Sorafenib and edaravone protect against renal fibrosis induced by unilateral ureteral obstruction via inhibition of oxidative stress, inflammation, and RIPK-3/MLKL pathway.

Renal fibrosis is the common endpoint of nearly all chronic and progressive nephropathies. Cell death and sterile inflammation are the main characteristics of renal fibrosis, which can lead to end-stage renal failure. The inflammatory reaction triggered by tissue damage is strongly related to necroptosis, a type of caspase-independent, regulated cell death. Using an animal model of unilateral ureteral obstruction (UUO), the anti-fibrotic effects of sorafenib (SOF), a multi-kinase inhibitor, and edaravone (EDV), a potent antioxidant and free radical scavenger, were examined in rats with obstructive nephropathy. Experimentally, animals were divided randomly into five groups: sham; UUO; UUO + SOF (5 mg/kg/day, P.O.); UUO + EDV (20 mg/kg/day, P.O.); and UUO + SOF + EDV groups. The kidney function biomarkers, oxidant/antioxidant status, renal mRNA expressions of TNF-α, collagen-1α, protein expressions of RIPK-1, RIPK-3, MLKL, caspase-8, HYP, MPO, and TNF-α were all significantly modulated by UUO. Administration of either SOF or EDV significantly attenuated cellular and molecular changes induced by UUO. Also, histopathological changes were improved. Moreover, SOF in combination with EDV, significantly improved UUO-induced renal fibrosis compared with each drug alone. Collectively, administration of either SOF or EDV or both of them significantly attenuated the rats with obstructive nephropathy, possibly by blocking the RIPK-3/MLKL necroptotic pathway and suppressing renal oxidative stress and inflammation.

Controlling redox state by edaravone at transplantation site enhances bone regeneration.

In cell-based bone augmentation, transplanted cell dysfunction and apoptosis can occur due to oxidative stress caused by the overproduction of reactive oxygen species (ROS). Edaravone (EDA) is a potent free radical scavenger with potential medical applications. This study aimed to investigate the effect of controlling oxidative stress on bone regeneration using EDA. Bone marrow-derived cells were collected from 4-week-old rats, and EDA effects on cell viability and osteogenic differentiation were evaluated. Collagen gels containing PKH26-prelabeled cells were implanted into the calvarial defects of 12-week-old rats, followed by daily subcutaneous injections of normal saline or 500 µM EDA for 4 d. Bone formation was examined using micro-computed tomography and histological staining. Immunofluorescence staining was performed for markers of oxidative stress, macrophages, osteogenesis, and angiogenesis. EDA suppressed ROS production and hydrogen peroxide-induced apoptosis, recovering cell viability and osteoblast differentiation. EDA treatment in vivo increased new bone formation. EDA induced the transition of the macrophage population toward the M2 phenotype. The EDA group also exhibited stronger immunofluorescence for vascular endothelial growth factor and CD31. In addition, more PKH26-positive and PKH26-osteocalcin-double-positive cells were observed in the EDA group, indicating that transplanted cell survival was prolonged, and they differentiated into bone-forming cells. This could be attributed to oxidative stress suppression at the transplantation site by EDA. Collectively, local administration using EDA facilitates bone regeneration by improving the local environment and angiogenesis, prolonging survival, and enhancing the osteogenic capabilities of transplanted cells.

Effect of food on oral pharmacokinetics of edaravone coamorphous dispersion containing bile salts as coformers- part II.

OBJECTIVES: Edaravone (EDR) is an effective neuroprotective agent in various neurological diseases; however, its use is restricted due to poor oral absorption. Bile salts are known for improving solubility and inhibiting drug crystallization in supersaturated conditions of the gastrointestinal tract (GIT). In our previous work, we prepared coamorphous dispersion (COAM) of EDR with sodium taurocholate (NaTC) using spray drying. The optimized EDR COAM exhibited superior in vitro performance compared to plain EDR. EDR is well absorbed in fasted-over-fed conditions. METHODS: The present work, we conducted a pharmacokinetic study for EDR and EDR COAM in fasted and fed conditions to check effect of food on its oral absorption. The LC-MS/MS-based method was developed and validated to determine the amount of EDR in plasma. RESULTS: The results suggested that EDR COAM did not show a significant difference in Cmax (p=0.3544) and AUC (p=0.1696) of fasted and fed states. On the other hand, plain EDR showed 2-fold and 3-fold reduced Cmax (p<0.0001) and AUC (p=0.0094) in the fed condition, respectively. The Cmax and AUC of EDR COAM were improved in fasted (AUC:2.56-fold) and fed states (AUC: 5.74-fold) than plain EDR, suggesting better oral absorption of COAM than crystalline EDR without having the effect of food. CONCLUSIONS: The unique structural attributes of NaTC had the potential to inhibit the recrystallization of EDR in GIT, while concurrently reducing the impact of food on the oral absorption of EDR.

