的炎症反应[J].脑与神经疾病杂志, 2021, 29(5): 274-279. [Qiao HM, Dong M, Chen LY, et al. Down-regulation of p-p38, p-JNK, and NF-κB by tretinoin attenuates inflammatory responses after cerebral infarction[J]. Journal of Brain and Neurological Diseases, 2021, 29(5): 274-279.] https://www.cnki.com.cn/Article/CJFDTotal-LYSJ202105003.htm.

35.Jurcau A, Simion A. Neuroinflammation in cerebral ischemia and ischemia/reperfusion injuries: from pathophysiology to therapeutic strategies[J]. Int J Mol Sci, 2021, 23(1): 14. DOI: 10.3390/ijms23010014.

36.Li M, Tang H, Li Z, et al. Emerging treatment strategies for cerebral ischemia-reperfusion injury[J]. Neuroscience, 2022, 507: 112-124. DOI: 10.1016/j.neuroscience.2022.10.020.

37.张朝弘, 刘丹彦. 雷公藤红素后处理对大鼠局灶性脑缺血再灌注损伤后脑组织NF-κB及TNF-α、IL-1β的影响[J]. 重庆医科大学学报, 2015, 40(1): 37-41. [Zhang ZH, Liu DY. Effect of triptolide on NF-κB, TNF-α and IL-1β in cerebral tissue after focal cerebral ischemia-reperfusion injury in rats[J]. Journal of Chongqing Medical University, 2015, 40(1): 37-41.] DOI: 10.13406/j.cnki.cyxb.000109.

38.胡高峰, 黄诚, 程魁红, 等. 雷公藤红素通过抑制氧化应激对脑缺血再灌注损伤的保护研究[J]. 赣南医学院学报, 2018, 38(10): 968-971,984. [Hu GF, Huang C, Cheng KH, et al. Protective effect of tripterygium on cerebral ischemia-reperfusion injury by inhibiting oxidative stress[J]. Journal of Gannan Medical College, 2018, 38(10): 968-971,984.] DOI: 10.3969/j.issn.1001- 5779.2018.10.003.

39.刘茂竹. 雷公藤红素通过激活Nrf2/HO-1信号通路调节氧化应激减轻小鼠局灶性脑缺血再灌注损伤[D]. 重庆: 重庆医科大学, 2022.

40.Hong Z, Cao J, Liu D, et al. Celastrol targeting Nedd4 reduces Nrf2-mediated oxidative stress in astrocytes after ischemic stroke[J]. J Pharm Anal, 2023, 13(2): 156-169. DOI: 10.1016/j.jpha.2022.12.002.

41.Liu M, Chen M, Luo Y, et al. Lipidomic profiling of ipsilateral brain and plasma after celastrol post-treatment in transient middle cerebral artery occlusion mice model[J]. Molecules 2021, 26(14): 4124. DOI: 10.3390/molecules26144124.

42.Chen M, Liu M, Luo Y, et al. Celastrol protects against cerebral ischemia/reperfusion injury in mice by inhibiting glycolysis through targeting HIF-1/PDK1 axis[J]. Oxid Med Cell Longev, 2022, 2022: 7420507. DOI: 10.1155/2022/7420507.

43.Liu J, Guo X, Yang L, et al. Effect of celastrol on LncRNAs and mRNAs profiles of cerebral ischemia-reperfusion injury in transient middle cerebral artery occlusion mice model[J]. Front Neurosci, 2022, 16: 889292. DOI: 10.3389/fnins.2022.889292.

44.杨雪莲, 蔡丽瑛, 顾夏菊, 等. 雷公藤红素对大鼠脑缺血后血管新生和神经保护作用的机制研究[J]. 上海中医药杂志, 2018, 52(8): 67-72, 77. [Yang XL, Cai LY, Gu XJ, et al. Effect of tripterygium on angiogenesis and neuroprotection after cerebral ischemia in rats[J]. Shanghai Journal of Traditional Chinese Medicine, 2018, 52(8): 67-72, 77.] DOI: 10.16305/j.1007-1334.2018.08.020.

45.杨雪莲, 孙鑑, 赵泽飞. 雷公藤红素联合tPA在大鼠脑缺血再灌注损伤时的作用研究[J]. 世界临床药物, 2013, 34(6): 342-346 . [Yang XL, Sun J, Zhao ZF. Effect of tripterygium combined with tPA on cerebral ischemia-reperfusion injury in rat [J]. World Clinical Medicine, 2013, 34(6): 342-346.] DOI: CNKI:SUN:GWHH.0.2013-06-009.

46.Wang R, Gu X, Dai W, et al. A lipidomics investigation into the intervention of celastrol in experimental colitis[J]. Mol Biosyst, 2016, 12(5): 1436-1444. DOI: 10.1039/c5mb00864f.

47.Akhter R. Circular RNA and Alzheimer's disease[J]. Adv Exp Med Biol, 2018, 1087: 239-243. DOI: 10.1007/978-981-13-1426-1_19.

48.He L, Zhang F, Zhu Y, et al. A crosstalk between circular RNA, microRNA, and messenger RNA in the development of various brain cognitive disorders[J]. Front Mol Neurosci, 2022, 15: 960657. DOI: 10.3389/fnmol.2022.960657.

49.Yang B, Zang L, Cui J, et al. Circular RNA TTC3 regulates cerebral ischemia-reperfusion injury and neural stem cells by miR-372-3p/TLR4 axis in cerebral infarction[J]. Stem Cell Res Ther, 2021, 12(1): 125. DOI: 10.1186/s13287-021-02187-y.

50.Kidwell CS, Latour L, Saver JL, et al. Thrombolytic toxicity: blood brain barrier disruption in human ischemic stroke[J]. Cerebrovasc Dis, 2008, 25(4): 338-343. DOI: 10.1159/000118379.

