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Current Neurovascular Research

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ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

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Research Article

DL-3-n-butylphthalide Attenuates Cerebral Ischemia-Reperfusion Injury by Inhibiting Mitochondrial Omi/HtrA2-Mediated Apoptosis

Author(s): Shuo Huang*, Qianyan He, Xin Sun, Yang Qu, Reziya Abuduxukuer, Jiaxin Ren, Kejia Zhang, Yi Yang and Zhen-Ni Guo

Volume 20, Issue 1, 2023

Published on: 27 March, 2023

Page: [101 - 111] Pages: 11

DOI: 10.2174/1567202620666230228100653

Price: $65

Abstract

Background: Ischemic stroke is a major cause of death and disability worldwide and results from inadequate cerebrovascular blood supply; mitochondrial dysfunction plays an essential role in its pathogenesis. DL-3-n-butylphthalide (NBP) is an effective medicine for ischemic stroke that reduces cell apoptosis and improves long-term prognosis.

Objective: Whether and how NBP regulates mitochondria-associated apoptosis in cerebral ischemia- reperfusion injury remains unclear.

Methods: Male Sprague Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) stroke and treated with low (20 mg/kg) or high (80 mg/kg) concentrations of NBP. The Omi/HtrA2 inhibitor UCF-101 was used as a positive control. Cerebral infarction, neuron injury and neuronal apoptosis were assessed to determine the efficacy of NBP compared to UCF-101. We assessed the expression of the Omi/HtrA2 signaling pathway by western blotting and tested the mRNA expression of mitochondrial metabolism-related genes by PCR.

Results: Compared to the MCAO group, both low and high concentrations of NBP substantially improved cerebral infarction, neuron injury, and neuronal apoptosis; high concentrations of NBP were more potent than low concentrations. The expression of proteins of the mitochondrial Omi/HtrA2 signaling pathway, including Omi/HtrA2, XIAP, PARL, OPA1, CHOP, and ClpP, was inhibited in the NBP group.

Conclusion: Overall, early application of NBP attenuated cerebral ischemia-reperfusion injury by inhibiting mitochondrial Omi/HtrA2-mediated apoptosis in rats. Our study supports a novel neuroprotective mechanism of NBP, making it a promising therapeutic agent for ischemic stroke.

