Angelica keiskei (Miq.) Koidz. is a traditional plant that is widely used in Asian countries because of its tonic, diuretic, and galactagogue properties. The chalcone compound 4-hydroxyderricin (4-HD), uniquely present in A. keiskei, has demonstrated inhibitory effects on inflammation in peripheral tissues. Nonetheless, its efficacy in central neuroinflammation and ischemic brain injury remains unclear.

This study aims to assess the ability of 4-HD to alleviate acute ischemic brain injury and the associated inflammatory response, and to elucidate the underlying mechanisms.

Mice underwent middle cerebral artery occlusion (MCAO) surgery to induce acute cerebral ischemic injury. The extent of brain injury was evaluated by TTC staining and neurological function scoring. Immunofluorescence was employed to observe glial cell activation, whereas ELISA and RT-PCR were used to quantify inflammatory cytokine expression in ischemic brain tissues. Oxygen-glucose deprivation (OGD) and lipopolysaccharide (LPS) stimulation of BV2 microglial cells were conducted in vitro to examine the direct impact of 4-HD on microglial inflammation. ELISA and RT-PCR were carried out to quantify inflammatory cytokine expression in BV2 cells. Western blotting and immunofluorescence techniques were used to detect protein expression and localization, respectively. Additionally, alterations in gene expression were measured using RNA-seq analysis profiling following 4-HD treatment of BV2 cells. A short hairpin RNA (shRNA) was used to silence the Haptoglobin (Hp) gene to elucidate the relationship between drug effects and Hp protein levels.

4-HD effectively reduced the infarct area and enhanced neurological function 24 h post-MCAO surgery by lowering inflammatory cytokine levels and inhibiting microglia activation in ischemic brain tissues. In OGD and LPS-stimulated BV2 microglia, 4-HD decreased the levels of inflammatory cytokines. Mechanistic research indicated that 4-HD enhanced Hp and reduced HMGB1 expression in BV2 cells. Moreover, the activation of the NF-κB and MAPK signaling pathways, two key pro-inflammatory pathways downstream of HMGB1, was inhibited by 4-HD treatment. In BV2 cells with Hp gene knockdown, the inhibitory effect of HMGB1 disappeared, and its anti-inflammatory effect was also significantly weakened.

4-HD has the potential to mitigate brain injury and neuroinflammation resulting from MCAO-induced acute ischemic damage. This neuroprotective effect is linked to the suppression of microglial activation and the inhibition of HMGB1 pro-inflammatory signaling, facilitated by the increased expression of the Hp protein. This study revealed, for the first time, the protective effects and mechanisms of 4-HD on ischemic brain injury. Additionally, we present the Hp protein as a new target for a small-molecule compound to protect against ischemic brain injury, offering a novel strategy for developing new neuroprotective drugs.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with damage to motor neurons and leading to severe muscle weakness and, eventually, death. Over the past decade, understanding of the key pathogenetic links of ALS, including glutamate-mediated excitotoxicity and oxidative stress, has significantly advanced. This review considers the recent evidence on molecular mechanisms of these processes, as well as the therapeutic strategies aimed at their modulation. Special attention is paid to antiglutamatergic and antioxidant drugs as approaches to the ALS pathogenetic therapy.

Edaravone, a pyrazalone derivative, is an antioxidant and free radical scavenger used to treat oxidative stress-related diseases. It is a proven drug to mitigate conditions prevailing to oxidative stress by inhibiting lipid peroxidation, reducing inflammation, and thereby preventing endothelial cell death. In recent years, considerable interest has been given by researchers in the derivatization of edaravone by adding varieties of substituents of versatile steric and functional properties to improve its antioxidant and pharmacological activity. This review accounts all the important methods developed for the derivatization of edaravone and the impacts of the structural modifications on the antioxidant activity of the motif.

Edaravone (Eda), a well-known free radical scavenger, has been reported as a possible therapeutic agent for ischemic stroke patients' recovery. This study aimed to investigate the effects of time-dependent treatment with Eda on medial prefrontal cortex (mPFC) ischemia. Mice were randomly allocated into six groups: control, sham, normal saline, Eda-I, Eda-II, and Eda-III. After induction of a photothrombotic ischemia in the mPFC region, Eda-I, Eda-II, and Eda-III groups received 3 mg/kg Eda intraperitoneally at the times of 0, 2, and 6 h post-surgery. After 1 day of recovery, the mice underwent behavioral tests (open field, novel object recognition, and T-maze). Next, necroptosis, NOD-like receptor protein 3 (NLRP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related protein levels were measured in the lesioned area using western blot analysis. For double confirmation, IL-1β and IL-18 were also assessed by immunofluorescence in the area. Further, histological evaluations were performed to measure tissue damage. The results showed that mPFC ischemia impaired recognition and spatial working memory without affecting locomotor activity, while immediate Eda administration improved cognitive impairments. Furthermore, acute Eda treatment reduced RIP1, RIP3, and MLKL levels, inhibited NLRP3 inflammasome proteins (NLRP3, ASC, and Cas1), decreased IL-1β and IL-18, upregulated Nrf2 and its targets (NQO-1 and HO-1), and diminished tissue damage. Our results highlighted the effects of acute administration of Eda post-stroke on improving cognitive impairments by suppressing necroptosis and NLRP3 inflammasome pathways and activating the Nrf2 antioxidant defense mechanism.