Edaravone dexborneol attenuates oxidative stress in experimental subarachnoid hemorrhage via Keap1/Nrf2 signaling pathway.

Background: Subarachnoid hemorrhage (SAH) serves as a disease characterized by high incidence rate, which is exceedingly prevalent and severe. Presently, there is no unambiguous or efficacious intervention for the neurological impairment following SAH. Administering multi-targeted neuroprotective agents to reduce oxidative stress (OS) and neuroinflammation caused by early brain injury (EBI) has been demonstrated to improve neurological function and prognosis following SAH. Edaravone dexborneol (EDB), a novel multi targeted neuroprotective medication, combines four parts edaravone (EDA) with 1 part (+)-borneol in proportion. Clinical trials conducted in China have revealed during 2 days of acute ischemic stroke (AIS), early administration of EDB leads to improved therapeutic outcomes compared to treatment in EDA monotherapy. Currently, there is no clear evidence that EDB can effectively treat SAH, therefore, our study aims to investigate its potential therapeutic effects and mechanisms on EBI after SAH. Method: We used the intravascular threading method to establish a mouse model of SAH to explore whether EDA and EDB could produce anti-OS and anti-apoptosis effects. Behavioral assessment of mice was conducted using the balance beam experiment and the modified Garcia scoring system. Neuronal damage due to OS and Keap1/Nrf2 signaling pathway were detected through techniques of immunofluorescence, Western blotting, spectrophotometry. The group of EDA and EDB were injected intraperitoneally for 72 h after SAH. Results: The experiment results indicated that EDB lead to remarkably positive results by significantly enhancing neurological function, reducing blood-brain barrier (BBB) injury, and effectively inhibiting neuronal apoptosis after SAH. Further examination indicated EDB significantly reduced the expression of Keap1 and increased the expression of Nrf2, and it inhibited MDA, and enhanced SOD activity after SAH. These outcomes surpassed the effectiveness observed in EDA monotherapy. However, the application of ML385 reversed the anti-OS effects of EDB and EDA. Conclusion: Our experimental findings indicated that EDB could activate Keap1/Nrf2 signaling pathway to reduce OS damage, thereby protecting neurological function and enhancing behavioral abilities after SAH. These outcomes could facilitate the creation of new approaches for the clinical management of SAH.

Effects of edaravone dexborneol on functional outcome and inflammatory response in patients with acute ischemic stroke.

BACKGROUND: Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the impact of edaravone dexborneol on functional outcomes and systematic inflammatory response in AIS patient. METHODS: All participants were recruited from the AISRNA study (registered 21/11/2019, NCT04175691 [ClinicalTrials.gov]) between January 2022 and December 2022. The AIS patients were divided into two groups based on whether they received the treatment of edaravone dexborneol (37.5 mg/12 hours, IV) within 48 h after stroke onset. Inflammatory response was determined by detecting levels of cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-8, IL-6, IL-10, IL-12p70, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], IFN-α, and IL-1ß) within 14 days after stroke onset. RESULTS: Eighty-five AIS patients were included from the AISRNA study. Patients treated with edaravone dexborneol showed a significantly higher proportion of modified Rankin Scale score < 2 compared to those who did not receive this treatment (70.7% versus 47.8%; P = 0.031). Furthermore, individuals receiving edaravone dexborneol injection exhibited lower expression levels of interleukin (IL)-1ß, IL-6, and IL-17, along with higher levels of IL-4 and IL-10 expression during the acute phase of ischemic stroke (P < 0.05). These trends were not observed for IL-2, IL-5, IL-8, IL-12p70, tumor necrosis factor-α, interferon-γ [IFN-γ], and IFN-α (P > 0.05). CONCLUSIONS: Treatment with edaravone dexborneol resulted in a favorable functional outcome at 90 days post-stroke onset when compared to patients without this intervention; it also suppressed proinflammatory factors expression while increasing anti-inflammatory factors levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT04175691. Registered November 21, 2019, https://www. CLINICALTRIALS: gov/ct2/show/NCT04175691 .

