Chimeric antigen receptor T-cell (CAR-T) therapies targeting CD19 have demonstrated effectiveness in the treatment of relapsed/refractory B-cell malignancies. Several CAR-T therapies have been approved in the United States, including axicabtagene ciloleucel (axi-cel), for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), and brexucabtagene autoleucel (brexu-cel), for B-cell precursor acute lymphoblastic leukemia and mantle cell lymphoma (MCL). However, use of CAR-T therapies can result in potentially severe adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This analysis of real-world data evaluated the incidence and management of CRS and ICANS in patients with B-cell malignancies following treatment with axi-cel or brexu-cel therapy. This retrospective observational cohort study analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult patients in the United States who received axi-cel or brexu-cel for any indication from October 2020 to December 2021 with ≥1 follow-up visit were included. The main outcome of interest was incidence of CRS and ICANS following CAR-T therapy, graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. Management of CRS and ICANS with preventive therapies and treatments administered following development of CRS and ICANS was also investigated. Overall, 927 patients across 87 US centers were included (axi-cel, n=707 [76.3%]; brexu-cel, n=220 [23.7%]). Median (range) age was 63 (19-89) years, and 65.3% (605/927) were male. Most patients (83.3% [n=589]) received axi-cel for diffuse large B-cell lymphoma or transformed follicular lymphoma. All patients who received brexu-cel had mantle cell lymphoma. Overall, 766 (82.6%) patients developed CRS (grade ≥2, 47.0%; 360/766). Of patients with available data, 12.4% (89/715) received CRS preventive therapy, most commonly with tocilizumab alone (79.8%; 71/89). Of patients who developed CRS, 76.6% (587/766) received CRS treatment, including 63.5% (258/406) of patients with grade 1 and 91.4% (329/360) with grade ≥2. The most common treatment was tocilizumab (97.3%; 571/587), alone or in combination. Of patients with available data, 49.8% (356/715) received ICANS prevention, mostly anti-epileptics alone (93.3%; 332/356). Of 876 evaluable patients, 424 (48.4%) developed ICANS (grade ≥2, 71.5%; 303/424). Of these, 85.6% (363/424) received treatment for ICANS, most commonly corticosteroids (92.3%; 335/363). Rates of CRS (82.6%) and ICANS (48.4%) were consistent with incidences expected based on prescribing information for axi-cel and brexu-cel, highlighting potential burdens of CAR-T therapy. These results also stress the importance of continuous patient monitoring and management during CAR-T therapy and demonstrate an evolving treatment landscape, including more aggressive management of CRS and interest in preventive therapies for CRS and ICANS.
Dextromethorphan-associated neurotoxicity with cerebellar edema syndrome is a recently described clinico-radiological condition resembling pediatric opioid use-associated neurotoxicity with cerebellar edema syndrome. To describe two children with dextromethorphan-associated neurotoxicity with cerebellar edema syndrome from a tertiary care hospital in North India. The clinical details were obtained from the medical case records of the children admitted with dextromethorphan-associated neurotoxicity with cerebellar edema syndrome during the month of August and September 2025. We report two children (3 years and 13 months) who presented with encephalopathy following ingestion of dextromethorphan-containing cough syrup for viral prodrome. Magnetic resonance imaging showed T2/FLAIR hyperintensities in bilateral cerebellar hemispheres with diffusion restriction, suggestive of cytotoxic edema. With supportive treatment and intravenous methylprednisolone, both patients recovered rapidly with no residual neurologic deficits. These two cases highlight the occurrence of dextromethorphan-associated neurotoxicity with cerebellar edema syndrome in young children. Sensitization of healthcare providers about dextromethorphan-associated neurotoxicity with cerebellar edema syndrome, early clinical suspicion, confirmation of diagnosis with neuroimaging, and supportive care, may be associate with good neurological recovery. Dextromethorphan-associated neurotoxicity with cerebellar edema syndrome is a new clinico-radiological condition that occurs following ingestion of dextromethorphan in young children. Similar to the recently published report and cases presented here, early identification and treatment may be associated with favorable neurological recovery. Therefore, this syndrome should be considered in the differential diagnosis at an early stage. There is a need to increase awareness among healthcare providers to avoid prescribing dextromethorphan-containing cough syrups to younger children.
