Dl‑butylphthalide inhibits rotenone‑induced oxidative stress in microglia via regulation of the Keap1/Nrf2/HO‑1 signaling pathway

Luo,Rixin; Zhu,Lihong; Zeng,Zhaohao; Zhou,Ruiyi; Zhang,Jiawei; Xiao,Shu; Bi,Wei

doi:10.3892/etm.2021.10029

Dl‑butylphthalide inhibits rotenone‑induced oxidative stress in microglia via regulation of the Keap1/Nrf2/HO‑1 signaling pathway

Authors:
- Rixin Luo
- Lihong Zhu
- Zhaohao Zeng
- Ruiyi Zhou
- Jiawei Zhang
- Shu Xiao
- Wei Bi
View Affiliations

Affiliations: Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China, Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
Published online on: April 9, 2021 https://doi.org/10.3892/etm.2021.10029
Article Number: 597
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Activated microglia are a source of superoxide which often increases oxidative stress in the brain microenvironment, increase production of reactive oxygen species (ROS) and directly or indirectly lead to dopaminergic neuronal death in the substantia nigra. Thus superoxide contributes to the pathogenesis of Parkinson's disease (PD). Evidence suggests that mitochondria are the main source of ROS, which cause oxidative stress in cells. Levels of ROS are thus associated with the function of the mitochondrial complex. Therefore, protecting the mitochondrial function of microglia is important for the treatment of PD. Dl‑butylphthalide (NBP), a compound isolated from Chinese celery seeds, has been approved by the China Food and Drug Administration for the treatment of acute ischemic stroke. Recently, NBP demonstrated therapeutic potential for PD. However, the mechanism underlying its neuroprotective effect remains unclear. The present study aimed to investigate the effect of NBP on rotenone‑induced oxidative stress in microglia and its underlying mechanisms. The results demonstrated that NBP treatment significantly increased mitochondrial membrane potential and decreased ROS level in rotenone‑induced microglia. Western blot analysis showed that NBP treatment promoted entry of nuclear respiratory factor‑2 (Nrf2) into the nucleus, increased heme oxygenase‑1 (HO‑1) expression and decreased the level of the Nrf2 inhibitory protein, Kelch‑like ECH‑associated protein 1. Overall, the findings indicated that NBP inhibited rotenone‑induced microglial oxidative stress via the Keap1/Nrf2/HO‑1 pathway, suggesting that NBP may serve as a novel agent for the treatment of PD.