Chronic cerebral hypoperfusion (CCH) is an important clinical condition characterized by a prolonged reduction in cerebral blood flow that contributes to several neurodegenerative diseases, including vascular dementia and Alzheimer's disease. A number of rodent models of CCH have been developed that mimic the human pathological conditions of reduced cerebral perfusion. These models have been instrumental in elucidating the molecular and cellular mechanisms involved in CCH-induced brain damage. Oxidative stress is induced by perturbations in cellular pathways caused by CCH, including mitochondrial dysfunction, ion pump dysfunction, and adenosine triphosphate (ATP) depletion. The deleterious stress leads to the accumulation of reactive oxygen species (ROS) and exacerbates damage to neuronal structures, significantly impairing cognitive function. Among the various therapeutic strategies being evaluated, edaravone, a potent antioxidant, is emerging as a promising drug due to its neuroprotective properties against oxidative stress. Initially approved for use in ischemic stroke, research using rodent CCH models has shown that edaravone has significant efficacy in scavenging free radicals and ameliorating oxidative stress-induced neuronal damage under CCH conditions. This mini-review summarizes the current literature on the rodent models of CCH and then discusses the therapeutic potential of edaravone to reduce neuronal and vascular damage caused by CCH-induced oxidative stress.

Naringin (NAR), a flavanone glycoside, occurs widely in citrus fruits, vegetables, and alcoholic beverages. Despite evidence of the neuroprotective effects of NAR on animal models of ischemic stroke, brain cell-type-specific data about the antioxidant efficacy of NAR and possible protein targets of such beneficial effects are limited. Here, we demonstrate the brain cell type-specific prophylactic role of NAR, an FDA-listed food additive, in an in vitro oxygen-glucose deprivation (OGD) model of cerebral ischemia using MTT and DCFDA assays. Using Bayes' theorem-based predictive model, we first ranked the top-10 protein targets (ALDH2, ACAT1, CTSB, FASN, LDHA, PTGS1, CTSD, LGALS1, TARDBP, and CDK1) from a curated list of 289 NAR-interacting proteins in neurons that might be mediating its antioxidant effect in the OGD model. When preincubated with NAR for 2 days, N2a and CTX-TNA2 cells could withstand up to 8 h of OGD without a noticeable decrease in cell viability. This cerebroprotective effect is partly mediated by reducing intracellular ROS production in the above two brain cell types. The antioxidant effect of NAR was comparable with the equimolar (50 µM) concentration of clinically used ROS-scavenger and neuroprotective edaravone. Molecular docking of NAR with the top-10 protein targets from Bayes' analysis showed the lowest binding energy for CDK1 (- 8.8 kcal/M). Molecular dynamics simulation analysis showed that NAR acts by inhibiting CDK1 by stably occupying its ATP-binding cavity. Considering diet has been listed as a risk factor for stroke, NAR may be explored as a component of functional food for stroke or related neurological disorders.

During the synthesis of a known drug, we synthesized a novel compound impromptu, which we have named resorcimoline. This compound exhibited significant antioxidative activity. In this report, we present the concentration-dependent free radical scavenging activity of resorcimoline against various free radical species. The scavenging activity of resorcimoline was evaluated against nine free radicals using electron spin resonance spectroscopy with a spin-trapping method. These free radicals were hydroxyl radical, superoxide anion, tert-butyl peroxyl radical, tert-butoxyl radical, ascorbyl free radical, singlet oxygen, nitric oxide, 2,2-diphenyl-1-picrylhydrazyl, and tyrosyl radical. Sigmoid concentration-response curves were fitted to estimate the reaction rate constants of resorcimoline for the free radicals, and these were compared with those of edaravone, the only current clinically approved free radical scavenger. The antioxidative activity of resorcimoline against lipid peroxidation within tissue was assessed using the thiobarbituric acid reactive substance (TBARS) assay. The cytotoxicity and stability of resorcimoline were also evaluated. Resorcimoline demonstrated significant concentration-dependent scavenging activity against all tested free radicals. Notably, the reaction rate constants for superoxide anion and nitric oxide were significantly higher than those of edaravone, while the rate constant for hydroxyl radical was significantly lower. The TBARS assay revealed that resorcimoline inhibited tissue lipid peroxidation in a concentration-dependent manner. Moreover, resorcimoline exhibited no cytotoxicity at concentrations up to 100 μM and remained stable at room temperature under ambient light for 7 d. These findings indicate that resorcimoline's direct free radical scavenging activity could contribute to its potential clinical antioxidative effects.

Brachial plexus root avulsion (BPRA) is often caused by road collisions, leading to total loss of motor function in the upper limb. At present, effective treatment options remain limited. Edaravone (EDA), a substance that eliminates free radicals, exhibits numerous biological properties, including neuroprotective, antioxidant and anti-inflammatory effects. However, the specific role and molecular mechanisms of EDA in the treatment of BPRA remain to be fully elucidated. The present study used a rat model of BPRA, following avulsion of the fifth, sixth and seventh cervical (C5, C6 and C7) anterior roots. Notably, C6 was replanted following a subcutaneous injection of either saline or 30 mg/kg/day EDA for seven continuous days. Subsequently, behavioral, histochemical, Western blot and reverse transcription-quantitative PCR (RT-PCR) analyses were conducted. Results of the present study revealed that treatment with EDA improves motor dysfunction, indicated by the increased Grooming test score, usage of the affected limb, and Irvine, Beatties and Bresnahan (IBB) score, following BPRA. In addition, EDA reduced the death of motoneurons (MNs), indicated by the increased number of Nissl-positive neuron, at the site of the affected limb, inhibited neuroinflammation and cellular pyroptosis, indicated by the decreased expression levels of IL-1β, IL-6, TNF-α, IL-18, p-p65, NLRP3, GSDMD and Caspase-1, improved the morphology of the abnormal myocutaneous nerve fibers, promoted axon remyelination, indicated by increased mRNA expression levels of remyelination-associated genes, including egr2, GAP-43, hmgcr, L1CAM, mpz, pmp22 and prx and demyelination-associated genes, including ngfr, notch1, pou3f1 and sox2, and alleviated muscle atrophy, indicated by the increased weight and volume of biceps brachii muscle, and the decreased number of fibroblasts and increased diameters in the fibers. Collectively, results of the present study suggested that EDA may support axonal remyelination and inhibit pyroptosis-associated neuroinflammation, enhancing MN survival and facilitating functional motor recovery. Thus, the present study may provide a novel theoretical basis for the use of EDA in the treatment of BPRA.

