Search Results (84)

(1) Aminoglycosides remain indispensable in modern medicine but share a serious dose-limiting adverse effect: irreversible cochleovestibular ototoxicity. (2) This scoping review systematically maps experimental and clinical strategies aimed at preventing aminoglycoside-induced hearing loss, integrating mechanistic insights across preclinical and translational domains. (3) Preclinical evidence, encompassing in vitro and in vivo studies, delineates three principal mechanistic ways of protection: (A) antioxidant and redox modulation, including N-acetyl-L-cysteine (NAC), vitamin C, edaravone, and selected phytochemicals, which counteract reactive oxygen species-mediated hair cell apoptosis; (B) mitochondrial stabilization with compounds such as mitoquinone, celastrol, and histone deacetylase inhibitors restoring bioenergetic and proteostatic balance; and (C) restriction of aminoglycoside entry through partial blockade of the mechano-electrical transduction channel, notably by ORC-13661 and related modulators. Additional strategies involve nitric oxide modulation, vasodilatory agents, and iron chelation. Efficacy, however, remains compound- and antibiotic-specific, with paradoxical effects observed for several drugs. Clinical evidence remains limited and methodologically diverse. Of the investigated pharmacologic interventions, aspirin provides the most robust and reproducible evidence of protection against gentamicin-induced hearing loss, whereas NAC demonstrates a consistent, but population-specific benefit among dialysis patients. In contrast, vitamin E—despite promising experimental findings—has failed to show clinically significant otoprotective effects in randomized human studies. (4) In conclusion, while experimental data establish a strong mechanistic basis for pharmacologic otoprotection, clinical studies remain few, underpowered, and methodologically inconsistent. Standardized, adequately powered, and mechanistically informed clinical trials are urgently needed to translate experimental promise into actionable otoprotective strategies. Full article

Ischemic stroke remains one of the leading causes of disability and mortality worldwide, and effective therapeutic options are still limited. Therefore, this study aimed to evaluate the neuroprotective effect of the aqueous extract of Bacopa procumbens (B. procumbens) in a murine model of ischemia/reperfusion induced by middle cerebral artery occlusion (MCAO). This widely used model is generated by the transient intraluminal insertion of a nylon filament through the external carotid artery to occlude the middle cerebral artery, allowing controlled induction and subsequent reperfusion. Wistar rats underwent 2 h MCAO, followed by tail vein administration of B. procumbens extract (40 mg/kg) or Edaravone (0.45 mg/kg) before reperfusion. Neurological, histological, and molecular parameters were assessed 48 h later. Additionally, in silico analyses were performed to predict the antioxidant activity of the extract’s major metabolites and to explore Nrf2-related signaling. B. procumbens treatment improved neurological condition, reduced the volume of the infarct lesion, increased the expression and activation of Akt and Nrf2, reduced lipid peroxidation (4-HNE), and downregulated AQP4, the main water channel involved in cerebral edema formation. These molecular effects were associated with enhanced neuronal survival and collectively resulted in significant neuroprotection in the MCAO model. In silico analysis identified key metabolites with high antioxidant potential through free radical scavenging, lipid peroxidation inhibition, and redox enzyme modulation. Nrf2-centered interactome analysis revealed eighty-two proteins linked to ischemia, neuroinflammation, neuronal death regulation, and oxidative stress response. These findings support the therapeutic potential of B. procumbens metabolites as neuroprotective agents against ischemic cerebral injury. Full article