« Previous Next »
[1]
Johnson CO, Nguyen M, Roth GA, et al. GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18(5): 439-58.
[http://dx.doi.org/10.1016/S1474-4422(19)30034-1] [PMID: 30871944]
[2]
Lee H, Ding Y. Temporal limits of therapeutic hypothermia onset in clinical trials for acute ischemic stroke: How early is early enough? Brain Circ 2020; 6(3): 139-44.
[http://dx.doi.org/10.4103/bc.bc_31_20] [PMID: 33210036]
[3]
Chamorro Á, Lo EH, Renú A, van Leyen K, Lyden PD. The future of neuroprotection in stroke. J Neurol Neurosurg Psychiatry 2021; 92(2): 129-35.
[http://dx.doi.org/10.1136/jnnp-2020-324283] [PMID: 33148815]
[4]
Geng X, Jiang S, Dandu C. Clinical application of nitric oxide in ischemia and reperfusion injury: A literature review. Brain Circ 2020; 6(4): 248-53.
[http://dx.doi.org/10.4103/bc.bc_69_20] [PMID: 33506147]
[5]
Peng B, Cui LY. Treatment for acute ischemic stroke: new evidence from China. Chin Med J (Engl) 2013; 126(18): 3403-4.
[PMID: 24034078]
[6]
Cui LY, Zhu YC, Gao S, et al. Ninety-day administration of dl-3-n-butylphthalide for acute ischemic stroke: a randomized, double-blind trial. Chin Med J (Engl) 2013; 126(18): 3405-10.
[PMID: 24034079]
[7]
Wang B, Wu C, Chen Z, et al. DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress. Acta Pharmacol Sin 2021; 42(3): 347-60.
[http://dx.doi.org/10.1038/s41401-020-00583-3] [PMID: 33462377]
[8]
Que R, Zheng J, Chang Z, et al. Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment. Front Immunol 2021; 12: 794770.
[http://dx.doi.org/10.3389/fimmu.2021.794770] [PMID: 34925379]
[9]
Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443(7113): 787-95.
[http://dx.doi.org/10.1038/nature05292] [PMID: 17051205]
[10]
Hu Y, Bi Y, Yao D, Wang P, Li Y. Omi/HtrA2 Protease Associated Cell Apoptosis Participates in Blood-Brain Barrier Dysfunction. Front Mol Neurosci 2019; 12: 48.
[http://dx.doi.org/10.3389/fnmol.2019.00048] [PMID: 30853894]
[11]
Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: Evaluation of the model and development of a neurologic examination. Stroke 1986; 17(3): 472-6.
[http://dx.doi.org/10.1161/01.STR.17.3.472] [PMID: 3715945]
[12]
Darreh-Shori T, Rezaeianyazdi S, Lana E, et al. Increased Active OMI/HTRA2 Serine Protease Displays a Positive Correlation with Cholinergic Alterations in the Alzheimer’s Disease Brain. Mol Neurobiol 2019; 56(7): 4601-19.
[http://dx.doi.org/10.1007/s12035-018-1383-3] [PMID: 30361890]
[13]
Clausen T, Southan C, Ehrmann M. The HtrA family of proteases: Implications for protein composition and cell fate. Mol Cell 2002; 10(3): 443-55.
[http://dx.doi.org/10.1016/S1097-2765(02)00658-5] [PMID: 12408815]
[14]
Hegde R, Srinivasula SM, Zhang Z, et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 2002; 277(1): 432-8.
[http://dx.doi.org/10.1074/jbc.M109721200] [PMID: 11606597]
[15]
Martins LM, Morrison A, Klupsch K, et al. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol 2004; 24(22): 9848-62.
[http://dx.doi.org/10.1128/MCB.24.22.9848-9862.2004] [PMID: 15509788]
[16]
Broughton BRS, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009; 40(5): e331-9.
[http://dx.doi.org/10.1161/STROKEAHA.108.531632] [PMID: 19182083]
[17]
Wang K, Zhang J, Liu J, et al. Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death. Age (Omaha) 2013; 35(3): 733-46.
[http://dx.doi.org/10.1007/s11357-012-9406-x] [PMID: 22535253]
[18]
Klupsch K, Downward J. The protease inhibitor Ucf-101 induces cellular responses independently of its known target, HtrA2/Omi. Cell Death Differ 2006; 13(12): 2157-9.
[http://dx.doi.org/10.1038/sj.cdd.4401955] [PMID: 16691211]
[19]
Hu Y, Huang M, Wang P, Xu Q, Zhang B. Ucf-101 protects against cerebral oxidative injury and cognitive impairment in septic rat. Int Immunopharmacol 2013; 16(1): 108-13.
[http://dx.doi.org/10.1016/j.intimp.2013.03.019] [PMID: 23557966]
[20]
Kuninaka S, Iida S-I, Hara T, et al. Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation. Oncogene 2007; 26(17): 2395-406.
[http://dx.doi.org/10.1038/sj.onc.1210042] [PMID: 17130845]
[21]
Lei Y, Wang S, Ren B, et al. CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy. PLoS One 2017; 12(8): e0183680.
[http://dx.doi.org/10.1371/journal.pone.0183680] [PMID: 28841673]
[22]
Moisoi N, Klupsch K, Fedele V, et al. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ 2009; 16(3): 449-64.
[http://dx.doi.org/10.1038/cdd.2008.166] [PMID: 19023330]
[23]
Signorile A, Santeramo A, Tamma G, et al. Mitochondrial cAMP prevents apoptosis modulating Sirt3 protein level and OPA1 processing in cardiac myoblast cells. Biochim Biophys Acta Mol Cell Res 2017; 1864(2): 355-66.
[http://dx.doi.org/10.1016/j.bbamcr.2016.11.022] [PMID: 27890624]
[24]
Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 2007; 178(5): 749-55.
[http://dx.doi.org/10.1083/jcb.200704110] [PMID: 17709429]
[25]
Yoshioka H, Katsu M, Sakata H, et al. The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia. J Cereb Blood Flow Metab 2013; 33(11): 1658-65.
[http://dx.doi.org/10.1038/jcbfm.2013.139] [PMID: 23921894]
[26]
Shen L, Hu P, Zhang Y, et al. Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation. Cell Metab 2021; 33(5): 971-987.e6.
[http://dx.doi.org/10.1016/j.cmet.2021.03.006] [PMID: 33798471]
[27]
Liu N, Luo J, Kuang D, et al. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α–mediated tumor progression. J Clin Invest 2019; 129(2): 631-46.
[http://dx.doi.org/10.1172/JCI123027] [PMID: 30431439]
[28]
Li P, Deng X, Luo J, et al. ATP6V0d2 mediates leucine-induced mTORC1 activation and polarization of macrophages. Protein Cell 2019; 10(8): 615-9.
[http://dx.doi.org/10.1007/s13238-019-0636-x] [PMID: 31134526]
[29]
Zhang C, Zang Y, Song Q, et al. Effects of butylphthalide injection on treatment of transient ischemic attack as shown by diffusion-weighted magnetic resonance imaging abnormality. Int J Neurosci 2020; 130(5): 454-60.
[http://dx.doi.org/10.1080/00207454.2019.1692835] [PMID: 31822157]
[30]
Tang SC, Luo CJ, Zhang KH, et al. Effects of dl-3-n-butylphthalide on serum VEGF and bFGF levels in acute cerebral infarction. Eur Rev Med Pharmacol Sci 2017; 21(19): 4431-6.
[PMID: 29077149]
[31]
Li L, Zhang B, Tao Y, et al. dl-3-n-butylphthalide protects endothelial cells against oxidative/nitrosative stress, mitochondrial damage and subsequent cell death after oxygen glucose deprivation in vitro. Brain Res 2009; 1290: 91-101.
[http://dx.doi.org/10.1016/j.brainres.2009.07.020] [PMID: 19616517]

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