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.

Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone. MECHANISM OF ACTION: The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals. PHARMACOKINETICS: Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates. CLINICAL TRIALS: The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure. THERAPEUTIC ADVANCE: Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.

The value of thromboelastography in evaluating the efficacy of Xueshuantong combined with edaravone in the treatment of acute cerebral infarction.

To explore the value of thromboelastography (TEG) in evaluating the efficacy of Xueshuantong combined with edaravone for the treatment of acute cerebral infarction (ACI). We retrospectively analyzed the clinical data of 96 patients with ACI treated with Xueshuantong combined with edaravone and monitored by TEG. The correlation between the results of TEG examination and treatment outcomes in patients after treatment was analyzed. After treatment, 65 of 96 patients showed good efficacy and 31 had poor efficacy. kinetic time (KT), reaction time (RT), and the percentage of clot lysis at 30 minutes after Ma value (LY30) of patients with good therapeutic effects were significantly higher than those with poor therapeutic effects; However, maximum amplitude (MA) and coagulation index (CI) were significantly lower than those with poor efficacy (P < .05). There was a significant positive correlation between KT, RT, and LY30 and the therapeutic effect of ACI, and a significant negative correlation between the therapeutic effects of MA, CI, and ACI (P < .05). Logistic analysis confirmed that KT, RT, and LY30 were protective factors for the therapeutic effect of ACI; MA and CI were risk factors for the therapeutic effect of ACI (P < .05). TEG has a high value in evaluating the efficacy of Xueshuantong combined with edaravone in the treatment of ACI. It can clarify changes in the coagulation function of patients, thereby guiding clinical follow-up treatment.

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.

Edaravone for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: The effectiveness and long-term efficacy of edaravone, a recommended treatment for amyotrophic lateral sclerosis (ALS), has not been examined in real-world settings. This study aims to evaluate the effectiveness and long-term efficacy of edaravone. METHODS: The OVID Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched for articles published between January 1, 2000, and May 1, 2023. Two investigators independently screened the retrieved articles for randomized controlled trials (RCTs), cohort studies, or single-arm trials that evaluated the effect of edaravone on amyotrophic lateral sclerosis (ALS). The risk of bias was evaluated using the revised Cochrane Risk-of-Bias (RoB 2.0) tool for randomized controlled trials (RCTs) and the Risk-of-Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. The primary outcome was the ALSFRS-R score assessed at month 6, with secondary outcomes including the ALSFRS-R scores evaluated at months 9, 12, and 18, forced vital capacity (FVC), and adverse events. The certainty of evidence was assessed using the GRADE approach. RESULTS: The analysis included 16 studies with a total of 4828 participants. Among these, four were randomized controlled trials (RCTs) and 12 were observational studies. Of the RCTs, four were rated as having a low risk of bias, while six of the observational studies were rated as having a low risk of bias. Edaravone was associated with slightly slower progression in the reduction of ALSFRS-R score at month 6 compared to placebo (mean difference 1.01, 95%CI -0.87 to 3.09, p = 0.293), as shown by evidence from RCTs. However, observational studies did not show any benefit of adding edaravone to routine practice (mean difference 1.85, 95%CI -2.05 to 5.75, p = 0.352). The change from baseline in ALSFRS-R score was -2.1, -4.04, -7.5, -6.82, and -7.9 at months 3, 6, 9, 12, and 18, respectively. The GRADE assessment indicated moderate certainty for evidence from RCTs, while evidence from observational studies had very low certainty. CONCLUSION: Due to the limited number of studies and confounding issues in observational studies, further examination of the added benefits of edaravone to routine practice is necessary through RCTs, particularly regarding its long-term efficacy.

Edaravone dexborneol alleviates ischemic injury and neuroinflammation by modulating microglial and astrocyte polarization while inhibiting leukocyte infiltration.

