Y-2 reduces oxidative stress and inflammation and improves neurological function of collagenase-induced intracerebral hemorrhage rats

Yao, Hua; Zhou, Limei; Yang, Weidong; An, Wenji; Kou, Xiao-Lin; Ren, Jian; Su, Hailang; Chen, Rong; Zhang, Zhengping; Zou, Jianjun; Zhao, Zhihong

doi:10.1016/j.ejphar.2021.174507

Cited by 11 publications

(6 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We successfully established a rat I/R model and found that the infarct volume, bloodbrain barrier, and neurological impairment improved significantly after C.EDA treatment. This result agrees with previous studies (Hua et al, 2021), which demonstrated that C.EDA has neuroprotective effects.…”

Section: Ceda Reduces the Activation Of Microglia And Modulates M1/m2...supporting

confidence: 94%

Edaravone dexborneol alleviates cerebral ischemia‐reperfusion injury through NF‐κB/NLRP3 signal pathway

Shen

Lou

et al. 2023

The Anatomical Record

View full text Add to dashboard Cite

Inflammatory injury following ischemia‐reperfusion (I/R) severely limits the efficacy of stroke treatment. Edaravone dexborneol (C.EDA) has been shown to reduce inflammation following a cerebral hemorrhage. However, the precise anti‐inflammatory mechanism of C.EDA is unknown. In this study, we investigated whether C.EDA provides neuroprotection after I/R in rats, as well as the potential mechanisms involved. A middle cerebral artery occlusion/reperfusion (I/R) model was created using Sprague‐Dawley rats. The blood flow of the central cerebral artery was monitored by a laser speckle imaging system. The neurological score was used to assess behavioral improvement. Cerebral infarction volume was measured by TTC staining. And the integrity of the blood–brain barrier was detected by Evan's blue staining. The expression of the nuclear factor kappa‐B (NF‐κB)/ the NOD‐like receptor protein (NLRP3) inflammasome signal pathway and microglia polarization were detected by immunofluorescence and Western blotting. The cerebral blood flow ratio indicates that the cerebral I/R model was successfully established. After reperfusion for 72 h, the improvement of neurological scores, infarct volume reduction, and integrity of the blood–brain barrier was observed in I/R rats with C.EDA treatment. Meanwhile, the immunofluorescence result showed that the expression of iNOS, NLRP3, and NF‐κB protein was decreased and the level of Arg1 was increased. Western blot analysis showed that the expression of NF‐κB/NLRP3 signal pathway‐related protein was decreased. In conclusion, this study indicates that C.EDA alleviates I/R injury by blocking the activation of the NLRP3 inflammasome and regulating the polarization of M1/M2 microglia via the NF‐κB signal pathway.

show abstract

Section: Ceda Reduces the Activation Of Microglia And Modulates M1/m2...supporting

confidence: 94%

Edaravone dexborneol alleviates cerebral ischemia‐reperfusion injury through NF‐κB/NLRP3 signal pathway

Shen

Lou

et al. 2023

The Anatomical Record

View full text Add to dashboard Cite

show abstract

“…Y-2 single sublingual administration (containing 30 mg of Eda and 6 mg of (+)-borneol) or a single i.p. injection of 7.5 mg/kg Y-2 (containing 6 mg/kg Eda and 1.5 mg/kg (+)-Borneol) displayed similar concentration-time curves (AUC 0 − inf ) in plasma (Eda: AUC 0 − inf , 5290 vs. 5460 h ng/mL; borneol: AUC 0 − inf , 30.8 vs. 30.2 h ng/mL) [ 30 ]. We then designed a workflow, and a schematic showed the experimental design (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…(+)-Borneol, a naturally occurring terpene and bicyclic organic compound, has been found to inhibit the production of inflammatory factors and protect brain function in preclinical studies [ 27 , 28 ], possibly by targeting NF-κB (p65), nitric oxide synthase, and ICAM-1 [ 27 , 29 ]. Recently, Y-2, an intravenous solution containing concentrated Eda and (+)-Borneol, has been approved for the treatment of AIS in China and Y-2 sublingual tablets, another Y-2 formulation containing 30 mg of Eda and 6 mg of (+)-Borneol per tablet, are undergoing a phase I clinical trial in US ( www.clinicaltrials.gov , NCT03495206), and a phase III clinical trial in China for AIS treatment ( www.chinadrugtrials.org.cn , CTR20210233) [ 30 ]. Notably, in patients with AIS, Y-2 has shown better neuroprotective potency compared to Eda alone [ 31 ], indicating a potential for neurological diseases.…”