Neurotoxicity is a rare, often dose-limiting adverse effect of methotrexate (MTX) therapy that disproportionally affects Latino children. Factors contributing to the observed disparity are not well understood. This study leveraged admixture mapping to identify genetic regions associated with MTX-related neurotoxicity susceptibility among Latino children undergoing therapy for pediatric acute lymphoblastic leukemia (ALL). The study cohort was composed of 429 self-identifying Latino children diagnosed with ALL (2005-2019) between the ages of 2 and 20 years treated at one of six US pediatric cancer treatment centers. MTX-related neurotoxicity was defined as neurologic episodes (e.g., seizures, stroke-like symptoms, altered mental status, and tremors) occurring within 21 days of intravenous (IV) and/or intrathecal (IT) MTX that were documented by magnetic resonance imaging (MRI) abnormalities and/or clinical symptoms. Among the 429 patients, we identified 46 (10.7%) Latino children with neurotoxicity. Admixture mapping was used to identify local genomic regions that are associated with the risk of MTX-related neurotoxicity among Latino children with ALL. Ultimately, this study identified 11 genomic regions carrying suggestive associations with MTX-neurotoxicity risk among Latino children with ALL. Review of biological plausibility of the loci within these regions revealed associations with areas of the brain or downstream regulatory functions. Results from this study may guide future work to further interrogate these regions through fine-mapping to identify genetic variants associated with increased risk of MTX-related neurotoxicity among Latino children with ALL.
Local anaesthetics are essential to regional anaesthesia but may exert neurotoxic effects on peripheral nerves under specific conditions. Although perioperative nerve injury is increasingly recognised, the contribution of local-anaesthetic neurotoxicity, the relative toxicity of different agents and concentrations, and the influence of patient-related risk factors remain incompletely defined. This evidence-based narrative review synthesises experimental and clinical data on peripheral nerve neurotoxicity associated with local anaesthetics and discusses implications for clinical practice and future research. A prospectively registered search was conducted across major biomedical databases for studies published between 1990 and 2024. Experimental evidence consistently demonstrates dose-dependent and time-dependent neurotoxicity for all clinically used local anaesthetics, characterised by ultrastructural damage, oxidative stress, mitochondrial dysfunction and activation of apoptotic and intracellular signalling pathways. Relative toxicity varies between agents and concentrations, with lidocaine and bupivacaine often appearing more potent than ropivacaine or chloroprocaine in preclinical models, while findings for articaine remain heterogeneous. Diabetic and metabolically compromised nerves exhibit increased susceptibility, supporting a 'two-hit' model of injury. In contrast, clinical evidence directly linking specific agents, concentrations or exposure durations to permanent peripheral nerve injury is limited, and such injuries are typically multifactorial. Overall, chemical neurotoxicity should be considered one component of a broader perioperative risk profile. Risk mitigation should prioritise avoidance of intraneural injection, adherence to recommended doses and cautious use of high concentrations or prolonged exposure, particularly in vulnerable nerves. Further research should integrate mechanistic and clinical outcomes while accounting for patient-level risk factors.