Objective: Although the etiologies and pathogenesis of common hearing disorders—noise-induced hearing loss (NIHL), age-related hearing loss (ARHL), and idiopathic sudden sensorineural hearing loss (ISSNHL)—are diverse, accumulating evidence indicates that reactive oxygen species (ROS) contribute to hearing loss and that antioxidants may help prevent or treat it. We conducted a literature review to examine the relationship between hearing loss and ROS/free radicals in both humans and animal models. Methods: We performed a comprehensive literature search of PubMed/MEDLINE, Embase, the Cochrane Library, Scopus, and Google Scholar to evaluate the induction and role of ROS in the development and treatment of hearing loss. Results: We synthesized evidence across NIHL, ARHL, and ISSNHL. Factors and reactive species implicated in hearing loss included cytomegalovirus infection, genetic polymorphisms, NADPH oxidase 4 (NOX4), NOX transgenic models (NOX-Tg), lipid hydroperoxides (LOOH), and malondialdehyde (MDA). Antioxidant strategies examined for prevention or treatment included vitamins A, C, and E with magnesium; rebamipide; α-lipoic acid; LLY-283; edaravone; melatonin; glutathione peroxidase; superoxide dismutase; glucose; hydrogen-saturated saline; activation of nuclear factor erythroid 2-related factor 2 (Nrf2); inhaled hydrogen gas; and caffeic acid. Conclusions: Elevated ROS and free radicals appear to contribute to the pathogenesis of hearing loss. Although definitive conclusions cannot yet be drawn, current evidence suggests that antioxidant approaches may aid in prevention and treatment. Further studies are needed to elucidate underlying mechanisms, refine therapeutic targets and dosing, and validate efficacy in rigorously designed clinical trials. Full article

Background/Objectives: The efficacy of ST909, an innate immune cGAS/STING/IRF3 pathway regulator, against ischemic brain injury was investigated, and its pharmacological mechanism was elucidated. Methods: The efficacy and pharmacological mechanism of ST909 in ischemic brain injury were evaluated using the middle cerebral artery occlusion (MCAO) rat model, with brain tissue staining, MRI, behavioral tests (balance beam, screen), and ELISA detection of brain injury markers (neuron-specific enolase [NSE], homocysteine [Hcy], and S100β). Results: ST909 significantly reduces cerebral ischemic area, restores blood–brain barrier integrity, and improves neuronal function, outperforming clinical drugs (3-n-butylphthalide and edaravone) in preclinical models. ST909 markedly reduces neuroinflammation while upregulating neurotrophic factors (e.g., BDNF, NGF) in brain tissue. Through PI3K/Akt pathway activation in microglia, ST909 induces M1-to-M2 phenotype polarization, rebalances the M1/M2 ratio, and enhances secretion of anti-inflammatory cytokines and neurotrophic factors, thereby reducing chronic inflammation and promoting neurological recovery. These findings elucidate ST909’s potential pharmacological mechanism against ischemic brain injury, involving microglial polarization via STING/IRF3 and PI3K/Akt pathway. Conclusions: ST909 has a significant pharmacological effect on improving the ischemic area of the brain and repairing the function of the brain neuronal tissues. Targeting the STING/IRF3 pathway, ST909 exhibits neurorestorative potential in post-ischemic brain injury recovery. Full article

Background: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function. Methods: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT²). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain–Eyelid Thermoregulatory Tunnel. CBIT² induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function. Case presentation: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT², resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming. Discussion: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT² may extend to Alzheimer’s, Parkinson’s, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT² establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT² now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders. Full article

Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease is a progressive neurodegenerative disease that attacks and kills motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy, eventually causing respiratory failure and death within 2–5 years after diagnosis. By 2040, the global population of individuals living with ALS is projected to approach 400,000. Since ALS was discovered by Charcot 150 years ago, only two drugs (Edaravone and Riluzole) have been available, offering modest clinical benefits in slowing disease progression. The increasing number of cases, along with the high costs of treatment and care, creates a growing burden on communities and the healthcare system. However, despite this rising burden and the failure of most clinical trials, the ALS community remains hopeful because of the patients themselves. ALS patients are the beating heart of the ALS community. They engage in efforts to improve lives for others, raising awareness through their real-life experiences, participating in research activities, fundraising, providing samples for research, and advocating strongly in front of communities and governments to raise funds. Their engagement is highly valuable, and collaboration with the research community is essential to understanding the disease process and developing effective disease-modifying therapies. Here, we share the story of Mrs. Sherry Wityshyn, an ALS patient and a true ALS warrior from Winnipeg, Manitoba, Canada. We believe her story will inspire and motivate the entire community to learn more about ALS. Furthermore, her story gives hope to everyone impacted. In this manuscript, we also emphasize the different stages of Sherry’s journey from weakness to diagnosis and our efforts to share her enduring words with policymakers in the government. Full article