Poststroke inflammation is essential in the mechanism of secondary injury, and it is orchestrated by resident microglia, astrocytes, and circulating immune cells. Edaravone dexborneol (EDB) is a combination of edaravone and borneol that has been identified as a clinical protectant for stroke management. In this study, we verified the anti-inflammatory effect of EDB in the mouse model of ischemia and investigated its modulatory action on inflammation-related cells. C57BL/6 male mice, which had the transient middle cerebral artery occlusion (tMCAO), were treated (i.p.) with EDB (15 mg/kg). EDB administration significantly reduced the brain infarction and improved the sensorimotor function after stroke. And EDB alleviated the neuroinflammation by restraining the polarization of microglia/macrophages and astrocyte toward proinflammatory phenotype and inhibiting the production of proinflammatory cytokines (such as IL-1ß, TNF-α, and IL-6) and chemokines (including MCP-1 and CXCL1). Furthermore, EDB ameliorated the MCAO-induced impairment of Blood-brain barrier (BBB) by suppressing the degradation of tight junction protein and attenuated the accumulation of peripheral leukocytes in the ischemic brain. Additionally, systemic EDB administration inhibited the macrophage phenotypic shift toward the M1 phenotype and the macrophage-dependent inflammatory response in the spleen and blood. Collectively, EDB protects against ischemic stroke injury by inhibiting the proinflammatory activation of microglia/macrophages and astrocytes and through reduction by invasion of circulating immune cells, which reduces central and peripheral inflammation following stroke.

Nebulized pH-Responsive Nanospray Combined with Pentoxifylline and Edaravone to Lungs for Efficient Treatments of Acute Respiratory Distress Syndrome.

The COVID-19 pandemic has become an unprecedented global medical emergency, resulting in more than 5 million deaths. Acute respiratory distress syndrome (ARDS) caused by COVID-19, characterized by the release of a large number of pro-inflammatory cytokines and the production of excessive toxic ROS, is the most common serious complication leading to death. To develop new strategies for treating ARDS caused by COVID-19, a mouse model of ARDS was established by using lipopolysaccharide (LPS). Subsequently, we have constructed a novel nanospray with anti-inflammatory and antioxidant capacity by loading pentoxifylline (PTX) and edaravone (Eda) on zeolite imidazolate frameworks-8 (ZIF-8). This nanospray was endowed with synergetic therapy, which could kill two birds with one stone: (1) the loaded PTX played a powerful anti-inflammatory role by inhibiting the activation of inflammatory cells and the synthesis of pro-inflammatory cytokines; (2) Eda served as a free radical scavenger in ARDS. Furthermore, compared with the traditional intravenous administration, nanosprays can be administered directly and inhaled efficiently and reduce the risk of systemic adverse reactions greatly. This nanospray could not only coload two drugs efficiently but also realize acid-responsive release on local lung tissue. Importantly, ZIF8-EP nanospray showed an excellent therapeutic effect on ARDS in vitro and in vivo, which provided a new direction for the treatment of ARDS.

Effect of Cyclosporin H on ischemic injury and neutrophil infiltration in cerebral infarct model of rats via PET imaging.

BACKGROUND: Brain ischemia-reperfusion injury is a complex process, and neuroinflammation is an important secondary contributing pathological event. Neutrophils play major roles in ischemic neuroinflammation. Once activated, neutrophils express formyl peptide receptors (FPRs), which are special receptors of a class of chemoattractants and may be potential targets to regulate the activity of neutrophils and control cerebral ischemic injury. This study was aimed to explore the ameliorating effect of Cyclosporin H (CsH), a potent FPR antagonist, on brain ischemic injury by inhibiting the activation and migration of neutrophils, and improving cerebral blood flow. METHODS: We employed a middle cerebral artery occlusion (MCAO) Model on rats and performed behavioral, morphological, and microPET imaging assays to investigate the potential restoring efficacy of CsH on cerebral ischemic damages. Peptide N-cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF), an antagonist to the neutrophil FPR with a high binding affinity, was used for imaging neutrophil distribution. RESULTS: We found that CsH had similar effect with edaravone on improving the neurobehavioral deficient symptoms after cerebral ischemia-reperfusion, and treatment with CsH also alleviated ischemic cerebral infarction. Compared with the MCAO Model group, [18F]FDG uptake ratios of the CsH and edaravone treatment groups were significantly higher. The CsH-treated groups also showed significant increases in [18F]FDG uptake at 144 h when compared with that of 24 h. This result indicates that like edaravone, treatment with both doses of CsH promoted the recovery of blood supply after cerebral ischemic event. Moreover, MCAO-induced cerebral ischemia significantly increased the radiouptake of [68Ga]Ga-cFLFLF at 72 h after ischemia-reperfusion operation. Compared with MCAO Model group, radiouptake values of [68Ga]-cFLFLF in both doses of CsH and edaravone groups were all decreased significantly. These results showed that both doses of CsH resulted in a similar therapeutic effect with edaravone on inhibiting neutrophil infiltration in cerebral infarction. CONCLUSION: Potent FPR antagonist CsH is promisingly beneficial in attenuating neuroinflammation and improving neurobehavioral function against cerebral infarction. Therefore, FPR may become a novel target for regulating neuroinflammation and improving prognosis for ischemic cerebrovascular disorders.

