L-3-n-butylphthalide promotes restoration after an experimental animal model of intracerebral hemorrhage

Pi, Zhendong; Jianyang, Liu; Xiao, Han

doi:10.7150/ijms.60342

Cited by 6 publications

(3 citation statements)

References 38 publications

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“…We confirmed that UBIAD1 is expressed in cerebral tissues, where it is found in neurons, astrocytes, and microglia. In agreement with previous studies [ 28 , 48 , 49 ], suppressed UBIAD1 levels due to cerebral I/R were noted in both in vivo and vitro models. The upregulated UBIAD1 levels prevented brain tissues and neuronal impairments by inhibiting ferroptosis and lipid peroxidation during cerebral I/R.…”

Section: Discussionsupporting

confidence: 93%

UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult

Huang

Liu

et al. 2022

Cell Biosci

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Background Neuronal death due to over-oxidative stress responses defines the pathology of cerebral ischemic/reperfusion (I/R) insult. Ferroptosis is a form of oxidative cell death that is induced by disruption of the balance between antioxidants and pro-oxidants in cells. However, the potential mechanisms responsible for cerebral I/R-induced ferroptotic neuronal death have not been conclusively determined. UBIAD1, is a newly identified antioxidant enzyme that catalyzes coenzyme Q10 (CoQ10) and vitamin K2 biosynthesis in the Golgi apparatus membrane and mitochondria, respectively. Even though UBIAD1 is a significant mediator of apoptosis in cerebral I/R challenge, its roles in ferroptotic neuronal death remain undefined. Therefore, we investigated whether ferroptotic neuronal death is involved in cerebral I/R injury. Further, we evaluated the functions and possible mechanisms of UBIAD1 in cerebral I/R-induced ferroptotic neuronal death, with a major focus on mitochondrial and Golgi apparatus dysfunctions. Results Ferroptosis occurred in cerebral I/R. Ferroptotic neuronal death promoted cerebral I/R-induced brain tissue injury and neuronal impairment. UBIAD1 was expressed in cerebral tissues and was localized in neurons, astrocytes, and microglia. Under cerebral I/R conditions overexpressed UBIAD1 significantly suppressed lipid peroxidation and ferroptosis. Moreover, upregulated UBIAD1 protected against brain tissue damage and neuronal death by alleviating I/R-mediated lipid peroxidation and ferroptosis. However, UBIAD1 knockdown reversed these changes. Enhanced UBIAD1-mediated ferroptosis elevated the antioxidative capacity by rescuing mitochondrial and Golgi apparatus dysfunction in cerebral I/R-mediated neuronal injury. They improved the morphology and biofunctions of the mitochondria and Golgi apparatus, thereby elevating the levels of SOD, T-AOC and production of CoQ10, endothelial nitric oxide synthase (eNOS)-regulated nitric oxide (NO) generation as well as suppressed MDA generation. Conclusions The neuroprotective agent, UBIAD1, modulates I/R-mediated ferroptosis by restoring mitochondrial and Golgi apparatus dysfunction in damaged brain tissues and neurons, thereby enhancing antioxidative capacities. Moreover, the rescue of impaired mitochondrial and Golgi apparatus as a possible mechanism of regulating ferroptotic neuronal death is a potential treatment strategy for ischemic stroke. Graphical Abstract

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Section: Discussionsupporting

confidence: 93%

UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult

Huang

Liu

et al. 2022

Cell Biosci

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“…The neuronal cells after Nissl staining had a square shape. TUNEL staining showed reduced apoptotic cells (Pi et al, 2021). Ferroptosis is another type of cell death (Gao et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effect of Dl-3-n-butylphthalide against ischemia–reperfusion injury is mediated by ferroptosis regulation via the SLC7A11/GSH/GPX4 pathway and the attenuation of blood–brain barrier disruption

Li²,

Li³

et al. 2023

Front. Aging Neurosci.