Chlorpyrifos (CPF) is a broad-spectrum chlorinated organophosphate insecticide. It was classified as a persistent organic pollutant under the Stockholm Convention in 2024 due to its harmful effects on the environment and human health, including neurotoxicity. The classical mechanism of CPF-induced neurotoxicity is attributed to acetylcholinesterase inhibition by its metabolite, chlorpyrifos-oxon (CPO), in cholinergic neurons. Emerging studies indicate that CPF also induces toxicity in dopaminergic neurons through mitochondrial dysfunction. In this study, the molecular mechanisms and targets associated with CPF-induced neurotoxicity in humans were investigated using network toxicology, molecular docking, molecular dynamics, and in vitro study. Comprehensive database analyses identified 271 potential targets associated with CPF-induced neurotoxicity. Gene ontology enrichment and gene-gene interaction analyses revealed significant enrichment related to mitochondria and oxidative phosphorylation. Protein-protein interaction and centrality analyses identified 15 hub targets. Molecular docking and molecular dynamics simulations demonstrated that CPF and CPO bind to mitochondrial Complex I, especially with NDUFA2, more strongly than rotenone, a known Complex I inhibitor. In vitro analysis in SH-SY5Y cells demonstrated that CPF impaired mitochondrial complex I-associated activity in a concentration-dependent manner, with significant inhibition observed at concentrations of 75 µM and higher. These findings suggest that CPF, and to a lesser extent CPO, may exert inhibitory effects on mitochondrial complex I in neurons, thereby contributing to neurotoxicity in humans. Overall, these results are in line with previous experimental reports and highlight the effectiveness of integrated computational approaches in identifying key mitochondrial mechanisms involved in CPF-induced neurotoxicity.
Krait (Genus: Bungarus) envenoming is characterised by progressive neuromuscular paralysis. In Sri Lanka, the absence of a species-specific antivenom for envenoming by the endemic Sri Lankan krait (Bungarus ceylonicus) necessitates reliance on Indian polyvalent antivenoms, despite limited evidence of their efficacy. This study investigated the time window during which commercial Indian (BHARAT, VINS) and Australian polyvalent (Seqirus) antivenoms can prevent neurotoxicity induced by Sri Lankan Krait (B. ceylonicus) and Common Krait (Bungarus caeruleus) venoms using the chick biventer cervicis nerve-muscle preparation. Venoms were added at concentrations producing either predominantly pre-synaptic or post-synaptic neurotoxicity, and antivenoms were added 30 or 90 min after venom exposure. When added after venom, all antivenoms showed a consistent, time-dependent decline in efficacy against pre-synaptic neurotoxicity, with only partial prevention when added after 30 min and complete failure when added after 90 min. In contrast, post-synaptic neurotoxicity remained more amenable to neutralisation after a delay; BHARAT partially prevented post-synaptic effects of both venoms at 30 min, while VINS fully prevented post-synaptic neurotoxicity of B. caeruleus at the same time point. These findings support the hypothesis that pre-synaptic toxins rapidly enter motor nerve terminals, limiting antivenom access and reversibility, whereas the effects of post-synaptic toxins are more readily reversible due to their extracellular mode of action.
The neurotoxicity of cisplatin (CIS) in the hippocampal leads to cognitive effects caused by oxidative stress, neuroinflammation, apoptosis, and dysfunction of neurotransmitters. The major bioactive phytonutrient in Aloe vera is barbaloin (BLN), which has been shown to have antioxidant and anti-inflammatory effects, but its neuroprotective ability against CIS-induced neurotoxicity has not been investigated. To assess the neuroprotective action of BLN in CIS-induced hippocampal neurotoxicity in rats and to understand the molecular interactions between BLN and major neuroinflammatory and apoptotic proteins. A total of 24 male Wistar rats were split into 4 groups (n = 6): control, CIS (5 mg/kg), CIS + BLN 25 mg/kg, and CIS + BLN 50 mg/kg over 21 days. Cognitive ability (Morris water maze), oxidative stress indicators (MDA, GSH, SOD, CAT), neuroinflammatory cytokines (TNF-α, IL-1β, IL-6, NF-κB, TGF-β1), caspase-3, neurotransmitters, and hippocampal histopathology were measured. Molecular docking and 100-ns molecular dynamics simulations (MDS) with MM-GBSA analysis were done with TNF-α, TGF-β1, NF-κBp65, and caspase-3. BLN significantly reduced cognitive impairment, oxidative stress, neuroinflammation, and apoptosis, and restored neurotransmitter homeostasis and hippocampal cytoarchitecture (all p < 0.0001). Molecular docking demonstrated positive binding energies (- 7.226 to -8.566 kcal/mol), and MDS revealed the presence of stable BLN-protein complexes (ΔGbind = -56.07 kcal/mol for TGF-β1). BLN exhibits considerable neuroprotective properties against CIS-induced neurotoxicity in the hippocampus, suggesting its potential as a natural dietary phytonutrient supplement to ameliorate chemotherapy-induced cognitive impairment.