Edaravone: A Novel Possible Drug for Cancer Treatment?

Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.

Cost-effectiveness of edaravone dexborneol versus dl-3-n-butylphthalide for the treatment of acute ischemic stroke: a Chinese health care perspective.

BACKGROUND: Edaravone dexborneol and dl-3-n-butylphthalide are two innovative brain cytoprotective drugs from China that have been approved and widely prescribed for acute ischemic stroke, and the cost of the two drugs are partially paid by the Chinese medical insurance system. This study aimed to investigate and compare the cost-effectiveness of edaravone dexborneol versus dl-3-n-butylphthalide for acute ischemic stroke from the Chinese healthcare system's perspective. METHODS: A model combining a short-term decision tree model with 90 days and a long-term Markov model with a life-time horizon (40 years) was developed to simulate the cost-effectiveness of edaravone dexborneol versus dl-3-n-butylphthalide for acute ischemic stroke over a lifetime horizon. Since the absence of a head-to-head clinical comparison of two therapies, an unanchored matching-adjusted indirect comparison (MAIC) was conducted by adjusting the patient characteristics using individual patient data from pivotal phase III trial of edaravone dexborneol and published aggregated data of dl-3-n-butylphthalide. Health outcomes were measured in quality-adjusted life years (QALYs). Utilities and costs (Chinese Yuan, CNY) were derived from publications and open-access database. One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of results. RESULTS: Compared with patients in dl-3-n-butylphthalide arm, edaravone dexborneol arm was found to be cost-effective in 90 days and highly cost-effective as the study horizons extended. With a similar direct medical cost, patients in edaravone dexborneol arm slightly gained an additional 0.1615 QALYs in life-time. In the long term (40 years), patients in edaravone dexborneol arm and dl-3-n-butylphthalide arm yielded 8.0351 and 7.8736 QALYs with the overall direct medical cost of CNY 29,185.23 and CNY 29,940.28, respectively. The one-way sensitivity analysis suggested that the incremental cost-effectiveness ratio was most sensitive to the price of edaravone dexborneol and dl-3-n-butylphthalide. CONCLUSION: Edaravone dexborneol is a cost-effective alternative compared with dl-3-n-butylphthalide for acute ischemic stroke patients in current medical setting of China.

Effects of decompressive craniectomy combined with edaravone on postoperative neurological functions and hemodynamics of patients with severe traumatic brain injury.

OBJECTIVES: To assess the effects of decompressive craniectomy combined with edaravone on the postoperative neurological functions and hemodynamics of patients with severe traumatic brain injury (STBI). METHODS: The subjects included totally 186 STBI patients admitted during January 2018 and January 2021. The random number table method was adopted to set an operation group (n=82) and a combined medication group (n=104) for the subjects. The changes of the clinical indicators were observed. RESULTS: Compared with the operation group, the combined medication group had higher Neurobehavioral Cognitive Status Examination score, Barthel index score, total response rate and heart rate (p<0.05). Besides, by contrast to those of the operation group, the mean arterial pressure, myocardial zymogram indicators, postoperative neurological function indicators and total incidence rate of complications of the combined medication group were reduced (p<0.05). In comparison with the operation group, the combined medication group exhibited raised ipsilateral contralateral blood velocities (p<0.05). Furthermore, the combined medication group had a better postoperative 1-year prognosis than the operation group (p<0.05). CONCLUSION: Edaravone in combination with decompressive craniectomy benefits the postoperative improvement of neurological functions of STBI patients, effectively stabilizes the hemodynamics, induces few complications and improves the prognosis.