Ischemic stroke, a clinical emergency and disease with a poor prognosis, has a negative impact on the survival index of patients. It is frequently precipitated by a multitude of risk factors, including trauma. Currently, there is a paucity of predictive indicators for early intervention. As stable and abundant RNA in the body, circRNAs play a regulatory role in miRNAs and proteins, which affect the occurrence and development of diseases. Moreover, circRNAs can serve as predictors of clinical diseases. Several studies have demonstrated that circRNAs play pivotal roles in numerous aspects of ischemic stroke. Consequently, circRNAs have emerged as key areas of investigation in the field of ischemic stroke.

Edaravone is marketed in nine countries, although only Japan has approved edaravone for improvement of neurological symptom, disability of activities of daily living (ADL), and functional disability associated with acute stroke. This study aimed to elucidate the association of edaravone use with ADL using real-world data of older patients with atherothrombotic stroke.

This retrospective observational research using the Medical Data Vision database in Japan included patients aged 65 years and older who had acute ischemic stroke of the atherothrombotic subtype. Primary outcome was ADL improvement defined as change in Barthel Index from admission to discharge of greater than zero points. The major secondary outcome was good functional outcome (Barthel Index ≥ 90 or modified Rankin Scale 0-2 at discharge). Multivariate logistic regression analyses were conducted to calculate odds ratios with 95% confidence intervals for the outcomes. We further compared the change in Barthel Index from admission to discharge and in-hospital death rate between the edaravone- and non-edaravone- treated patients.

A total of 5,576 patients were included in this study, and were divided into edaravone group (n = 3,825) and non-edaravone group (n = 1,751). The median age of this cohort was 79 years, and median Barthel Index at admission was 30 points. Edaravone use was associated with improved ADL with an adjusted odds ratio of 1.18 (95% confidence interval: 1.01‒1.37). However, no significant association was observed between edaravone use and good functional outcome. The edaravone group had significantly greater change in Barthel Index from admission to discharge than the non-edaravone group, with a difference of 5 points. The in-hospital death rate was comparable between the two groups.

Edaravone use may contribute to improve ADL at discharge in patients aged 65 years and older with atherothrombotic stroke.

Nelonemdaz selectively antagonizes the 2B subunit of the N-methyl-d-aspartate glutamate receptor and scavenges free radical species.

To evaluate whether nelonemdaz enhances the clinical outcomes of patients with acute ischemic stroke undergoing emergent reperfusion therapy.

This multicenter double-blind placebo-controlled randomized phase 3 trial (December 25, 2021, to June 30, 2023, in South Korea) recruited patients with acute ischemic stroke who met the following criteria: National Institutes of Health Stroke Scale score greater than or equal to 8, Alberta Stroke Program Early Computed Tomography score greater than or equal to 4, and endovascular thrombectomy within 12 hours after stroke onset.

Patients were assigned in a 1:1 ratio to receive intravenous infusions of nelonemdaz twice a day for 5 days or a matching placebo.

The primary end point was a favorable shift in the modified Rankin scale (mRS) 12 weeks after stroke onset. The secondary end points included various composites of the mRS at 5 and 12 weeks, symptomatic intracranial hemorrhage, and infarct volume. Both intention-to-treat and per-protocol analyses were conducted.

A total of 496 patients were enrolled across 24 Korean stroke centers, of whom 39 dropped out (254 men [55.6%]; mean [SD] age, 72.9 [12.1] years). Baseline characteristics of study participants did not significantly differ. For the primary end point, the distribution of the mRS scores at 12 weeks did not significantly differ between the nelonemdaz and placebo groups (common odds ratio, 0.95; 95% CI, 0.69-1.31). For the secondary end points, a median of mRS at 5 weeks (3 vs 3) and mRS 0 at 12 weeks (18.1% vs 18.2%) did not differ substantially between groups. The occurrence of symptomatic intracranial hemorrhage (2.7% vs 0.9%) and infarct volume within 24 hours of the last trial drug infusion (42 vs 38 mL) did not differ significantly between groups. No serious adverse events were reported regarding the trial drug and placebo.

In this randomized clinical trial, nelonemdaz did not meet the primary efficacy end point compared with placebo.

ClinicalTrials.gov Identifier: NCT05041010.

Oxidative stress imposes a substantial cellular burden on the brain and contributes to diverse neurodegenerative diseases. Various antioxidant signaling pathways have been implicated in oxidative stress and have a protective effect on brain cells by increasing the release of numerous enzymes and through anti-inflammatory responses to oxidative damage caused by abnormal levels of reactive oxygen species (ROS). Although many molecules evaluated as antioxidants have shown therapeutic potentials in preclinical studies, the results of clinical trials have been less than satisfactory. This review focuses on several signaling pathways involved in oxidative stress that are associated with antioxidants. These pathways have a protective effect against stressors by increasing the release of various enzymes and also exert anti-inflammatory responses against oxidative damage. There is no doubt that oxidative stress is a crucial therapeutic target in the treatment of neurological diseases. Therefore, it is essential to understand the discovery of multiple routes that can efficiently repair the damage caused by ROS and prevent neurodegenerative disorders. This paper aims to provide a concise and objective review of the oxidative and antioxidant pathways and their potential therapeutic applications in treating oxidative injury in the brain.