Edaravone Dexborneol ameliorates the cognitive deficits of APP/PS1 mice by inhibiting TLR4/MAPK signaling pathway via upregulating TREM2.

Currently, there are no effective therapeutic agents available to treat Alzheimer's disease (AD). However, edaravone dexborneol (EDB), a novel composite agent used to treat acute ischemic stroke, has recently been shown to exert efficacious neuroprotective effects. However, whether EDB can ameliorate cognitive deficits in AD currently remains unclear. To this end, we explored the effects of EDB on AD and its potential mechanisms using an AD animal model (male APP/PS1 mice) treated with EDB for 10 weeks starting at 6 months of age. Subsequent analyses revealed that EDB-treated APP/PS1 mice exhibited improved cognitive abilities compared to untreated APP/PS1 mice. Administration of EDB in APP/PS1 mice further alleviated neuropathological alterations of the hippocampus, including Aß deposition, pyramidal cell karyopyknosis, and oxidative damage, and significantly decreased the levels of inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and COX-2 in the hippocampus of APP/PS1 mice. Transcriptome sequencing analysis demonstrated the critical role of the inflammatory reaction in EDB treatment in APP/PS1 mice, indicating that the alleviation of the inflammatory reaction by EDB in the hippocampus of APP/PS1 mice was linked to the action of the TREM2/TLR4/MAPK signaling pathway. Further in vitro investigations showed that EDB suppressed neuroinflammation in LPS-stimulated BV2 cells by inhibiting the TLR4/MAPK signaling pathway and upregulating TREM2 expression. Thus, the findings of the present study demonstrate that EDB is a promising therapeutic agent for AD-related cognitive dysfunction.

Therapeutic effect and psychological impact of aspirin plus edaravone on patients with cerebral infarction.

BACKGROUND: Cerebral infarction (CI) is characterized by a high prevalence, disability, and mortality. Timely or improper treatment greatly affects patient prognosis. AIM: To explore the drug efficacy of aspirin plus edaravone and to explore their effect on quality of life (QOL), anxiety and depression in CI patients. METHODS: We retrospectively analyzed the records of 124 CI patients treated between June 2019 and February 2021 who were assigned to an observation group (OG) (combination therapy of aspirin and edaravone, 65 patients) or a control group (CG) (aspirin monotherapy, 59 patients). The therapeutic effects, pre- and posttreatment National Institutes of Health Stroke Scale (NIHSS) scores, activities of daily living, degree of cognitive impairment, protein levels of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and S-100B, occurrence of adverse reactions, and serum high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were evaluated, detected and compared between the two groups. Finally, posttreatment QOL, anxiety, and depression were assessed by the Medical Outcomes Study 36- Item Short Form Health Survey Scale, Self-rating Depression Scale (SDS), and Self-rating Anxiety Scale (SAS), respectively. RESULTS: Compared with the CG, the OG had markedly better therapeutic effects, greater improvements in activities of daily living, and better alleviation in cognitive dysfunction after treatment, as well as lower posttreatment NIHSS scores and serum NSE, GFAP, S-100B, hs-CRP, IL-6, and TNF-α levels; the OG was similar to the CG in terms of adverse reactions but was better than the CG in terms of posttreatment QOL; and the OG also had lower SDS and SAS scores than the CG after treatment. CONCLUSION: Aspirin plus edaravone had a good curative effect on CI. It can reverse cranial nerve damage in patients, improve neurological function and prognosis, and alleviate inflammation, anxiety, and depression; thus, it is considered safe and worthy of clinical application.

Edaravone Alleviates Traumatic Brain Injury by Inhibition of Ferroptosis via FSP1 Pathway.