Regulatory T cells (Tregs) maintain immune homeostasis and suppress inflammation, and emerging evidence indicates they also modulate neuronal function and regeneration. Dorsal root ganglion (DRG) sensory neurons transmit pain signals and are damaged by chemotherapeutic agents such as paclitaxel (PTX), leading to neuropathic pain. Although Tregs show therapeutic promise in neuropathic pain, the mechanisms of Treg-neuron interactions remain poorly defined. Using in vitro co-culture, we examined interactions between primary DRG neurons and Tregs and their effect on PTX-induced neurotoxicity. Live-cell imaging showed that activated Tregs enhanced neurite length and branching and preferentially localised to neuron/neurite-rich regions. Additionally, activated Tregs rescued PTX-induced inhibition of neurite outgrowth. Pharmacological blockade identified Treg-derived amphiregulin (AREG) as essential for neurite outgrowth, while both AREG and neuropeptide Y were required for Treg-mediated protection against PTX-induced neurotoxicity. These findings identify Tregs as direct promoters of sensory neuron growth and protection from PTX-induced neurotoxicity through specific molecular mediators, supporting their potential therapeutic relevance in peripheral neuropathic pain.
Quantum dots (QDs) are semiconductor nanocrystals with unique photophysical properties, rendering them promising for applications in biomedical imaging, neuroscience, and various industrial sectors. However, the rapid expansion of their production and application inevitably leads to the release of QDs into the environment throughout their life cycle, classifying them as an emerging class of contaminants of concern. Their potential neurotoxicity not only represents a major bottleneck obstructing their clinical translation but also poses environmental and health risks that warrant serious attention. This review summarizes recent advances in the neurotoxicity of QDs, with a focus on their adverse effects on the central and peripheral nervous systems. It indicates that the mechanisms of QD neurotoxicity involve a complex network comprising oxidative stress, metabolic reprogramming, neuroinflammation, and multiple cell death pathways. Notably, the peripheral nervous system is highlighted as an early-warning target, and the significant risks associated with long-term, low-dose environmental exposure are emphasized.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuronal death of unclear etiology. While levodopa remains the gold standard for managing PD motor symptoms, it lacks disease-modifying efficacy, necessitating new neuroprotective therapies. Mitochondrial dysfunction and impaired autophagy are key hallmarks of PD. This study utilized 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells to investigate the neuroprotective mechanisms of catalpol, an iridoid glycoside derived from Rehmannia glutinosa. We found that catalpol attenuated MPP+-induced neurotoxicity, mitochondrial membrane depolarization, and ATP depletion. This protection was critically dependent on autophagy; it was enhanced by the activator rapamycin but abolished by the inhibitor wortmannin and the autophagosome-lysosome fusion inhibitor bafilomycin A1. Catalpol activated autophagy by increasing autophagosome formation, elevating Beclin 1 and LC3-II levels, and promoting p62 degradation. Furthermore, catalpol reversed MPP+-induced mitophagy suppression and restored the regulatory protein PINK1 and DJ-1 expression. Given that Akt/BDNF/Bcl-2 and TrkB/BDNF pathways promote neuronal survival, we investigated their involvement. We found that the TrkB agonist 7,8-DHF mimicked catalpol's neuroprotection against MPP+-induced neurotoxicity, whereas the pan-Trk inhibitor GNF-5837 abolished it. Western blotting demonstrated that catalpol reversed MPP+-mediated suppression of TrkB and Akt phosphorylation, as well as BDNF and Bcl-2 expression. Molecular docking indicated that catalpol may interact with the TrkB ligand-binding domain as 7,8-DHF and shares key binding residues. Our findings suggest that catalpol exerts neuroprotection via a dual mechanism: preserving mitochondrial function through PINK1/DJ-1-mediated mitophagy and activating the TrkB/Akt/BDNF/Bcl-2 survival pathway, potentially by interacting with the TrkB receptor, highlighting its therapeutic potential for PD.