Electroretinography (ERG) is a non-invasive technique for evaluating the retinal function in various ocular diseases. Its results are useful for diagnosing ocular disorders and assessing disease progression or treatment effectiveness. Since numerous studies are based on animal models, validating the ERG results from animals is pivotal. The first part of this paper presents basic information on the types of ERG tests used on rodents, and the second part describes the recorded functional changes in rodents' retinas when various antioxidant treatments for diabetic retinopathy were used. Our study showed that among the tests for diabetic retinopathy diagnosis in rodents, full-field ERG is accurate and the most commonly used, and pattern ERG and the photopic negative response of the flash ERG tests are rarely chosen. Furthermore, antioxidants generally protect retinas from functional losses. Their beneficial influence is expressed in the preserved amplitudes of the a- and b-waves and the oscillatory potentials. However, prolonging the drug exposure showed that the antioxidants could delay the onset of adverse changes but did not stop them. Future studies should concentrate on how long-term antioxidant supplementation affects the retinal function.

We aimed to evaluate the safety of intravenous edaravone for the treatment of acute ischemic stroke among Filipino patients. The study, categorized as Phase IV, spans from December 2022 to November 2023. The primary objective is to document side effects and serious adverse events during the 14-day edaravone infusion period.

The protocol gained approval from the Institutional Review Board, and participants provided written consent. Inclusion criteria involved patients aged 18-70 with acute ischemic stroke within 24 h. Exclusion criteria included extremes of age, pregnancy, severe hepatic impairment, and participation in other clinical trials. Edaravone was administered for 14 days, underwent continuous monitoring, and adverse events were actively recorded.

Out of 64 enrolled patients, 58 completed the treatment, while 4 did not finish, and 2 dropped out. The majority were male (n = 35), median age of 53.5 years, and 81.03% exhibited moderate stroke severity. Two patients reported headaches, and one reported dizziness. No serious adverse events or other untoward effects were documented. Dropouts, attributed to a low ejection fraction, showed normal laboratory results and no side effects during edaravone infusion. Thrombolytic therapy was given to 37.93% of patients.

Our study contributes insights into edaravone's safety, revealing a favorable profile with mild side effects, aligning with existing literature. Notably, no serious adverse events occurred, emphasizing edaravone's tolerability. Headache and dizziness, which were the common side effects in our case, did not lead to treatment discontinuation. The findings support the growing evidence of edaravone's safety in acute ischemic stroke treatment. Overall, edaravone demonstrates promise in stroke management, necessitating vigilant monitoring, especially considering individual cardiovascular health.

This network meta-analysis aims to explore the efficacy and safety of neuroprotective agents in patients with ischemic stroke and attempts to identify which drug is the most effective in improving outcomes for patients with acute ischemic stroke (AIS) through a ranking method.

We comprehensively searched the PubMed, Medline, Embase, Web of Science, and Cochrane library databases from their establishment to 30 June 2024. Data were extracted from the studies identified, and their quality was assessed using the Cochrane risk-of-bias tool or the Newcastle-Ottawa Scale (NOS). The outcome measures were for a favorable prognosis, based on the modified Rankin Scale score (mRS) or National Institutes of Health Stroker Scale (NIHSS) score, mortality, and adverse effect with different drug regimens. We utilized Stata version 16.0 and Review Manager (RevMan) version 5.3.0 for statistical analysis.

A total of 35 studies were included: 25 randomized control trials, eight retrospective studies, and two prospective studies. The total sample size was 18,423 cases and included nine interventions: citicoline, edaravone (EDV), edaravone dexborneol, cinepazide maleate, cerebrolysin, minocycline, ginkgolide, ginkgo diterpene lactone meglumine (GDLM), and conventional (CON) treatment. Our analysis revealed that, except for edaravone dexborneol, the ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM treatment schemes reduced the mortality of patients with AIS compared with CON. Each drug regimen significantly improved the neural function of these patients compared with CON, which from highest to lowest was citicoline + vinpocetine, GDLM, citicoline, edaravone dexborneol, cinepazide maleate, ginkgolide, EDV, and CON. Moreover, we also found that, except for citicoline, the ginkgolide, EDV, edaravone dexborneol, GDLM, and cinepazide maleate treatment schemes had a high total treatment effective rate in these patients, the order from highest to lowest being ginkgolide, EDV, edaravone dexborneol, GDLM, cinepazide maleate, CON, and citicoline. In terms of the ineffective rate, we found that, compared with CON, the edaravone dexborneol, EDV, citicoline, GDLM, ginkgolide, and cinepazide maleate treatment schemes all had a lower ineffective rate. Finally, our analysis revealed that, except for cinepazide maleate and ginkgolide, the EDV, minocycline, edaravone dexborneol, GDLM, citicoline, and cerebrolysin schemes all had a higher rate of adverse effect on patients compared to CON. Based on the impact of the adverse effect with different surgical interventions, we further analyzed the effect of these drug treatments by the total treatment effective rate combined with adverse effect, revealing that EDV, ginkgolide, and edaravone dexborneol were the safest and most effective treatments.