Traumatic brain injury (TBI) is a highly severe form of trauma with complex series of reactions in brain tissue which ultimately results in neuronal damage. Previous studies proved that neuronal ferroptosis, which was induced by intracranial haemorrhage and other reasons, was one of the most primary causes of neuronal damage following TBI. However, the association between neuronal mechanical injury and ferroptosis in TBI and relevant treatments remain unclear. In the present study, we first demonstrated the occurrence of neuronal ferroptosis in the early stage of TBI and preliminarily elucidated that edaravone (EDA), a cerebroprotective agent that eliminates oxygen radicals, was able to inhibit ferroptosis induced by TBI. A cell scratching model was established in PC12 cells, and it was confirmed that mechanical injury induced ferroptosis in neurons at the early stage of TBI. Ferroptosis suppressor protein 1 (FSP1) plays a significant role in inhibiting ferroptosis, and we found that iFSP, a ferroptosis agonist which is capable to inhibit FSP1 pathway, attenuated the anti-ferroptosis effect of EDA. In conclusion, our results suggested that EDA inhibited neuronal ferroptosis induced by mechanical injury in the early phase of TBI by activating FSP1 pathway, which could provide evidence for future research on prevention and treatment of TBI.

Edaravone dexborneol regulates γ-aminobutyric acid transaminase in rats with acute intracerebral hemorrhage.

OBJECTIVES: Edaravone dexborneol is neuroprotective against ischemic stroke, with free radical-scavenging and anti-inflammatory effects, but its effects in hemorrhagic stroke remain unclear. We evaluated whether edaravone dexborneol has a neuroprotective effect in intracerebral hemorrhage, and its underlying mechanisms. MATERIALS AND METHODS: Bioinformatics were used to predict the pathway of action of edaravone dexborneol. An intracerebral hemorrhage model was established using type IV collagenase in edaravone dexborneol, intracerebral hemorrhage, Sham, adeno-associated virus + edaravone dexborneol, and adeno-associated virus + intracerebral hemorrhage groups. The modified Neurological Severity Score was used to evaluate neurological function in rats. Brain water content was measured using the dry-wet weight method. Tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and γ-aminobutyric acid levels were determined by enzyme-linked immunosorbent assay. The expression levels of neurofilament light chain and γ-aminobutyric acid transaminase were determined by western blot. Nissl staining was used to examine neuronal morphology. Cognitive behavior was evaluated using a small-animal treadmill. RESULTS: Edaravone dexborneol alleviated neurological defects, improved cognitive function, and reduced cerebral edema, neuronal degeneration, and necrosis in rats with cerebral hemorrhage. The expression levels of neurofilament light chain, tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and γ-aminobutyric acid were decreased, while γ-aminobutyric acid transaminase expression was up-regulated. CONCLUSIONS: Edaravone dexborneol regulates γ-aminobutyric acid content by acting on the γ-aminobutyric acid transaminase signaling pathway, thus alleviating oxidative stress, neuroinflammation, neuronal degeneration, and death caused by excitatory toxic injury of neurons after intracerebral hemorrhage.

Computational screening of damaging nsSNPs in human SOD1 genes associated with amyotrophic lateral sclerosis identifies destabilising effects of G38R and G42D mutations through in silico evaluation.

Amyotrophic lateral sclerosis (ALS), a complicated neurodegenerative disorder affected by hereditary and environmental variables, is a condition. In this study, the genetic makeup of ALS is investigated, with a focus on the SOD1 gene's single-nucleotide polymorphisms (SNPs) and their ability to affect disease risk. Eleven high-risk missense variations that may impair the functionality of the SOD1 protein were discovered after a thorough examination of SNPs in the SOD1 gene. These mutations were chosen using a variety of prediction approaches, highlighting their importance in the aetiology of ALS. Notably, it was discovered that the stability of the SOD1 wild-type protein structure was compromised by the G38R and G42D SOD1 variants. Additionally, Edaravone, a possible ALS medication, showed a greater affinity for binding mutant SOD1 structures, pointing to potential personalised treatment possibilities. The high-risk SNPs discovered in this investigation seem to have functional effects, especially on the stability of proteins and their interactions with other molecules. This study clarifies the complex genetics of ALS and offers insights into how these genetic variations may affect the effectiveness of therapeutic interventions, particularly in the context of edaravone. In this study advances our knowledge of the genetic mechanisms causing ALS vulnerability and prospective therapeutic strategies. Future studies are necessary to confirm these results and close the gap between individualised clinical applications and improved ALS care.