Section: Introductionmentioning

confidence: 99%

Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer’s disease by inhibiting neuroinflammation and neuronal necroptosis

Xu,

Mei,

Yang

et al. 2024

Cell Biosci

Self Cite

View full text Add to dashboard Cite

Background Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients. Results We examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD+ depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes. Conclusions Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.

show abstract

“…In a rat model of intracerebral hemorrhage induced by collagenase IV injection, Y-2 (1, 3, and 6 mg/kg) improved sensorimotor dysfunction, reduced cell death, alleviated histological changes, decreased brain edema, and preserved the blood-brain barrier integrity. Y-2 was superior to edaravone in terms of efficacy [ 31 ]. Eda-Bor also inhibited interleukin-6 (IL-6) and cyclooxygenase-2 generation in RAW264.7 cells stimulated by LPS.…”

Section: Discussionmentioning

confidence: 99%

Edaravone Dexborneol Alleviates Cerebral Ischemic Injury via MKP-1-Mediated Inhibition of MAPKs and Activation of Nrf2

Zhang

Yang

Gao

et al. 2022

BioMed Research International

View full text Add to dashboard Cite

The edaravone and dexborneol concentrated solution for injection (edaravone-dexborneol) is a medication used clinically to treat neurological impairment induced by ischemic stroke. This study was aimed at investigating the preventive effects and the underlying mechanisms of edaravone-dexborneol on cerebral ischemic injury. A rat four-vessel occlusion (4-VO) model was established, and the neuronal injury and consequent neurological impairment of rats was investigated. Brain tissue malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels were determined. The levels of proteins in mitogen-activated protein kinases (MAPKs), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-κB (NF-κB) signaling pathways were determined by western immunoblotting. The function of mitogen-activated protein kinase phosphatase 1 (MKP-1) was investigated using both western blot and immunofluorescence methods, and the effect of the MKP-1 inhibitor, (2E)-2-benzylidene-3-(cyclohexylamino)-3H-inden-1-one (BCI), was investigated. The results indicated that edaravone-dexborneol alleviated neurological deficiency symptoms and decreased apoptosis and neuron damage in the hippocampal CA1 area of the ischemic rats. Edaravone-dexborneol increased the MKP-1 level; decreased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK); inhibited NF-κB p65 activation; and boosted Nrf2 activation, all of which were partially reversed by the MKP-1 inhibitor, BCI. The above results indicated that the upregulation of MKP-1 contributed to the protective effects of edaravone-dexborneol against ischemic brain injury. Our findings support the hypothesis that edaravone-dexborneol can alleviate cerebral ischemic injury via the upregulation of MKP-1, which inhibits MAPKs and activates Nrf2.

show abstract

Y-2 reduces oxidative stress and inflammation and improves neurological function of collagenase-induced intracerebral hemorrhage rats

Cited by 11 publications

References 70 publications

Edaravone dexborneol alleviates cerebral ischemia‐reperfusion injury through NF‐κB/NLRP3 signal pathway

Edaravone dexborneol alleviates cerebral ischemia‐reperfusion injury through NF‐κB/NLRP3 signal pathway

Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer’s disease by inhibiting neuroinflammation and neuronal necroptosis

Edaravone Dexborneol Alleviates Cerebral Ischemic Injury via MKP-1-Mediated Inhibition of MAPKs and Activation of Nrf2

Contact Info

Product

Resources

About