View Figures

View References

1	Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE and Lang AE: Parkinson disease. Nat Rev Dis Primers. 3(17013)2017.PubMed/NCBI View Article : Google Scholar
2	Nicholls DG: Mitochondrial membrane potential and aging. Aging Cell. 3:35–40. 2004.PubMed/NCBI View Article : Google Scholar
3	Zorov DB, Juhaszova M and Sollott SJ: Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 94:909–950. 2014.PubMed/NCBI View Article : Google Scholar
4	Ganguly G, Chakrabarti S, Chatterjee U and Saso L: Proteinopathy, oxidative stress and mitochondrial dysfunction: Cross talk in Alzheimer's disease and Parkinson's disease. Drug Des Devel Ther. 11:797–810. 2017.PubMed/NCBI View Article : Google Scholar
5	Dias V, Junn E and Mouradian MM: The role of oxidative stress in Parkinson's disease. J Parkinsons Dis. 3:461–491. 2013.PubMed/NCBI View Article : Google Scholar
6	Subramaniam SR and Chesselet MF: Mitochondrial dysfunction and oxidative stress in Parkinson's disease. Prog Neurobiol. 106-107:17–32. 2013.PubMed/NCBI View Article : Google Scholar
7	Heikkila RE, Nicklas WJ, Vyas I and Duvoisin RC: Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: Implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett. 62:389–394. 1985.PubMed/NCBI View Article : Google Scholar
8	Johnson ME and Bobrovskaya L: An update on the rotenone models of Parkinson's disease: Their ability to reproduce the features of clinical disease and model gene-environment interactions. Neurotoxicology. 46:101–116. 2015.PubMed/NCBI View Article : Google Scholar
9	Maturana MG, Pinheiro AS, de Souza TL and Follmer C: Unveiling the role of the pesticides paraquat and rotenone on α-synuclein fibrillation in vitro. Neurotoxicology. 46:35–43. 2015.PubMed/NCBI View Article : Google Scholar
10	Ye J, Jiang Z, Chen X, Liu M, Li J and Liu N: Electron transport chain inhibitors induce microglia activation through enhancing mitochondrial reactive oxygen species production. Exp Cell Res. 340:315–326. 2016.PubMed/NCBI View Article : Google Scholar
11	Yuan YH, Sun JD, Wu MM, Hu JF, Peng SY and Chen NH: Rotenone could activate microglia through NFkB associated pathway. Neurochem Res. 38:1553–1560. 2013.PubMed/NCBI View Article : Google Scholar
12	Xu ZQ, Zhou Y, Shao BZ, Zhang JJ and Liu C: A systematic review of neuroprotective efficacy and safety of DL-3-N-butylphthalide in ischemic stroke. Am J Chin Med. 47:507–525. 2019.PubMed/NCBI View Article : Google Scholar
13	Chinese Society of Cerebral Blood Flow and Metabolism. The Chinese guidelines for the evaluation and management of cerebral collateral circulation in ischemic stroke (2017). Zhonghua Nei Ke Za Zhi. 56:460–471. 2017.PubMed/NCBI View Article : Google Scholar : (In Chinese).
14	Wang S, Ma F, Huang L, Zhang Y and Peng Y, Xing C, Feng Y, Wang X and Peng Y: Dl-3-n-butylphthalide (NBP): A promising therapeutic agent for ischemic stroke. CNS Neurol Disord Drug Targets. 17:338–347. 2018.PubMed/NCBI View Article : Google Scholar
15	Huang L, Wang S, Ma F, Zhang Y and Peng Y, Xing C, Feng Y, Wang X and Peng Y: From stroke to neurodegenerative diseases: The multi-target neuroprotective effects of 3-n-butylphthalide and its derivatives. Pharmacol Res. 135:201–211. 2018.PubMed/NCBI View Article : Google Scholar
16	Luo R, Wangqin R, Zhu L and Bi W: Neuroprotective mechanisms of 3-n-butylphthalide in neurodegenerative diseases. Biomed Rep. 11:235–240. 2019.PubMed/NCBI View Article : Google Scholar
17	Zhao CY, Lei H, Zhang Y, Li L, Xu SF, Cai J, Li PP, Wang L, Wang XL and Peng Y: L-3-n-Butylphthalide attenuates neuroinflammatory responses by downregulating JNK activation and upregulating Heme oxygenase-1 in lipopolysaccharide-treated mice. J Asian Nat Prod Res. 18:289–302. 2016.PubMed/NCBI View Article : Google Scholar
18	Yang XD, Cen ZD, Cheng HP, Shi K, Bai J, Xie F, Wu HW, Li BB and Luo W: L-3-n-butylphthalide protects HSPB8 K141N mutation-induced oxidative stress by modulating the mitochondrial apoptotic and Nrf2 pathways. Front Neurosci. 11(402)2017.PubMed/NCBI View Article : Google Scholar
19	Liu Z, Wang H, Shi X, Li L, Zhou M, Ding H, Yang Y, Li X and Ding K: DL-3-n-butylphthalide (NBP) provides neuroprotection in the mice models after traumatic brain injury via Nrf2-ARE signaling pathway. Neurochem Res. 42:1375–1386. 2017.PubMed/NCBI View Article : Google Scholar
20	Li Q, Cheng Y, Bi M, Lin H, Chen Y, Zou Y, Liu Y, Kang H and Guo Y: Effects of N-butylphthalide on the activation of Keap1/Nrf-2 signal pathway in rats after carbon monoxide poisoning. Environ Toxicol Pharmacol. 40:22–29. 2015.PubMed/NCBI View Article : Google Scholar
21	Zhu BL, Xie CL, Hu NN, Zhu XB and Liu CF: Inhibiting of GRASP65 phosphorylation by DL-3-N-butylphthalide protects against cerebral ischemia-reperfusion injury via ERK signaling. Behav Neurol. 2018(5701719)2018.PubMed/NCBI View Article : Google Scholar
22	Wang S, Huang L, Zhang Y and Peng Y, Wang X and Peng Y: Protective effects of L-3-n-butylphthalide against H2O2-induced injury in neural stem cells by activation of PI3K/Akt and mash1 pathway. Neuroscience. 393:164–174. 2018.PubMed/NCBI View Article : Google Scholar
23	Chen J, Wang J, Zhang J and Pu C: 3-n-Butylphthalide reduces the oxidative damage of muscles in an experimental autoimmune myositis animal model. Exp Ther Med. 14:2085–2093. 2017.PubMed/NCBI View Article : Google Scholar
24	Bose A and Beal MF: Mitochondrial dysfunction in Parkinson's disease. J Neurochem. 139 (Suppl 1):216–231. 2016.PubMed/NCBI View Article : Google Scholar
25	Pivovarov AS, Calahorro F and Walker RJ: Na(+)/K(+)-pump and neurotransmitter membrane receptors. Invert Neurosci. 19(1)2018.PubMed/NCBI View Article : Google Scholar
26	Giacomello M, Pyakurel A, Glytsou C and Scorrano L: The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 21:204–224. 2020.PubMed/NCBI View Article : Google Scholar
27	Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, Babenko VA, Zorov SD, Balakireva AV, Juhaszova M, et al: Mitochondrial membrane potential. Anal Biochem. 552:50–59. 2018.PubMed/NCBI View Article : Google Scholar
28	Sakamuru S, Attene-Ramos MS and Xia M: Mitochondrial membrane potential assay. Methods Mol Biol. 1473:17–22. 2016.PubMed/NCBI View Article : Google Scholar
29	Mitsuishi Y, Motohashi H and Yamamoto M: The Keap1-Nrf2 system in cancers: Stress response and anabolic metabolism. Front Oncol. 2(200)2012.PubMed/NCBI View Article : Google Scholar
30	Lu MC, Ji JA, Jiang ZY and You QD: The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: An update. Med Res Rev. 36:924–963. 2016.PubMed/NCBI View Article : Google Scholar
31	Loboda A, Damulewicz M, Pyza E, Jozkowicz A and Dulak J: Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism. Cell Mol Life Sci. 73:3221–3247. 2016.PubMed/NCBI View Article : Google Scholar
32	Chau LY: Heme oxygenase-1: Emerging target of cancer therapy. J Biomed Sci. 22(22)2015.PubMed/NCBI View Article : Google Scholar
33	Chen QM and Maltagliati AJ: Nrf2 at the heart of oxidative stress and cardiac protection. Physiol Genomics. 50:77–97. 2018.PubMed/NCBI View Article : Google Scholar