Inhalational anesthesia, which includes anesthetics such as sevoflurane, isoflurane, and desflurane, is widely used in clinical settings for surgical interventions across all age groups. Nonetheless, recent findings from preclinical research raise important questions regarding their potential neurotoxic effects, especially within the developing brain, though clinical implications remain to be fully established. This narrative review was conducted through a literature search of the PubMed database and synthesizes preclinical investigations into gene modifications associated with neurotoxicity following exposure to inhalation anesthetics. Emphasis was placed on anesthetic exposure in human and animal-derived cell lines, neurodevelopmental animal models, as well as adult and aged animals. In various models, the neurotoxic mechanisms of inhalational anesthesia involve a complex interaction of apoptosis, oxidative stress, mitochondrial dysfunction, neuroinflammation, and epigenetic remodeling. Developmental studies indicate additional susceptibilities, including impaired neuronal migration, myelination deficits, and transgenerational epigenetic effects, whereas aging models exhibit oxidative stress injury, microglial activation, and heightened perioperative neurocognitive sensitivity. Understanding these neurotoxic mechanisms is essential for identifying risk factors, formulating age-specific neuroprotective strategies, and enhancing the overall safety of anesthetic use, particularly in vulnerable populations.
Cow milk constitutes a fundamental component of the human diet. Along with high nutritional value, contains neuroprotective components, caseins, lactoferrin, phospholipids and tryptophan. However, due to the use of pesticides in agriculture, veterinary drugs in livestock, and the presence of other contaminants, cow milk is frequently contaminated by these chemicals posing a risk to human health, namely through neurotoxicity. Strategies to decrease these contaminants include detoxification via microorganisms. Concomitantly, increased consumption of plant-based protein to substitute animal sources has been seen globally, being soy beverages (SB) utilized as an alternative to cow milk. Soy products are almost equivalent to animal sources in protein quality, and moreover, soy isoflavones like genistein, daidzein and glycitein and saponins, as well as soy peptides, may play neuroprotective roles. Conversely, neurotoxic risks associated with the consumption of soy beverages also exist, mainly due to the presence of excess of manganese, mycotoxins and consequences of human interventions during cultivation, resulting in pesticide residues, and pollution of soils, namely with metals. Due to the neurotoxicity and bioaccumulation of these contaminants, the fact that both cow milk and soy beverages are routinely ingested by all ages, and represent key ingredients in many processed foods, including baby foods, strict surveying of their levels is suggested.
Regulatory toxicity studies traditionally rely on in vivo apical endpoints for hazard characterization and risk assessment; when available, relevant and reliable in vitro assays are anticipated to aid this interpretation. Developmental neurotoxicity (DNT) related parameters such as brain morphometry can be especially challenging to interpret, based on technical challenges such as sample preparation artifacts. This study employed the Developmental Neurotoxicity In Vitro Battery (DNT-IVB), designed to provide functional insights on key neurodevelopmental processes (KNDPs), to provide context for equivocal brain morphometry effects observed in a legacy in vivo DNT study conducted with acibenzolar-S-methyl (ASM), a plant host defense inducer. ASM and its major mammalian metabolite, acibenzolar acid (AA), were tested in all 17 in vitro assays comprised within the current iteration of the DNT-IVB. In vitro testing concentrations were derived to match the existing in vivo DNT study by applying physiologically based pharmacokinetic (PBPK) modeling with adjustment for rat versus human toxicokinetics. All concentration-response DNT-IVB assay data were analyzed using the US EPA ToxCast Pipeline. ASM showed no effect on any KNDP in vitro. AA was active only in the rat network formation assay with low potency AC50 ranges of 96.1-150 µM that modelling shows will not be achieved in vivo at doses where the apical effects in question were observed. This case study demonstrates the potential of the DNT-IVB to be used as a tool to assess equivocal findings from in vivo DNT studies and contribute to a weight of evidence to support conclusions on chemical-mediated DNT.