In patients with AIS, ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM were associated with a reduction in mortality rate. Moreover, ginkgolide, EDV, edaravone dexborneol, and GDLM treatment schemes revealed not only a high total treatment effective rate but also a low rate of treatment inefficacy. When considering the combination of the total treatment effective rate with adverse effect, EDV, ginkgolide, and edaravone dexborneol were revealed as the safest and most effective.

Selective endovascular brain hypothermia has been proposed as a potential neuroprotective strategy; however, its effectiveness is still not well established. The primary objective of this trial is to investigate the efficacy and safety of selective endovascular brain hypothermia with edaravone dexborneol for endovascular treatment in acute ischemic stroke (AIS).

The SHE study is a multicenter, single-blind, randomized controlled clinical trial. Patients with acute anterior circulation ischemic stroke who received endovascular treatment within 24 h after stroke onset and achieved successful recanalization will be enrolled and centrally randomized into combined selective endovascular brain hypothermia with edaravone dexborneol or edaravone dexborneol alone groups in a 1:1 ratio (n = 564). Patients allocated to the hypothermia group will receive 300 mL cool saline at 4°C through guiding catheter (30 mL/min) into target vessel within 3 min after recanalization and then receive edaravone dexborneol (edaravone dexborneol 15 mL + NS 100 mL ivgtt bid for 10-14 days) within 24 h after admission. The control group will receive 300 mL 37°C saline (30 mL/min) infused into target vessel through guiding catheter and then receive edaravone dexborneol. All patients enrolled will receive standard care according to current guidelines for stroke management. The primary outcome is the proportion of functional independence, defined as a mRS score of 0-2 at 90 days after randomization.

This is a randomized clinical trial with a large sample size to compare combined selective endovascular brain hypothermia and edaravone dexborneol with edaravone dexborneol alone in patients with acute anterior ischemic stroke. The SHE trial aims to provide further evidence of the benefit of selective endovascular brain hypothermia in AIS patients who received endovascular treatment.

Acupuncture is a traditional Chinese medicine therapy that is treatment by placing a needle or pressure in a specific position on the patient's skin. Although used in the treatment of various diseases, acupuncture is effective in the treatment of ischemic stroke (IS), and has made some progress in the mechanism of action of the treatment of this disease. IS is difficult to treat, and there is a high rate of disability. Drug therapy is usually the first line of treatment, but adjuvant therapy has outstanding efficacy in promoting the rehabilitation of the disease and preventing sequelae. Among them, acupuncture is getting more and more attention as a more popular treatment method. Therefore, this study excavates the high-quality randomized controlled trials and meta-analysis of acupuncture for IS in recent years to further summarize the efficacy of acupuncture for IS. In this review, we provide an overview of the current understanding of acupuncture and IS, and the current studies investigating the effectiveness of acupuncture in the treatment of IS.

Ischemic stroke is one of the leading causes of death and disability. Occlusion and reperfusion of cerebral blood vessels (i.e., ischemia/reperfusion (I/R) injury) generates reactive oxygen species (ROS) that contribute to brain cell death and dysfunction of the blood-brain barrier (BBB) via oxidative stress. BBB disruption influences the pathogenesis of ischemic stroke by contributing to cerebral edema, hemorrhagic transformation, and extravasation of circulating neurotoxic proteins. An improved understanding of mechanisms for ROS-associated alterations in BBB function during ischemia/reperfusion (I/R) injury can lead to improved treatment paradigms for ischemic stroke. Unfortunately, progress in developing ROS targeted therapeutics that are effective for stroke treatment has been slow. Here, we review how ROS are produced in response to I/R injury, their effects on BBB integrity (i.e., tight junction protein complexes, transporters), and the utilization of antioxidant treatments in ischemic stroke clinical trials. Overall, knowledge in this area provides a strong translational framework for discovery of novel drugs for stroke and/or improved strategies to mitigate I/R injury in stroke patients.

Cerebral ischemia has the highest global rate of morbidity and mortality. It occurs when a sudden occlusion develops in the arterial system, and consequently some parts of the brain are deprived from glucose and oxygen due to the cessation of blood flow. The ensuing reperfusion of the ischemic area results in a cascade of pathological alternations like neuronal apoptosis by producing excessive reactive oxygen species (ROS), oxidative stress and neuroinflammation. Edaravone Dexborneol is a novel agent, comprised of Edaravone and Dexborneol in a 4:1 ratio. It has documented neuroprotective effects against cerebral ischemia injury. Edaravone Dexborneol improves neurobehavioral and sensorimotor function, cognitive function, brain edema, and blood-brain barrier (BBB) integrity in experimental models. It at dosages ranging between 0.375 and 15 mg/kg (from immediately after ischemia until the 28th post-ischemic days) has shown neuroprotective effects in experimental models of cerebral ischemia by inhibiting cell death-signaling pathways. For example, it inhibits apoptosis by increasing Bcl2, and reducing Bax and caspase-3 expression. Edaravone Dexborneol also inhibits pyroptosis by attenuating NF-κB/NLRP3/GSDMD signaling, as well as ferroptosis by activating the Nrf-2/HO-1/GPX4 signaling pathway. It also inhibits autophagy by targeting PI3K/Akt/mTOR signaling pathway. Here, we provide a review on the impacts of Edaravone Dexborneol on cerebral ischemia.