Preventive effect of free radical scavenger edaravone lotion on cyclophosphamide chemotherapy-induced alopecia.

PURPOSE: We investigated the inhibitory effect of edaravone (EDR) lotion on chemotherapy-induced alopecia (CIA) to improve the quality of life for patients with cancer. METHODS: Wistar rats were intraperitoneally injected with cyclophosphamide (CPA, 75 mg/kg) to induce CIA and divided into six groups: (1) Control; (2) EDR 0%; (3) EDR 0.3%; (4) EDR 3%. The TUNEL-positive area was examined histologically, and mRNA expression levels of the apoptosis-related factors, such as B-cell/CLL lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax), were determined. RESULTS: In the three CPA-treated groups, a decrease in the coverage score (percentage of hairs covered) was observed from days 16 to 18. In addition, coverage scores on day 21, the last day of observation, showed a tendency for the suppression of hair loss to increase, though hair loss was observed in all groups. The coverage scores of the EDR 0.3% and 3% groups after day 17 were significantly higher than those of the EDR 0% group. The TUNEL-positive area of skin tissue on day 16 was extensive in the EDR 0% group and decreased in the EDR 0.3% and 3% groups. The mRNA expression ratio of Bcl-2/Bax on day 21 was maintained at the same level as that of the control group only in the EDR 3% group. CONCLUSION: This study confirmed the use of EDR lotion to inhibit hair loss, indicating that the clinical application of EDR lotion may improve the quality of life for patients with cancer and their willingness to undergo treatment.

The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation.

A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions.

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

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 Aß-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, Aß 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 Aß pathologies including Aß burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aß-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.

Edaravone dexborneol attenuates cognitive impairment in a rat model of vascular dementia by inhibiting hippocampal oxidative stress and inflammatory responses and modulating the NMDA receptor signaling pathway.

Exploring the intricate pathogenesis of Vascular Dementia (VD), there is a noted absence of potent treatments available in the current medical landscape. A new brain-protective medication developed in China, Edaravone dexboeol (EDB), has shown promise due to its antioxidant and anti-inflammatory properties, albeit with a need for additional research to elucidate its role and mechanisms in VD contexts. In a research setup, a VD model was established utilizing Sprague-Dawley (SD) rats, subjected to permanent bilateral typical carotid artery occlusion (2VO). Behavioral assessment of the rats was conducted using the Bederson test and pole climbing test, while cognitive abilities, particularly learning and memory, were evaluated via the novel object recognition test and the Morris water maze test. Ensuing, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), IL-1ß, IL-6, IL-4, and tumor necrosis factor-α (TNF-α) were determined through Enzyme-Linked Immunosorbent Assay (ELISA). Synaptic plasticity-related proteins, synaptophysin (SYP), post-synaptic density protein 95 (PSD-95), and N-methyl-D-aspartate (NMDA) receptor proteins (NR1, NR2A, NR2B) were investigated via Western blotting technique. The findings imply that EDB has the potential to ameliorate cognitive deficiencies, attributed to VD, by mitigating oxidative stress, dampening inflammatory responses, and modulating the NMDA receptor signaling pathway, furnishing new perspectives into EDB's mechanism and proposing potential avenues for therapeutic strategies in managing VD.

Role of reactive carbonyls and superoxide radicals in protein damage by cigarette smoke extracts: Comparison of Heat-not-Burn e-cigarettes to conventional cigarettes.

Oxidative protein damage involving carbonylation of respiratory tract proteins typically accompanies exposure to tobacco smoke. Such damage can arise via multiple mechanisms, including direct amino acid oxidation by reactive oxygen species or protein adduction by electrophilic aldehydes. This study investigated the relative importance of these pathways during exposure of a model protein to fresh cigarette emission extracts. Briefly, protein carbonyl adducts were estimated in bovine serum albumin following incubation in buffered solutions with whole cigarette emissions extracts prepared from either a single 1R6F research cigarette or a single "Heat-not-Burn" e-cigarette. Although both extracts caused concentration-dependent protein carbonylation, conventional cigarette extracts produced higher adduct yields than e-cigarette extracts. Superoxide radical generation by conventional and e-cigarette emissions was assessed by monitoring nitro blue tetrazolium reduction and was considerably lower in extracts made from "Heat-Not-Burn" e-cigarettes. The superoxide dismutase/catalase mimic EUK-134 strongly suppressed radical production by whole smoke extracts from conventional cigarettes, however, it did not diminish protein carbonyl adduction when incubating smoke extracts with the model protein. In contrast, edaravone, a neuroprotective drug with strong carbonyl-trapping properties, strongly suppressed protein damage without inhibiting superoxide formation. Although these findings require extension to appropriate cell-based and in vivo systems, they suggest reactive aldehydes in tobacco smoke make greater contributions to oxidative protein damage than smoke phase radicals.

