Nobiletin Alleviates Cerebral Ischemic-reperfusion Injury Via MAPK Signaling Pathway

Overview

Journal Am J Transl Res

Specialty General Medicine

Date 2019 Oct 22

PMID 31632564

Citations 19

Authors

Tao Wang

Feng Wang

Lu Yu

Zaiwang Li

Affiliations

Soon will be listed here.

Abstract

Background: Nobiletin (NOB), isolated from Citrus nobilis, has been reported to inhibit cerebral ischemia/reperfusion (I/R) induced cell apoptosis in the brain. The mechanisms and the protective ability of NOB on cerebral I/R rats are unclear.

Methods: A middle cerebral artery occlusion (MCAO) rat model was established and treated with different doses of NOB. The neurological deficits, brain water content and brain index were explored after reperfusion, and TTC staining was applied to assess the infarct area. The production of reactive oxygen species (ROS) related enzymes in the ischemic cortex samples from each group was measured. TUNEL staining was performed to evaluate neuronal cell apoptosis in brain tissues. The expression of cell apoptosis related proteins, p-p38 and MAPKAP-2 and the levels of inflammatory factors were examined by western blotting assay and ELISA.

Results: NOB treatment notably improved the neurological deficits, brain water content and brain index in an MCAO model, accompanied by decreased infarct area in the brain tissue. Apoptosis induced by cerebral I/R was also decreased by NOB administration via upregulating Bcl-2 and downregulating Bax and caspase3. The levels of pro-inflammatory mediators TNF-α, IL-6 were reduced and anti-inflammatory cytokine IL-10 was increased by NOB treatment in MCAO rats. Further, we found that the expression of p-p38 and MAPKAP-2 was reduced by NOB treatment in MCAO rats.

Conclusion: The present results suggest that NOB serves a protective role in I/R-induced cerebral-neuron injury. The mechanisms underlying these effects may be associated with the MAPK signaling pathway.

Citing Articles

Natural products derived from traditional Chinese medicines targeting ER stress for the treatment of kidney diseases.

Wang M, Chen Z, Tang Z, Tang S Ren Fail. 2024; 46(2):2396446.

PMID: 39192602 PMC: 11360642. DOI: 10.1080/0886022X.2024.2396446.

Nobiletin restores HFD-induced enteric nerve injury by regulating enteric glial activation and the GDNF/AKT/FOXO3a/P21 pathway.

Pang Y, Zhang L, Zhong Z, Yang N, Zheng Y, Ding W Mol Med. 2024; 30(1):113.

PMID: 39095693 PMC: 11297793. DOI: 10.1186/s10020-024-00841-8.

Exploring Chinese herbal medicine for ischemic stroke: insights into microglia and signaling pathways.

Zhang W, Xu H, Li C, Han B, Zhang Y Front Pharmacol. 2024; 15:1333006.

PMID: 38318134 PMC: 10838993. DOI: 10.3389/fphar.2024.1333006.

A review on recent advances on nobiletin in central and peripheral nervous system diseases.

Pang Y, Xiong J, Wu Y, Ding W Eur J Med Res. 2023; 28(1):485.

PMID: 37932838 PMC: 10626649. DOI: 10.1186/s40001-023-01450-7.

Polyphenols Mediate Neuroprotection in Cerebral Ischemic Stroke-An Update.

Abdelsalam S, Renu K, Abu Zahra H, Abdallah B, Ali E, Veeraraghavan V Nutrients. 2023; 15(5).

PMID: 36904106 PMC: 10005012. DOI: 10.3390/nu15051107.

References

Sp N, Kang D, Joung Y, Park J, Kim W, Lee H . Nobiletin Inhibits Angiogenesis by Regulating Src/FAK/STAT3-Mediated Signaling through PXN in ER⁺ Breast Cancer Cells. Int J Mol Sci. 2017; 18(5). PMC: 5454848. DOI: 10.3390/ijms18050935. View

Xue X, Qu X, Yang Y, Sheng X, Cheng F, Jiang E . Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor κB p65 activation. Biochem Biophys Res Commun. 2010; 403(3-4):398-404. DOI: 10.1016/j.bbrc.2010.11.042. View

Xiong X, Pan F, Chen R, Hu D, Qiu X, Li C . Neuroglobin boosts axon regeneration during ischemic reperfusion via p38 binding and activation depending on oxygen signal. Cell Death Dis. 2018; 9(2):163. PMC: 5833339. DOI: 10.1038/s41419-017-0260-8. View

Zhang L, Zhao H, Zhang X, Chen L, Zhao X, Bai X . Nobiletin protects against cerebral ischemia via activating the p-Akt, p-CREB, BDNF and Bcl-2 pathway and ameliorating BBB permeability in rat. Brain Res Bull. 2013; 96:45-53. DOI: 10.1016/j.brainresbull.2013.04.009. View