Postovulatory aging (POA) significantly contributes to fertility decline, primarily through oxidative stress, which impairs oocyte quality, reduces embryonic developmental competence, and may adversely affect offspring health. Edaravone (EDA), a potent free radical scavenger, is known for its cytoprotective effects in various disease models. This study aimed to evaluate whether EDA can mitigate the detrimental effects of POA on mouse oocyte and embryo quality and confirm its reproductive safety. Supplementation with 10 nM EDA significantly reduced meiotic abnormalities, restored mitochondrial distribution, enhanced mitochondrial membrane potential and ATP production, and decreased intracellular reactive oxygen species (ROS) in aged oocytes. Although EDA did not markedly improve fertilization or blastocyst formation rates, it enhanced embryo quality, with morphokinetic parameters comparable to those of young oocytes. Moreover, F₁ offspring derived from embryos produced by EDA-treated POA oocytes were healthy, and female progeny exhibited normal reproductive competence. These findings demonstrate that EDA safely improves oocyte quality by alleviating POA-induced oxidative damage, offering a potential antioxidant strategy to enhance assisted reproductive technology (ART) outcomes when applied to IVF clinics. Full article

Global cerebral hypoxia triggers (mal-)adaptive responses that can lead to neuronal damage. This study evaluated edaravone’s neuroprotective effects in a rat hypoxia model, focusing on sex differences, treatment durations, and behavioral outcomes. Male and female rats underwent global cerebral hypoxia induced by rocuronium, with post-hypoxia edaravone treatment. Motor coordination and activity were assessed through exploratory behavior tests. Histological analyses evaluated neuronal integrity and apoptosis, while microglial activity and gene expression were analyzed via immunofluorescence and qPCR. Edaravone showed transient neuroprotective effects on motor behavior and early immune responses, particularly in the cerebellum and hippocampus. No gross morphological damage was observed, though functional impairments occurred despite preserved cytoarchitecture. Microglial activity was initially suppressed in treated and later activated in untreated hypoxic brains, suggesting modulating immune responses. Gene expression analysis revealed region-specific, time-dependent, and sex-specific changes, including early upregulation of CCR7, S100B, and NSE in treated animals. Males were more susceptible to hypoxic damage, while females showed higher baseline resistance and better functional recovery. Seven-day edaravone treatment increased apoptotic markers in male cerebellum, indicating sex-specific differences in cell death mechanisms. These findings highlight the potential for personalized therapy and underscore the importance of considering sex differences in both research and clinical practice. Full article

Spinal cord injury (SCI) is a debilitating neurological condition marked by primary mechanical damage followed by a complex secondary injury cascade, in which oxidative stress plays a central role. Mitochondrial dysfunction, ionic imbalance, and inflammatory responses drive excessive generation of reactive oxygen and nitrogen species, leading to lipid peroxidation, protein and DNA damage, apoptosis, and progressive neurological impairment. Antioxidant-based therapies have emerged as promising neuroprotective strategies, with compounds such as A91 peptide, curcumin, edaravone, ginsenosides, and glutathione demonstrating preclinical efficacy in reducing oxidative damage, restoring redox balance, modulating signaling pathways (e.g., Nrf2, NF-κB, MAPK, PI3K/Akt), and enhancing neuronal survival. While therapeutic outcomes depend on injury severity, timing, and combinatorial approaches, translating these findings into clinical practice and integrating antioxidants with cell-based therapies, biomaterials, and rehabilitation offers a critical avenue for improving functional recovery in SCI. Full article