Heavy metals pose a profound threat to neurological health across all stages of human life, from prenatal development to old age. Heavy metals such as lead, mercury, cadmium, and arsenic are pervasive environmental pollutants that disrupt neural function through mechanisms including oxidative stress, inflammation, mitochondrial dysfunction, and neurotransmitter system imbalances. During critical developmental windows such as fetal growth and early childhood, exposure can impair neurogenesis, synaptic plasticity, and myelination, leading to lifelong cognitive deficits, behavioral disorders, and increased vulnerability to neurodegenerative diseases in later life. Even in adulthood and aging, chronic exposure exacerbates neurodegeneration, accelerating conditions like Alzheimer's and Parkinson's diseases through persistent oxidative damage and inflammatory cascades. This chapter underscores the dual role of nutrition as both a shield and a therapeutic tool against heavy metal neurotoxicity. Key nutrients, such as polyphenols, vitamins, and essential minerals, counteract heavy metal-induced damage by scavenging free radicals, enhancing antioxidant defenses, modulating inflammation, and promoting neuronal repair. By integrating evidence from epidemiological, preclinical, and clinical studies, this chapter emphasizes actionable strategies, such as fortified infant formulas, plant-based proteins, and micronutrient supplementation to reduce heavy metal bioavailability and bolster neurological resilience. Public health initiatives targeting vulnerable populations, alongside policies regulating environmental pollutants, are critical to curbing this silent epidemic. This chapter advocates for a proactive, nutrition-centered approach to safeguarding brain health, demonstrating that dietary interventions are not merely complementary but foundational in combating the pervasive threat of heavy metal neurotoxicity across generations.
Air pollution, composed of several complex particles, is regarded as one of the major causes of adverse health outcomes, and particulate matter (PM), which occurs primarily as PM10, PM2.5, and PM0.1 according to its aerodynamic diameter, is considered to be the most dangerous fraction. It is known to impair the healthy functioning of organ systems, including the cardiovascular system, respiratory system, gastrointestinal system, and reproductive system. Upon inhalation, the respirable fraction of PM can travel through the olfactory bulb and reach the brain, disrupting the blood-brain barrier (BBB), or act through peripheral responses, thereby causing neuroinflammation and oxidative stress in the brain. PM exposure activates unfolded protein response (UPR) and proapoptotic signals like CHOP and caspase-12, which drive brain cell death. It also impairs oxidative phosphorylation, increases ROS, and initiates mitochondrial permeability transition, which results in neuronal energy failure. Upon entering the system, it compromises the autophagic flux and lysosomal integrity, leading to its accumulation. Although the systemic effects of PM are widely recognized, its capacity to penetrate the central nervous system (CNS) poses a significant biological concern. This review maps how PM alters CNS components, leading to neuroinflammation and ultimately neurotoxicity, and examines the upstream and downstream mechanisms underlying these actions.
Manganese (Mn) is an essential metal required for many physiological functions, and deficiency or over-exposure is associated with neurological dysfunction and neuropathology. Tight homeostatic control of Mn in the body is required to maintain optimal physiological levels and protect against toxicity. Mn homeostasis has been studied for decades, but there has been limited knowledge of the molecular mechanisms until recently, when the first human genetic disorders of Mn metabolism were described. These discoveries led to the identification of the Mn transporters SLC30A10, SLC39A14, and SLC39A8, which spurred a transformation of research into Mn homeostatic mechanisms. This review will provide an overview of Mn physiology and homeostasis, the role of the critical Mn transporters, and discuss the progress made within recent years towards understanding how these transporters work together to regulate brain Mn biology under both physiological and pathophysiological Mn conditions.