Edaravone dexborneol promotes M2 microglia polarization against lipopolysaccharide-induced inflammation via suppressing TLR4/MyD88/NF-κB pathway.

Edaravone dexborneol (ED) is a novel neuroprotective compound that consists of two active ingredients, edaravone and ( +)-borneol in a 4:1 ratio, which has been shown the anti-inflammatory properties in animal models of ischemic stroke, cerebral hemorrhage, and autoimmune encephalomyelitis. However, the effect of ED on the polarization of microglia in neuroinflammation has not been elucidated. This study was to investigate the effects of ED on the polarization of microglia induced by lipopolysaccharide (LPS) and potential mechanisms. BV-2 microglial cells were incubated with ED (100, 200, and 400 µM) for 2 h, followed by lipopolysaccharide (LPS, 1 µg/ml) for 12 h. The researchers used the Griess method, western blot, immunocytochemistry, and subcellular fractionation to assess the effects and potential mechanisms of ED on neuroinflammatory reactions. The expression of ROS and the activities of antioxidant enzymes (SOD, GPx, and CAT) in LPS-induced BV-2 cells were also measured using the DCFH-DA fluorescent probe and colorimetric methods, respectively. It was observed that ED significantly declined the levels of TLR4/NF-κB pathway-associated proteins (TLR4, MyD88, p65, p-p65, IκBα, p-IκBα, IKKß, p-IKKß) and therefore inhibited LPS-induced production of NO, IL-1ß, and TNF-α. Moreover, ED markedly downregulated the M1 marker (iNOS) and upregulated the M2 marker (Arginase-1, Ym-1). In addition, ED also reduced ROS generation and enhanced GPx activity. ED induced the polarization of LPS-stimulated microglia from M1 to M2 against inflammation by negatively regulating the TLR4/MyD88/NF-κB signaling pathway. Additionally, ED performed antioxidative function by depleting the intracellular excessive ROS caused by LPS through the enhancement of the enzymatic activity of GPx. ED may be a potential agent to attenuate neuroinflammation via regulating the polarization of microglia.

Edaravone counteracts redox and metabolic disruptions in an emerging zebrafish model of sporadic ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the death of motor neurons leads to loss of muscle function. Additionally, cognitive and circadian disruptions are common in ALS patients, contributing to disease progression and burden. Most ALS cases are sporadic, and environmental exposures contribute to their aetiology. However, animal models of these sporadic ALS cases are scarce. The small vertebrate zebrafish is a leading organism to model neurodegenerative diseases; previous studies have proposed bisphenol A (BPA) or ß-methylamino-l-alanine (BMAA) exposure to model sporadic ALS in zebrafish, damaging motor neurons and altering motor responses. Here we characterise the face and predictive validity of sporadic ALS models, showing their potential for the mechanistic study of ALS drugs. We phenotypically characterise the BPA and BMAA-induced models, going beyond motor activity and motor axon morphology, to include circadian, redox, proteostasis, and metabolomic phenotypes, and assessing their predictive validity for ALS modelling. BPA or BMAA exposure induced concentration-dependent activity impairments. Also, exposure to BPA but not BMAA induced motor axonopathy and circadian alterations in zebrafish larvae. Our further study of the BPA model revealed loss of habituation to repetitive startles, increased oxidative damage, endoplasmic reticulum (ER) stress, and metabolome abnormalities. The BPA-induced model shows predictive validity, since the approved ALS drug edaravone counteracted BPA-induced motor phenotypes, ER stress, and metabolic disruptions. Overall, BPA exposure is a promising model of ALS-related redox and ER imbalances, contributing to fulfil an unmet need for validated sporadic ALS models.