Edaravone is used to treat motor neurone disease (MND) by slowing disease progression and prolonging survival time. Currently, it is available as an IV infusion (Radicava^®, Jersey City, NJ, USA) and an oral liquid suspension (Radicava ORS^®, Jersey City, NJ, USA). Development of novel edaravone formulations is still an active field of research that requires a validated stability-indicating assay capable of providing specific, precise, and accurate quantification of edaravone content. In this study, we developed and validated a stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) method for edaravone quantification. Ten RP-HPLC methods based on the previously published literature were evaluated during method development. The optimal method employed a gradient method on an Agilent ZORBAX Extend-C18 column (150 × 4.6 mm, 5 µm) and produced a sharp and symmetrical drug peak. The method was further validated according to ICH Q2(R2) guidelines for specificity, linearity, sensitivity, accuracy, and precision. Successful separation of edaravone from void signals and degradant products was achieved. The method was precise and accurate at the concentration range of 6.8–68.6 µg/mL and was recommended to use without methyl hydroxybenzoate (MHB) as an internal standard. Full article

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. Full article

Apomorphine (APO), a dopamine agonist, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts antioxidant effects, making it a promising candidate for neuroprotection against oxidative stress. This study evaluated neuroplasticity-enhancing properties of newly synthesized APO derivatives, focusing on their ability to promote neurite outgrowth in PC12 cells under nerve growth factor (NGF) stimulation. D55, an APO derivative, retains the hydroxyl group at APO’s 11th position while substituting the 10th with an ethoxy group. D55 exhibited the highest potency (EC₅₀ = 0.5661 nM), significantly enhancing neurite outgrowth. APO demonstrated the highest efficacy (Emax ~10-fold increase), while edaravone (Eda) required higher concentrations (EC₅₀ = 22.5 nM) for moderate effects (Emax ~4-fold increase). D30, in which the 11th hydroxyl was replaced with a methoxy group, had no effect. Neurite outgrowth-promoting effects of APO, D55, and Eda were significantly attenuated by Nrf2 siRNA knockdown, confirming that their neuroplasticity effects are Nrf2-mediated. These findings confirm that D55 is a highly potent Nrf2-activating compound with strong neuroprotective potential, providing new insights into its therapeutic applications for neurodegenerative diseases associated with oxidative stress. Full article

Background: Sleep deprivation (SD) is a common condition affecting many people in modern life. Edaravone (Eda) is a neuroprotective drug, but whether it can improve cognitive impairment caused by SD remains unclear. Methods: Animals received oral gavage doses of Eda (10, 20, and 40 mg/kg) for 8 and 5 days before and during SD. Starting from the 6th day, a modified multiple platform model was used to produce SD in mice for 72 h. The Lashley III maze was used for evaluating spatial learning and memory. Malondialdehyde (MDA) in the hippocampus and serum corticosterone were assessed. Total antioxidant capacity (TAC) and the activity of the enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) were measured. Growth-associated protein 43 (GAP-43), synapsin 1 (SYN-1), post-synaptic density-95 (PSD-95), synaptophysin (SYP), and signs of inflammation were detected using Western blotting. Results: SD caused cognitive impairment, whereas Eda pretreatment warded off such an effect. While serum corticosterone levels rose with SD as well, they decreased in SD mice that received Eda (p < 0.05). Moreover, Eda normalized the SD-induced decline in hippocampal activity of SOD and GPx, lowered MDA levels, and elevated TAC (p < 0.01). Additionally, the hippocampal levels of GAP-34, SYP, SYN-I, and PSD-95 were elevated, while IL-1β and tumor necrosis factor α (TNF-α) were lowered following Eda pretreatment (p < 0.05). Conclusions: SD caused memory impairment; however, pretreatment with Eda improved memory by upregulating synaptic proteins in the hippocampus and having anti-inflammatory and antioxidant effects. Full article