Stroke is the second leading cause of death worldwide, and its incidence is rising rapidly. Acute ischemic stroke is a subtype of stroke that accounts for the majority of stroke cases and has a high mortality rate. An effective treatment for stroke is to minimize damage to the brain's neural tissue by restoring blood flow to decreased perfusion areas of the brain. Many reports have concluded that both oxidative stress and excitotoxicity are the main pathological processes associated with ischemic stroke. Current measures to protect the brain against serious damage caused by stroke are insufficient. For this reason, it is important to investigate oxidative and antioxidant strategies to reduce oxidative damage. This review focuses on studies assessing the concentration of oxidative stress biomarkers and the level of antioxidants (enzymatic and non-enzymatic) and their impact on the clinical prognosis of patients after stroke. Mechanisms related to the production of ROS/RNS and the role of oxidative stress in the pathogenesis of ischemic stroke are presented, as well as new therapeutic strategies aimed at reducing the effects of ischemia and reperfusion.

Stroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown.

A rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium's neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen-glucose deprivation reperfusion was used to study meldonium's protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker® probes, mitochondrial stress, real-time ATP rate and western blotting.

Meldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia-reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3β signaling pathway to inhibit mitochondria-dependent neuronal apoptosis.

Our study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.

Honokiol, a bioactive component found in Magnolia officinalis, has shown in protecting against ischemic stroke in animal models. However, its poor water solubility has limited its clinical applications. In this study, we introduced a hydrophilic building block on the aromatic ring of honokiol, resulting in the synthesis of four new compounds (HH-A, -B, -C and -D) with significantly improved water solubility. We then investigated the neuroprotective effects of these compounds in mouse and rat models of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) brain injury. Among the compounds tested, HH-A, also known as (S)-6-((3',5-diallyl-2,4'-dihydroxy-[1,1'-biphenyl]-3-yl)amino)-6-oxohexane-1,5-diaminium chloride, showed the most promising results. HH-A was found to significantly reduced the infarct volume and brain edema in mice. It also outperformed the other three compounds and honokiol, even surpassing the effects of edaravone dexborneol. Additionally, HH-A demonstrated dose-dependent improvements in body weight, neurological deficits, and infarct volume. Further analysis in tMCAO/R rat model revealed that HH-A treatment led to significant upregulations of Nrf2 and HO-1 in the brain. HH-A also significantly reduced the expression of HNE, and exhibited anti-apoptotic effects by decreasing the expression of Bax and increasing the expression of Bcl-2. This was further supported by a decrease in the number of TUNEL positive cells. Taken together, the neuroprotective effects of HH-A may be attributed to its ability to target the Nrf2/HO-1 signaling pathway, leading to reduced oxidative stress and apoptosis in the brain. These findings suggest that HH-A has potential as a therapeutic agent for the treatment of ischemic stroke.

We present a case of ischemic stroke treated by stent retriever angioplasty for restenosis during mechanical thrombectomy. An 85-year-old man was admitted to our hospital because of left hemiplegia and left-sided hemispatial neglect caused by an occlusion at the origin of the right middle cerebral artery. Although mechanical thrombectomy transiently resulted in recanalization of the occluded lesion, restenosis immediately occurred and recurred repeatedly. On an angiogram, the stent retriever appeared poorly dilated at the stenosis and showed a contrast deficit. We concluded that restenosis was due to a secondary thrombus resulting from a ruptured atherosclerotic plaque. The stent retriever was kept deployed for 15 minutes. After the stent was retrieved, restenosis did not occur. Stent retriever angioplasty may be effective for determining the cause of restenosis after mechanical thrombectomy as well as for the treatment of restenosis.

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.

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.

Our findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.

This study aimed to evaluate the efficacy of combining diterpene ginkgolide meglumine injection (DGMI) with edaravone for the treatment of acute ischemic stroke. This is particularly relevant because Western drugs, excluding intravenous thrombolysis, have shown limited success.

A comprehensive search was conducted using multiple databases, including PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure WanFang, VIP, and Chinese Biomedical Database (CBM) until June 2023. The data were analyzed using fixed-effects and random-effects models in Review Manager. The mean difference with 95% confidence interval was calculated for each outcome.

Eighteen studies involving 1,636 participants were included in the analysis. The DGMI group showed significant reductions in the National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale (mRS) score, and C-reactive protein (CRP) level, compared to the control group. Furthermore, the DGMI group showed a significant improvement in superoxide dismutase (SOD) levels and a reduction in malondialdehyde (MDA) levels. The combination of DGMI and edaravone was more effective in reducing neuron-specific enolase (NSE) levels following brain tissue injury than edaravone alone. Additionally, DGMI complemented edaravone in reducing rheological parameters associated with ischemic stroke, including hematocrit, plasma viscosity, platelet adhesion rate, and erythrocyte deformation index.

The combination of DGMI and edaravone significantly improved the therapeutic efficacy in patients with acute ischemic stroke. However, more extensive and high-quality clinical trials are required to validate these underlying mechanisms.

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=260215, identifier: PROSPERO (CRD42021260215).

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).

Multi-centre, randomised, single-blinded, comparative clinical trial.

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.

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.

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.

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.

The short-term addition of edaravone to supplementary therapy treatment for alcohol-related brain damage (ARBD) improved executive cognitive function in patients with ARBD.