Edaravone dexborneol protects against cerebral ischemia/reperfusion-induced blood-brain barrier damage by inhibiting ferroptosis via activation of nrf-2/HO-1/GPX4 signaling.

PURPOSE: Ferroptosis has recently been recognized as a mechanism of cerebral ischemia-reperfusion (I/R) injury, attributed to blood-brain barrier (BBB) disruption. Edaravone dexboneol (Eda.B) is a novel neuroprotective agent widely employed in ischemic stroke, which is composed of edaravone (Eda) and dexborneol. This study aimed to investigate the protective effects of Eda.B on the BBB in cerebral I/R and explore its potential mechanisms. METHODS: Transient middle cerebral artery occlusion (tMCAO) Sprague-Dawley-rats model was used. Rats were randomly assigned to sham-operated group (sham, n = 20), model group (tMCAO, n = 20), Eda.B group (Eda.B, n = 20), Eda group (Eda, n = 20) and dexborneol group (dexborneol, n = 20), and Eda.B + Zinc protoporphyria group (Eda.B + ZnPP, n = 5). Infarct area, cellular apoptosis and neurofunctional recovery were accessed through TTC staining, TUNEL staining, and modified Garcia scoring system, respectively. BBB integrity was evaluated via Evans blue staining. Nuclear factor E2 related factor 2 (Nrf-2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) signaling were qualified by Western blot. Transmission electron microscopy (TEM) revealed alterations in ipsilateral brain tissue among groups. Glutathione (GSH) and malondialdehyde (MDA) levels, and Fe2+ tissue content determination were detected. RESULTS: Eda.B effectively improved neurological deficits, diminished infarct area and cellular apoptosis, as well as ameliorated BBB integrity in tMCAO rats. Further, Eda.B significantly inhibited ferroptosis, as evidenced by ameliorated pathological features of mitochondria, down-regulated of MDA and Fe2+ levels and up-regulated GSH content. Mechanistically, Eda.B attenuated BBB disruption via Nrf-2-mediated ferroptosis, promoting nuclear translocation of Nrf-2, increasing HO-1, GPX4 expression, alleviating the loss of zonula occludens 1 (ZO-1) and occludin as well as decreasing 4-hydroxynonenal (4-HNE) level. CONCLUSIONS: This study revealed for the first time that Eda.B safeguarded the BBB from cerebral I/R injury by inhibiting ferroptosis through the activation of the Nrf-2/HO-1/GPX4 axis, providing a novel insight into the neuroprotective effect of Eda.B in cerebral I/R.

Effects of edaravone on testicular torsion-detorsion injury in rats.

BACKGROUND AND OBJECTIVE: This study aimed to assess the protective ability of edaravone on testicular torsion-detorsion injury in rats. METHODS: Eighteen adult male Sprague-Dawley rats were randomly divided into three groups: Sham group (control, n = 6); testicular torsion/detorsion (T/D group, n = 6) and T/D+edaravone (T/D+E group, n = 6). The spermatic cords of rats of the T/D group and the T/D+E group were rotated 720° in a clockwise direction and maintained for 120 min in this torsion position. Around 90 min after the torsion, edaravone at a dose of 10 mg/kg dissolved in saline was administered IP to the T/D+E group. The testicle was counter-rotated to its normal position to allow reperfusion for 4 h. Left testes of each animal were excised 240 min after beginning of reperfusion. Oxidative stress markers (TAS, TOS, SOD, and MDA) and apoptotic pathways (Caspase 3, Caspase 8, Caspase 9, Bcl-2, and Bax,) were assessed by ELISA methods. Also, testicles were subjected to the histopathologic and ultrasound examinations. RESULTS: Ultrasound imaging showed that edaravone reduced the surface area and increased vascularization in testicles with T/D (p < 0.0001, p < 0.05, respectively). Edaravone pretreatment markedly decreased the levels of MDA, TOS, Bcl-2, Bax, Caspase 3, Caspase 8, and Caspase 9 (p < 0.0001). Also, it increased significantly TAS levels (p < 0.0001) and reduced insignificantly SOD activity. Histopathologic examinations demonstrated that edaravone significantly attenuated the histological damage caused by T/D in testicles. CONCLUSION: Taken together, the findings indicate that pretreatment of edaravone has protective effect against testicular T/D injury.

Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases.

The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.