Edaravone alleviated allergic airway inflammation by inhibiting oxidative stress and endoplasmic reticulum stress.

Oxidative stress and endoplasmic reticulum stress (ERS) was associated with the development of asthma. Edaravone (EDA) plays a classical role to prevent the occurrence and development of oxidative stress-related diseases. Herein, we investigated the involvement and signaling pathway of EDA in asthma, with particular emphasis on its impact on type 2 innate lymphoid cells (ILC2) and CD4+T cells, and then further elucidated whether EDA could inhibit house dust mite (HDM)-induced allergic asthma by affecting oxidative stress and ERS. Mice received intraperitoneally injection of EDA (10 mg/kg, 30 mg/kg), dexamethasone (DEX) and N-acetylcysteine (NAC), with the latter two used as positive control drugs. DEX and high dose of EDA showed better therapeutic effects in alleviating airway inflammation and mucus secretion in mice, along with decreasing eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) than NAC. Further, the protein levels of IL-33 in lung tissues were inhibited by EDA, leading to reduced activation of ILC2s in the lung. EDA treatment alleviated the activation of CD4+ T cells in lung tissues of HDM-induced asthmatic mice and reduced Th2 cytokine secretion in BALF. ERS-related markers (p-eIF2α, IRE1α, CHOP, GRP78) were decreased after treatment of EDA compared to HDM group. Malondialdehyde (MDA), glutathione (GSH), hydrogen peroxide (H2O2), and superoxide dismutase (SOD) were detected to evaluate the oxidant stress in lung tissues. EDA showed a protective effect against oxidant stress. In conclusion, our findings demonstrated that EDA could suppress allergic airway inflammation by inhibiting oxidative stress and ERS, suggesting to serve as an adjunct medication for asthma in the future.

Efficacy and safety of short-term edaravone or nerve growth factor add-on therapy for alcohol-related brain damage: A multi-centre randomised control trial.

AIMS: To measure the therapeutic effect of an anti-oxidant, edaravone (EDV), or neurotrophic treatment with nerve growth factor (NGF) as an add-on treatment for alcohol-related brain damage (ARBD). DESIGN: Multi-centre, randomised, single-blinded, comparative clinical trial. SETTING AND PARTICIPANTS: One hundred and twenty-two inpatients recruited from seven hospitals in different regions of China, all diagnosed with ARBD and aged 18 to 65 years old; among them, only two were female. INTERVENTION AND COMPARATOR: Patients were randomly assigned to receive one of three treatments for 2 weeks: 40 patients, treatment as usual (TAU: a combination of intramuscular injections of thiamine, intravenous infusions of other B vitamins with vitamin C and oral medication with vitamin E per day); 40, EDV add-on treatment to TAU (intravenous infusion with 30 mg of EDV twice per day); and 42, NGF add-on treatment to TAU (intramuscular injection of 20 µg of NGF per day). The patients underwent follow-up for 24 weeks. MEASUREMENTS: The primary outcome was the composite score of executive cognitive function in the 2nd week after treatment, which was measured as the mean of the Z scores of the assessments, including the digit symbol substitute test (DSST), digit span memory test-forward (DST-F), digit span memory test-reverse (DST-R) and space span memory test (SSMT). The secondary outcomes were the composite scores at later follow-ups, the score for each component of cognitive function, global cognitive function measured by the Montreal Cognitive Assessment (MoCA), craving for alcohol and the safety of the therapies. FINDINGS: EDV add-on treatment improved the composite score of executive cognitive function better than TAU in the 2nd week (adjusted mean difference: 0.24, 95% confidence interval 0.06 to 0.41; P = 0.008), but NGF add-on treatment did not (adjusted mean difference: 0.07, 95% confidence interval -0.09 to 0.24; P = 0.502). During the follow-up to 24 weeks, EDV add-on treatment improved the composite score of executive cognitive function and DST-R score better than TAU (both P < 0.01). Craving for alcohol was relieved in all three groups. No severe adverse events were observed. CONCLUSION: The short-term addition of edaravone to supplementary therapy treatment for alcohol-related brain damage (ARBD) improved executive cognitive function in patients with ARBD.

Kaempferol-3-O-(2″-O-galloyl-ß-D-glucopyranoside): a novel neuroprotective agent from Diospryros kaki against cerebral ischemia-induced brain injury.