Acute erythroid leukemia (AEL) is a rare and aggressive hematological malignancy managed with chemotherapy, targeted therapies, and stem cell transplantation. However, these treatments often suffer from limitations such as refractoriness, high toxicity, recurrence, and drug resistance, underscoring the urgent need for novel therapeutic approaches. Dibromo-edaravone (D-EDA) is a synthetic derivative of edaravone (EDA) with unreported anti-leukemic properties. In this study, D-EDA demonstrated potent cytotoxicity against HEL cells with an IC₅₀ value of 8.17 ± 0.43 μM using an MTT assay. Morphological analysis via inverted microscopy revealed reductions in cell number and signs of cellular crumpling and fragmentation. Flow cytometry analysis, Hoechst 33258 staining, Giemsa staining, a JC-1 assay, and a reactive oxygen species (ROS) assay showed that D-EDA induced apoptosis in HEL cells. Furthermore, D-EDA induced S-phase cell cycle arrest. Western blot analysis showed significant upregulation of key apoptosis-related proteins, including cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase (PARP), alongside a reduction in Bcl-2 expression. Additionally, oncogenic markers such as c-Myc, CyclinA2, and CDK2 were downregulated, while the cell cycle inhibitor p21 was upregulated. Mechanistic studies involving molecular docking, a cellular thermal shift assay (CETSA), the caspase inhibitor Z-VAD-FMK, JAK2 inhibitor Ruxolitinib, and STAT3 inhibitor Stattic revealed that D-EDA activates the caspase cascade and inhibits the JAK2-STAT3 signaling pathway in HEL cells. In vivo, D-EDA improved spleen structure, increased the hemolysis ratio, and extended survival in a mouse model of acute erythroleukemia. In conclusion, D-EDA induces apoptosis via the caspase cascade and JAK2-STAT3 signaling pathway, demonstrating significant anti-leukemia effects in vitro and in vivo. Thus, D-EDA may be developed as a potential therapeutic agent for acute erythroleukemia. Full article

Background/Objectives: The outcome for aneurysmal subarachnoid hemorrhage (SAH) remains poor, particularly for patients presenting with World Federation of Neurological Surgeons (WFNS) grades IV–V. This study was designed to identify independent prognostic factors in this group of patients with poor-grade SAH. Methods: We prospectively analyzed 357 SAH patients with admission WFNS grades IV–V enrolled in nine primary stroke centers in Mie prefecture, Japan, from 2013 to 2022. This study compared clinical variables, including treatments for angiographic vasospasm and delayed cerebral ischemia (DCI), between patients with favorable (modified Rankin Scale [mRS] scores 0–2) and unfavorable (mRS scores 3–6) outcomes at 90 days post-onset. Multivariate analyses were then performed to identify independent determinants of favorable 90-day outcomes, followed by propensity score matching analyses. Results: The median age was 68 years, and 53.5% of patients had admission WFNS grade V. DCI occurred in 12.9% of patients, and 66.9% had unfavorable outcomes. Independent variables related to unfavorable outcomes were older age, admission WFNS grade V, ventricular drainage, edaravone administration, and delayed cerebral infarction, while those for favorable outcomes were spinal drainage (adjusted odds ratio [aOR] 6.118, 95% confidence interval [CI] 2.687–13.927, p < 0.001), modified Fisher grade 3 (aOR 2.929, 95% CI 1.668–5.143, p < 0.001), and triple prophylactic anti-DCI medication consisting of cilostazol, fasudil hydrochloride and eicosapentaenoic acid (aOR 1.869, 95% CI 1.065–3.279, p = 0.029). Nimodipine is not approved in Japan, and statin and cerebral vasospasm did not influence outcomes. As spinal drainage and the triple prophylactic anti-DCI medication were intervenable variables, propensity score matchings were performed, and they confirmed that both spinal drainage and the triple prophylactic anti-DCI medication were useful to achieve favorable outcomes. Conclusions: In poor-grade SAH, spinal drainage and the triple prophylactic anti-DCI medication may be effective in improving outcomes, possibly by suppressing DCI pathologies other than cerebral vasospasm. Full article