Li Y, Liu X, Rong F . PUMA mediates the apoptotic signal of hypoxia/reoxygenation in cardiomyocytes through mitochondrial pathway. Shock. 2011; 35(6):579-84. DOI: 10.1097/SHK.0b013e318211601a. View

Mattson M, Gleichmann M, Cheng A . Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008; 60(5):748-66. PMC: 2692277. DOI: 10.1016/j.neuron.2008.10.010. View

Yasuda N, Ishii T, Oyama D, Fukuta T, Agato Y, Sato A . Neuroprotective effect of nobiletin on cerebral ischemia-reperfusion injury in transient middle cerebral artery-occluded rats. Brain Res. 2014; 1559:46-54. DOI: 10.1016/j.brainres.2014.02.007. View

Polster B, Fiskum G . Mitochondrial mechanisms of neural cell apoptosis. J Neurochem. 2004; 90(6):1281-9. DOI: 10.1111/j.1471-4159.2004.02572.x. View

Carden D, Granger D . Pathophysiology of ischaemia-reperfusion injury. J Pathol. 2000; 190(3):255-66. DOI: 10.1002/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6. View

10.

Yang S, Denning S, Mizuno S, DuPont B, Haynes B . A novel activation pathway for mature thymocytes. Costimulation of CD2 (T,p50) and CD28 (T,p44) induces autocrine interleukin 2/interleukin 2 receptor-mediated cell proliferation. J Exp Med. 1988; 168(4):1457-68. PMC: 2189071. DOI: 10.1084/jem.168.4.1457. View

11.

Hu Y, Deng H, Xu S, Zhang J . MicroRNAs Regulate Mitochondrial Function in Cerebral Ischemia-Reperfusion Injury. Int J Mol Sci. 2015; 16(10):24895-917. PMC: 4632781. DOI: 10.3390/ijms161024895. View

12.

Pan Y, Wang N, Xia P, Wang E, Guo Q, Ye Z . Inhibition of Rac1 ameliorates neuronal oxidative stress damage via reducing Bcl-2/Rac1 complex formation in mitochondria through PI3K/Akt/mTOR pathway. Exp Neurol. 2017; 300:149-166. DOI: 10.1016/j.expneurol.2017.10.030. View

13.

Mozaffarian D, Benjamin E, Go A, Arnett D, Blaha M, Cushman M . Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2015; 133(4):e38-360. DOI: 10.1161/CIR.0000000000000350. View

14.

Longa E, Weinstein P, Carlson S, Cummins R . Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20(1):84-91. DOI: 10.1161/01.str.20.1.84. View

15.

Gallucci G, Tong M, Chen X, Stonestreet B, Lin A, de la Monte S . Rapid Alterations in Cerebral White Matter Lipid Profiles After Ischemic-Reperfusion Brain Injury in Fetal Sheep as Demonstrated by MALDI-Mass Spectrometry. Pediatr Dev Pathol. 2019; 22(4):344-355. PMC: 7243471. DOI: 10.1177/1093526619826721. View

16.

Yang G, Lin C, Yang Y, Yuan L, Wang P, Wen X . Nobiletin Prevents Trimethylamine Oxide-Induced Vascular Inflammation via Inhibition of the NF-κB/MAPK Pathways. J Agric Food Chem. 2019; 67(22):6169-6176. DOI: 10.1021/acs.jafc.9b01270. View

17.

Bederson J, Pitts L, Tsuji M, Nishimura M, Davis R, Bartkowski H . Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke. 1986; 17(3):472-6. DOI: 10.1161/01.str.17.3.472. View

18.

Wei X, Liu H, Sun X, Fu F, Zhang X, Wang J . Hydroxysafflor yellow A protects rat brains against ischemia-reperfusion injury by antioxidant action. Neurosci Lett. 2005; 386(1):58-62. DOI: 10.1016/j.neulet.2005.05.069. View

19.

Haslund-Vinding J, McBean G, Jaquet V, Vilhardt F . NADPH oxidases in oxidant production by microglia: activating receptors, pharmacology and association with disease. Br J Pharmacol. 2016; 174(12):1733-1749. PMC: 5446574. DOI: 10.1111/bph.13425. View

20.

Zheng Y, Bu J, Yu L, Chen J, Liu H . Nobiletin improves propofol-induced neuroprotection via regulating Akt/mTOR and TLR 4/NF-κB signaling in ischemic brain injury in rats. Biomed Pharmacother. 2017; 91:494-503. DOI: 10.1016/j.biopha.2017.04.048. View