Our previous study demonstrated neuroprotective and therapeutic effects of a standardized flavonoid extract from leaves of Diospyros kaki L.f. (DK) on middle cerebral artery occlusion-and-reperfusion (MCAO/R)-induced brain injury and its underlying mechanisms. This study aimed to clarify flavonoid components responsible for the effects of DK using in vitro and in vivo transient brain ischemic models. Organotypic hippocampal slice cultures (OHSCs) subjected to oxygen- and glucose-deprivation (OGD) were performed to evaluate in vitro neuroprotective activity of DK extract and nine isolated flavonoid components. MCAO/R mice were employed to elucidate in vivo neuroprotective effects of the flavonoid component that exhibited the most potent neuroprotective effect in OHSCs. DK extract and seven flavonoids [quercetin, isoquercetin, hyperoside, quercetin-3-O-(2″-O-galloyl-ß-D-galactopyranoside), kaempferol, astragalin, and kaempferol-3-O-(2″-O-galloyl-ß-D-glucopyranoside) compound (9)] attenuated OGD-induced neuronal cell damage and compound (9) possessed the most potent neuroprotective activity in OHSCs. The MCAO/R mice showed cerebral infarction, massive weight loss, characteristic neurological symptoms, and deterioration of neuronal cells in the brain. Compound (9) and a reference drugs, edaravone, significantly attenuated these physical and neurological impairments. Compound (9) mitigated the blood-brain barrier dysfunction and the change of glutathione and malondialdehyde content in the MCAO mouse brain. Edaravone suppressed the oxidative stress but did not significantly affect the blood-brain barrier permeability. The present results indicated that compound (9) is a flavonoid constituent of DK with a potent neuroprotective activity against transient ischemia-induced brain damage and this action, at least in part, via preservation of blood-brain barrier integrity and suppression of oxidative stress caused by ischemic insult.

Enhanced the treatment of ischemic stroke through intranasal temperature-sensitive hydrogels of edaravone and borneol inclusion complex.

Since ischemic stroke occurs by a combination of multiple mechanisms, therapies that modulate multiple mechanisms are required for its treatment. The combination of edaravone (EDA) and borneol can significantly ameliorate the symptoms of neurological deficits in cerebral ischemia-reperfusion model in rats. In this study, the solubility of borneol and edaravone was improved by hydroxypropyl-ß-cyclodextrin and PEG400. Furthermore, a nasal temperature-sensitive hydrogel containing both edaravone and borneol inclusion complex (EDA-BP TSGS) was developed to overcome the obstacles of ischemic stroke treatment including the obstruction of the blood-brain barrier (BBB) and the unavailability and untimely of intravenous injection. The effectiveness of the thermosensitive hydrogel was investigated in transient middle cerebral artery occlusion/reperfusion model rats (MCAO/R). The results showed that EDA-BP TSGS could significantly alleviate the symptoms of neurological deficits and decrease the cerebral infarct area and the degree of brain damage. In summary, nasal EDA-BP TSGS is a secure and effective brain-targeting formulation that may provide a viable option for the clinical prophylaxis and treatment of ischemic stroke.

New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.

Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.

ASURE Clinical Trial Protocol: A Randomized, Placebo-Controlled, Proof-of-Concept Study Aiming to Evaluate Safety and Target Engagement following Administration of TW001 in Early Alzheimer's Disease Patients.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with complex disease etiology and pathological processes. These include formation of plaques and tangles, aberrant lipid processing, neuroinflammation, cerebrovascular dysregulation, ion channel and mitochondrial dysfunction, and oxidative stress. Disease-modifying therapies focusing on all these different facets are needed. TW001 is an oral formulation with the radical scavenger edaravone as its active ingredient, targeting oxidative stress. OBJECTIVES: This manuscript describes the trial design for Phase IIA Alzheimer Study Using oRal Edaravone (ASURE). METHODS: ASURE is a randomized, placebo-controlled, proof-of-concept study aiming to evaluate safety and target engagement following administration of TW001 in early AD patients. Patients should have a biomarker confirmed diagnosis to be included in the trial and will be treated for 90 days. The primary endpoints include safety and effect of TW001 on oxidative stress biomarkers. Exploratory endpoints focus on a panel of AD(-related) fluid-based biomarkers and EEG. In addition, a recently developed cognitive functional composite (CFC) score will measure early signs of cognitive and functional effects of TW001. RESULTS: This article outlines the design of the clinical study, no results are included. CONCLUSIONS: The ASURE trial design is discussed, with a particular focus on fluid biomarkers, EEG, and CFC as endpoints. By testing multiple measures related to pathology, pharmacodynamics, EEG as proxy for cognition, and cognitive functional scores, it is expected that small changes will be detectable in trials of shorter duration. Moreover, the wide range of endpoints allows to make well-informed decisions for designing pivotal studies later.

Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.

Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b-4c showing three substitution patterns A-C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate 2b, 4'-ester 2c and N1-carbamate-4'-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.

Neuroprotective effect and possible mechanism of edaravone in rat models of spinal cord injury: a protocol for a systematic review and meta-analysis.

BACKGROUND: Spinal cord injury (SCI) is one of the most disabling neurological conditions, afflicting thousands of human beings. Edaravone, a well-known reactive oxygen species scavenger, is expanding its new scope in field of SCI. The objective of this systematic review is to determine the neuroprotective effects and discuss the underlying mechanism of edaravone in management of SCI. METHODS: The systematic review will include the controlled studies evaluating the neurological roles of edaravone on experiment rat models following SCI. The primary outcome will be the 21-point Basso, Beattie, and Bresnahan locomotor rating scale. The secondary outcomes will include the preservation of white matter areas and malondialdehyde levels. Two researchers will independently search PubMed, Embase, Web of Science, Scopus and Cochrane Library from their inception date. Following study selection, data extraction, and assessment of methodological quality in included studies using the SYRCLE's RoB tool, data from eligible studies will be pooled and analyzed using random-effects models with RevMan 5.3 software. In case of sufficient data, subgroup analyses with respect to species, age, gender, injury characteristics, or administration details will be carried out to explore the factors modifying efficacy of edaravone. For exploring the appropriate dose of edaravone, a network meta-analysis approach will be conducted based on the Bayesian method. Importantly, the proposed mechanisms and changes of related molecules will be also extracted from included studies for comprehensively investigating the mechanisms underlying the neuroprotective effects of edaravone. DISCUSSION: In this study, we aim to quantitatively analyze the role of edaravone in locomotor recovery and tissue damage in SCI rat model. The efficacy of edaravone in distinct scenarios will be investigated by subgroup analyses, and we expect to predict the candidate dose that offers a superior treatment effect using network meta-analyses. Moreover, a comprehensive framework regarding the neuroprotective mechanisms behind edaravone will be constructed via a combination of systematic and traditional review. This study will bring implications for future preclinical studies and clinical applications of SCI. Nonetheless, in light of the anticipated limitations in animal experimental design and methodological quality, the results in this review should be interpreted with caution.

CNM-Au8: an experimental agent for the treatment of amyotrophic lateral sclerosis (ALS).

INTRODUCTION: Two established disease-specific therapies for the treatment of amyotrophic lateral sclerosis (ALS) are riluzole and edaravone. Limitations of these medications include minimal progression slowing or survival benefit, and effectiveness only in selected populations, particularly for edaravone. AMX0035 and tofersen received US FDA approval in September 2022 and April 2023, respectively. However, phase 3 trials, further examining both medications' efficacy, are ongoing. CNM-Au8 is an efficient catalyst of energy metabolism and is therefore a potential disease-modifying treatment for ALS, a neurodegenerative condition in which there is bioenergetics impairment. AREAS COVERED: In this review, we provide an overview of the current ALS treatment market, followed by a description of the pharmacodynamics and pharmacokinetics of CNM-Au8. The main preclinical and available early clinical evidence of CNM-Au8 is then described, as well as its potential as an ALS treatment. EXPERT OPINION: Oral treatment with CNM-Au8 failed to meet primary clinical and electrodiagnostic endpoints in phase 2/3 clinical trials. Despite this failure, a number of exploratory endpoints included in phase 2/3 trials suggest CNM-Au8 has the potential to significantly slow clinical worsening, improve quality of life, and prolong survival in ALS. Further study of CNM-Au8 in a phase 3 clinical trial is currently underway.