51.Fuentes AM, Stone McGuire L, Amin-Hanjani S. Sex differences in cerebral aneurysms and subarachnoid hemorrhage[J]. Stroke, 2022, 53(2): 624-633. DOI: 10.1161/STROKEAHA.121.037147.

52.van Gijn J, Kerr RS, Rinkel GJE. Subarachnoid haemorrhage[J]. Lancet, 2007, 369(9558): 306-318. DOI: 10.1016/S0140-6736(07)60153-6.

53.Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death[J]. Cell Mol Immunol, 2021, 18(5): 1106-1121. DOI: 10.1038/s41423-020-00630-3.

54.钟伟杰, 刘文武, 李轶. 坏死性凋亡与脑卒中的研究进展[J]. 解剖学杂志, 2022, 45(3): 269-272. [Zhong WJ, Liu WW, Li Y. Research progress of necrotic apoptosis and stroke[J]. Journal of Anatomy, 2022, 45(3): 269-272.] DOI: 10.3969/j.issn.1001-1633.2022.03.015.

55.Hou W, Liu B, Xu H. Celastrol: progresses in structure-modifications, structure-activity relationships, pharmacology and toxicology[J]. Eur J Med Chem, 2020, 189: 112081. DOI: 10.1016/j.ejmech.2020.112081.

56.Sun H, Liu X, Xiong Q, et al. Chronic inhibition of cardiac Kir2.1 and HERG potassium channels by celastrol with dual effects on both ion conductivity and protein trafficking[J]. J Biol Chem, 2006, 281(9): 5877-5884. DOI: 10.1074/jbc.M600072200.

57.Zhao W, Xiao L, Pan L, et al. Cardiac toxicity of Triptergium wilfordii Hook F. may correlate with its inhibition to hERG channel[J]. Heliyon, 2019, 5(10): e02527. DOI: 10.1016/j.heliyon.2019.e02527.

58.Liu C, Zhang C, Wang W, et al. Integrated metabolomics and network toxicology to reveal molecular mechanism of celastrol induced cardiotoxicity[J]. Toxicol Appl Pharmacol, 2019, 383: 114785. DOI: 10.1016/j.taap.2019.114785.

59.Chen Z, Zhuang Z, Meng C, et al. Induction of the ER stress response in NRVMs is linked to cardiotoxicity caused by celastrol[J]. Acta Biochim Biophys Sin, 2022, 54(8): 1180-1192. DOI: 10.3724/abbs.2022104.

60.Li M, Luo Q, Chen X, et al. Screening of major hepatotoxic components of Tripterygium wilfordii based on hepatotoxic injury patterns[J]. BMC Complement Med Ther, 2023, 23(1): 9. DOI: 10.1186/s12906-023-03836-w.

61.Jin C, Wu Z, Wang L, et al. CYP450s-activity relations of celastrol to interact with triptolide reveal the reasons of hepatotoxicity of Tripterygium wilfordii[J]. Molecules, 2019, 24(11): 2162. DOI: 10.3390/molecules24112162.

62.Dai M, Peng W, Zhang T, et al. Metabolomics reveals the role of PPARα in Tripterygium Wilfordii-induced liver injury[J]. J Ethnopharmacol, 2022, 289: 115090. DOI: 10.1016/j.jep.2022.115090.

63.Bai J, Shi Y, Fang X, et al. Effects of demethylzeylasteral and celastrol on spermatogenic cell Ca2+ channels and progesterone-induced sperm acrosome reaction[J]. Eur J Pharmacol, 2003, 464(1): 9-15. DOI: 10.1016/s0014-2999(03)01351-7.

64.Ge J, Qian Q, Gao Y, et al. Toxic effects of tripterygium glycoside tablets on the reproductive system of male rats by metabolomics, cytotoxicity, and molecular docking[J]. Phytomedicine, 2023, 114: 154813. DOI: 10.1016/j.phymed.2023.154813.

65.Xiao S, Zhang M, Liang Y, Wang D. Celastrol synergizes with oral nifedipine to attenuate hypertension in preeclampsia: a randomized, placebo-controlled, and double blinded trial[J]. J Am Soc Hypertens, 2017, 11(9): 598-603. DOI: 10.1016/j.jash.2017.07.004.

66.Yusri MAA, Sekar M, Wong LS, et al. Celastrol: a potential natural lead molecule for new drug design, development and therapy for memory impairment[J]. Drug Des Devel Ther, 2023, 17: 1079-1096. DOI: 10.2147/DDDT.S389977.

67.Song J, He GN, Dai L. A comprehensive review on celastrol, triptolide and triptonide: insights on their pharmacological activity, toxicity, combination therapy, new dosage form and novel drug delivery routes[J]. Biomed Pharmacother, 2023, 162: 114705. DOI: 10.1016/j.biopha.2023.114705.

68.Guo C, Diao N, Zhang D, et al. Achyranthes polysaccharide based dual-responsive nano-delivery system for treatment of rheumatoid arthritis[J]. Int J Biol Macromol, 2023, 234: 123677. DOI: 10.1016/j.ijbiomac.2023.123677.

69.Zhang X, Xu X, Wang X, et al. Hepatoma-targeting and reactive oxygen species-responsive chitosan-based polymeric micelles for delivery of celastrol[J]. Carbohydr Polym, 2023, 303: 120439. DOI: 10.1016/j.carbpol.2022.120439.

70.Wang N, Li Y, He F, et al. Assembly of celastrol to zeolitic imidazolate framework-8 by coordination as a novel drug delivery strategy for cancer therapy[J]. Pharmaceuticals 2022, 15(9): 1076. DOI: 10.3390/ph15091076.