Systemic sclerosis (SSc) is an autoimmune disease characterized by systemic skin hardening, which combines Raynaud's phenomenon and other vascular disorders, skin and internal organ fibrosis, immune disorders, and a variety of other abnormalities. Symptoms vary widely among individuals, and personalized treatment is sought for each patient. Since there is no fundamental cure for SSc, it is designated as an intractable disease with patients receiving government subsidies for medical expenses in Japan. Oxidative stress (OS) has been reported to play an important role in the cause and symptoms of SSc. HOCl-induced SSc mouse models are known to exhibit skin and visceral fibrosis, vascular damage, and autoimmune-like symptoms observed in human SSc. The antioxidant combination Twendee X® (TwX) is a dietary supplement consisting of vitamins, amino acids, and CoQ10. TwX has been proven to prevent dementia in humans with mild cognitive impairment and significantly improve cognitive impairment in an Alzheimer's disease mouse model by regulating OS through a strong antioxidant capacity that cannot be achieved with a single antioxidant ingredient. We evaluated the effectiveness of TwX on various symptoms of HOCl-induced SSc mice. TwX-treated HOCl-induced SSc mice showed significantly reduced lung and skin fibrosis compared to untreated HOCl-induced SSc mice. TwX also significantly reduced highly oxidized protein products (AOPP) in serum and suppressed Col-1 gene expression and activation of B cells involved in autoimmunity. These findings suggest that TwX has the potential to be a new antioxidant treatment for SSc without side effects.

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.

Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke (AIS). The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with AIS.

This is a randomised, double-blind, placebo-controlled, multicentre, parallel-group trial of Y-2 sublingual tablet on patients with AIS.An estimated 914 patients at age of 18-80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 days. Patients are at score 6-20 points on National Institutes of Health Stroke Scale (NIHSS) and had a modified Rankin Scale (mRS) ≤1 before this stroke, except mechanical thrombectomy and neuroprotective agents treatment.

The primary outcome is the proportion of patients with mRS ≤1 on day 90 after randomisation. Secondary efficacy outcomes include mRS score on day 90, the proportion of patients with mRS ≤2 on day 90; the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score ≤1 at the days 14, 30 and 90.

This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with AIS.

NCT04950920.

Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol.

To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS).

This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded.

Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 μg) twice daily for 14 days and were followed up until 90 days.

The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization.

Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]).

Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo.

ClinicalTrials.gov Identifier: NCT04950920.

The role of the nitric oxide synthases (NOSs) system in cerebral infarction has been examined in pharmacological studies with non-selective NOSs inhibitors. However, due to the non-specificity of the non-selective NOSs inhibitors, its role remains to be fully elucidated. We addressed this issue in mice in which neuronal, inducible, and endothelial NOS isoforms were completely disrupted.

We newly generated mice lacking all three NOSs by crossbreeding each single NOS-/- mouse. In the male, cerebral infarct size at 24 h after middle cerebral artery occlusion (MCAO) was significantly smaller in the triple n/i/eNOSs-/- genotype as compared with wild-type genotype. Neurological deficit score and mortality rate were also significantly lower in the triple n/i/eNOSs-/- than in the WT genotype. In contrast, in the female, there was no significant difference in the cerebral infarct size in the two genotypes. In the male triple n/i/eNOSs-/- genotype, orchiectomy significantly increased the cerebral infarct size, and in the orchiectomized male triple n/i/eNOSs-/- genotype, treatment with testosterone significantly reduced it. Cyclopaedic and quantitative comparisons of mRNA expression levels in cerebral infarct lesions between the male wild-type and triple n/i/eNOSs-/- genotypes at 1 h after MCAO revealed significant involvements of decreased oxidative stress and mitigated mitochondrial dysfunction in the alleviated cerebral infarction in the male triple n/i/eNOSs-/- genotype.

These results provide the first evidence that the NOSs system exerts a deleterious effect against acute ischemic brain injury in the male.

Geminal C-4 diarylation of substituted pyrazol-5(4H)-ones with in situ generated arynes as the aryl source has been achieved in a one-flask operation. All the newly accessed C4-gem-diarylated pyrazolone entities were found to be non-cytotoxic with varying AChE enzyme inhibitory activities and BBB permeability attributes that augur well for further advancement towards CNS therapeutics for untreatable disorders.

Stroke is a leading cause of morbidity and mortality worldwide and a leading cause of disability. None of the neuroprotective agents have been approved internationally except edaravone in Japanese guidelines in acute ischemic stroke. We here discuss that there are two types of endogenous defense mechanisms (EDMs) after acute stroke for neuromodulation and neuroregeneration, and if both can be activated simultaneously, then we can have better recovery in stroke.

We aimed to study the effect of combination of neuroprotection therapies acting on the two wings of EDM in acute large-vessel middle cerebral artery (LMCA) ischemic stroke.

Sixty patients of LMCA stroke were enrolled and randomized within 72 h into two groups of 30 patients each. The control group received standard medical care without any neuroprotective agents while the intervention group received standard medical care combined with oral citicoline with vinpocetine for 3 months with initial 1 week intravenous and edaravone and cerebrolysin injection, started within 72 h of onset of stroke. Patients were assessed on the basis of the National Institutes of Health Stroke Scale, Fugl-Meyer Assessment Score, Glasgow Coma Scale, and Mini-Mental Status Examination at admission, discharge, and after 90 days.

The intervention group showed significant and early improvements in motor as well as cognitive recovery.

Combination therapy for neuroprotection which is acting on two pathways of EDM can be useful in functional recovery after acute ischemic stroke.

Acute stroke is the second leading cause of death and the third leading cause of disability in the world. Ischemic stroke (IS) the most common type of stroke. In acute cerebral ischemia, damage to the brain tissue is complex and includes blood-brain barrier (BBB) dysfunction, neuroinflammation, oxidative stress, activation of intracellular and extracellular signaling pathways, expression of neurotoxic agents, excitotoxicity, and apoptosis. In acute IS, reperfusion therapy (RT), is one of the most prominent treatment options. Most of the randomized clinical trials demonstrated the efficacy and safety of RT. The use of novel neuroimaging techniques (CT-perfusion and new MRI modalities) significantly expanded the RT selection criteria in patients with IS. One of the possible ways to further expand the RT is to combine it with neurocytoprotection. According to many researchers, this could potentially significantly improve the efficacy and safety of RT. This opinion is based on the concept of preserving brain tissue in the ischemic penumbra region. The aim of this review was to analyze the current trials of neurocytoprotection in combination with RT in IS patients.