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BackgroundStroke is one of the most severe diseases worldwide, resulting in physical and mental problems. Dl-3-n-butylphthalide, a compound derived from celery seed, has been approved for treating ischemic stroke in China. No study has evaluated how Dl-3-n-butylphthalide affects the ferroptosis SLC7A11/GSH/GPX4 signal pathway and blood–brain barrier (BBB) PDGFRβ/PI3K/Akt signal pathways in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model of ischemic stroke.MethodsSprague–Dawley rats were used to develop the MCAO/R model. Our study used three incremental doses (10, 20, and 30) of Dl-3-n-butylphthalide injected intraperitoneally 24 h after MCAO/R surgery. The neuroprotective effect and success of the model were evaluated using the neurofunction score, brain water content determination, and triphenyl-tetrazolium chloride-determined infarction area changes. Pathological changes in the brain tissue and the degree of apoptosis were examined by hematoxylin and eosin, Nissl, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, pathway proteins and RNA expression levels were studied to verify the effects of Dl-3-n-butyphthalide on both pathways. At the same time, commercial kits were used to detect glutathione, reactive oxygen species, and malondialdehyde, to detect oxidative stress in brain tissues.ResultsThe middle dose of Dl-3-n-butylphthalide not only improved MCAO-induced brain dysfunction and alleviated pathological damage, brain inflammatory response, oxidative stress, and apoptosis but also protected against ferroptosis and reduced BBB damage. These changes resulted in improved neurological function in the cerebral cortex.ConclusionWe speculate that Dl-3-n-butylphthalide has a neuroprotective effect on focal cerebral ischemia/reperfusion, which may be mediated through ferroptosis-dependent SLC7A11/GSH/GPX4 signal pathway and PDGFRβ/PI3/Akt signal pathway.

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“…NBP can diminish brain cell apoptosis, safeguard neuronal cells, and repair neurological function, primarily through the upregulation of UBIAD1 expression. However, there has been limited investigation into the therapeutic potential of this compound in experimental models of hemorrhagic stroke (Pi et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Effects of Dl-3-n-butylphthalide on neurological function, hemodynamics and Hcy concentration in cerebral hemorrhage: a systematic review and meta-analysis

Ma,

Guo,

Wang

et al. 2024

Front. Pharmacol.

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BackgroundDl-3-n-Butylphthalide (NBP) has emerged as a potential therapeutic agent for cerebral hemorrhage, despite not being included in current guideline recommendations. Investigating the underlying physiological and pathological mechanisms of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment remains a critical area of research.ObjectiveThis review aims to evaluate the efficacy of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment and elucidate its potential biological mechanisms, thereby providing evidence to support treatment optimization.MethodsA comprehensive search of seven electronic databases (PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP, and Wanfang Database) was conducted for studies published up to September 2023. Screening and data extraction were performed by a team of researchers. The Cochrane collaboration tool was utilized for risk bias assessment, and Revman 5.3 along with Stata 17.0 were employed for statistical analysis.OutcomesWe searched 254 literature, and 19 were included in this meta-analysis. The results showed that Dl-3-n-Butylphthalide improved the clinical efficacy rate (RR = 1.25, 95% CI 1.19–1.31; p = 0.00), quality of life (MD = 13.93, 95% CI: 11.88–15.98; p = 0.000), increased cerebral blood flow and velocity, reduced cerebral edema volume, Hcy concentration, and did not have obvious adverse reactions (RR = 0.68, 95% CI: 0.39–1.18; p = 0.10).ConclusionThis meta-analysis is the first to demonstrate the potential of Dl-3-n-Butylphthalide in treating cerebral hemorrhage. It suggests that Dl-3-n-Butylphthalide may alleviate clinical symptoms by modulating neurological function and improving hemodynamics. Our findings provide robust evidence for incorporating Dl-3-n-Butylphthalide into cerebral hemorrhage treatment strategies, potentially guiding future clinical practice and research.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=355114, Identifier CRD42022355114.

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L-3-n-butylphthalide promotes restoration after an experimental animal model of intracerebral hemorrhage

Cited by 6 publications

References 38 publications

UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult

UBIAD1 alleviates ferroptotic neuronal death by enhancing antioxidative capacity by cooperatively restoring impaired mitochondria and Golgi apparatus upon cerebral ischemic/reperfusion insult

Neuroprotective effect of Dl-3-n-butylphthalide against ischemia–reperfusion injury is mediated by ferroptosis regulation via the SLC7A11/GSH/GPX4 pathway and the attenuation of blood–brain barrier disruption

Effects of Dl-3-n-butylphthalide on neurological function, hemodynamics and Hcy concentration in cerebral hemorrhage: a systematic review and meta-analysis

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