Acute ischemic stroke (AIS) afflicts millions of individuals worldwide. Despite the advancements in thrombolysis and thrombectomy facilitating proximal large artery recanalization, the resultant distal hypoperfusion, referred to "no-reflow" phenomenon, often impedes the neurological function restoration in patients. Over half a century of scientific inquiry has validated the existence of cerebral "no-reflow" in both animal models and human subjects. Furthermore, the correlation between "no-reflow" and adverse clinical outcomes underscores the necessity to address this phenomenon as a pivotal strategy for enhancing AIS prognoses. The underlying mechanisms of "no-reflow" are multifaceted, encompassing the formation of microemboli, microvascular compression and contraction. Moreover, a myriad of complex mechanisms warrant further investigation. Insights gleaned from mechanistic exploration have prompted advancements in "no-reflow" treatment, including microthrombosis therapy, which has demonstrated clinical efficacy in improving patient prognoses. The stagnation in current "no-reflow" diagnostic methods imposes limitations on the timely application of combined therapy on "no-reflow" post-recanalization. This narrative review will traverse the historical journey of the "no-reflow" phenomenon, delve into its underpinnings in AIS, and elucidate potential therapeutic and diagnostic strategies. Our aim is to equip readers with a swift comprehension of the "no-reflow" phenomenon and highlight critical points for future research endeavors.

Acute ischemic stroke constitutes a health challenge with great social impact due to its high incidence, with the social dependency that it generates being an important source of inequality. The lack of treatments serving as effective neuroprotective therapies beyond thrombolysis and thrombectomy is presented as a need. With this goal in mind, our research group's collaborative studies into cerebral ischemia and subsequent reperfusion concluded that there is a need to develop compounds with antioxidant and radical scavenger features. In this review, we summarize the path taken toward the identification of lead compounds as potential candidates for the treatment of acute ischemic stroke. Evaluations of the antioxidant capacity, neuroprotection of primary neuronal cultures and in vivo experimental models of cerebral ischemia, including neurological deficit score assessments, are conducted to characterize the biological efficacy of the various neuroprotective compounds developed. Moreover, the initial results in preclinical development, including dose-response studies, the therapeutic window, the long-term neuroprotective effect and in vivo antioxidant evaluation, are reported. The results prompt these compounds for clinical trials and are encouraging regarding new drug developments aimed at a successful therapy for ischemic stroke.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease in which the motor neuron circuitry displays progressive degeneration, affecting mostly the motor neurons in the brain and in the spinal cord. There are no effective cures, albeit three drugs, riluzole, edaravone, and AMX0035 (a combination of sodium phenylbutyrate and taurursodiol), have been approved by the Food and Drug Administration, with limited improvement in patients. There is an urgent need to build better and more effective treatment strategies for ALS. Since the disease is very heterogenous, numerous approaches have been explored, such as targeting genetic mutations, decreasing oxidative stress and excitotoxicity, enhancing mitochondrial function and protein degradation mechanisms, and inhibiting neuroinflammation. In addition, various chemical libraries or previously identified drugs have been screened for potential repurposing in the treatment of ALS. Here, we review previous drug discovery efforts targeting a variety of cellular pathologies that occur from genetic mutations that cause ALS, such as mutations in SOD1, C9orf72, FUS, and TARDP-43 genes. These mutations result in protein aggregation, which causes neuronal degeneration. Compounds used to target cellular pathologies that stem from these mutations are discussed and comparisons among different preclinical models are presented. Because the drug discovery landscape for ALS and other motor neuron diseases is changing rapidly, we also offer recommendations for a novel, more effective, direction in ALS drug discovery that could accelerate translation of effective compounds from animals to patients.

The aim of this study was to investigate the neuroprotective effects of intra-arterial administration of edaravone dexborneol in rats with acute ischemic stroke and determine the optimal dose.

Firstly, 120 male Sprague-Dawley rats (265-300 g) were selected to establish ischemic stroke models and were randomly divided into groups of sham-operation (Sham group), cerebral ischemia-reperfusion (IS group), permanent focal ischemia (PI group) and treatment (2MG group: 2 mg/kg, 4MG group: 4 mg/kg, 6MG group: 6 mg/kg) groups. There are 20 rats in each group, and ten rats in each group were randomly selected for Longa score and 2,3,5-triphenyl tetrazolium chloride staining to observe the changes in neurological function and the proportion of cerebral infarct volume in each group. Secondly, the remaining ten rats in each group were scored for Longa and tested for free radicals (hydroxyl radical; peroxynitrite; nitric oxide) and pro-inflammatory cytokines (interleukin 6; interleukin-1β; tumor necrosis factor-α). We monitored changes in the indicators in each group of rats.

There were no significant differences among the enrolled Sprague-Dawley rats concerning age, sex, and feeding conditions. Edaravone dexborneol could significantly reduce the cerebral levels of hydroxyl radical, interleukin 6, interleukin-1β, tumor necrosis factor-α, and their behavioral scores of acute ischemic stroke rats after a single dose in the carotid artery. The results suggested that 4 mg/kg might be an appropriate dose.

A single intra-arterial administration of edaravone dexborneol can improve neurobehavioral function and alleviate cerebral injury in acute ischemic stroke rats through anti-inflammatory and free radical scavenging effects.