Anakinra is increasingly used for corticosteroid-refractory and/or severe immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor (CAR) T-cell therapy; however, robust data on its efficacy and predictors of response are lacking. We evaluated the outcomes of 101 patients treated with anakinra for ICANS (corticosteroid-refractory, n = 90) and investigated factors associated with anakinra efficacy. The median time to ICANS resolution from anakinra initiation was 8 days, and the 28-day cumulative incidences of ICANS resolution and treatment-related mortality (TRM) were 86% and 13%, respectively. Anakinra treatment failure occurred in 28%. The day +28 antitumor response rate was 91% (complete response, 47%). Significant neurologic improvement (SNI; ≥2-grade improvement in ICANS) occurred in 43% of patients within 72 hours after anakinra initiation. Achieving 72-hour SNI was associated with faster time to ICANS resolution (median, 3 vs 9 days; P< .001) and hospital discharge (28-day cumulative incidence, 93% vs 53%; P< .001), lower 2-week cumulative exposure to dexamethasone (120 vs 190 mg; P = .029) and anakinra (3650 vs 6600 mg; P = .059), lower TRM (28-day cumulative incidence, 0% vs 21%; P = .011), and a trend toward superior overall survival (28 days, 98% vs 74%; P = .094). In multivariable analysis, older age, CAR T-cell product type, and higher day 0 C-reactive protein were independently associated with lower odds of 72-hour SNI. Our study benchmarks key clinical outcomes after anakinra treatment for ICANS; 72-hour SNI may provide a practical clinical decision point to identify patients who may require additional treatment strategies.
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Based on the evidence that fenfluramine-induced anorexia, weight loss, and cardiovascular toxicity are primarily mediated by the d-enantiomers of fenfluramine and its metabolite norfenfluramine, we investigated pharmacokinetic/pharmacodynamic correlations for the active enantiomers of fenfluramine and norfenfluramine in the rat maximal electroshock seizure (MES) test. This is part of a series of studies aimed at optimizing selection of an enantiomerically pure compound for development as a safer alternative to racemic fenfluramine. Median effective concentrations (EC50) in the MES model and median neurotoxic concentrations (TC50) of each enantiomer in plasma and brain were estimated after intraperitoneal administration of d-fenfluramine, l-fenfluramine, and l-norfenfluramine as well as racemates, and compared with the respective median effective (ED50) and neurotoxic (TD50) doses. A newly developed enantioselective assay allowed differentiation of concentrations of each enantiomer after administration of racemates. Protective indexes (PIs) were estimated based on dose (TD50/ED50) and concentration (TC50/EC50) in plasma and brain. Based on ED50, all enantiomers tested had comparable potency, but l-norfenfluramine had a lower PI than the other enantiomers. Based on EC50 in plasma and brain, l-norfenfluramine and d-fenfluramine had the highest potency, but l-norfenfluramine was consistently more toxic than the other enantiomers. The PIs of d-fenfluramine, l-fenfluramine, and l-norfenfluramine were 2.7, 2.4, and 1.2, respectively, based on plasma concentrations, and 4.1, 2.8, and 1.2, respectively, based on brain concentrations. Potency estimates for each enantiomer after dosing with racemic fenfluramine and norfenfluramine were consistently lower than after dosing with the pure enantiomers, indicating that both enantiomers contributed to antiseizure activity. Based on these results, l-fenfluramine has more favorable properties than l-norfenfluramine for potential development as an enantiomerically pure medication. Although our findings are consistent with those previously reported for the MES test in mice and the scn1Lab-/- mutant zebrafish, they differ from those reported for the audiogenic seizures mouse model. Further studies, preferably in disease-specific models, would be desirable.
Kraits are a group of medically important venomous snakes responsible for numerous snakebite cases annually leading to thousands of mortalities and associated co-morbidities in patients. The Sind krait (Bungarus sindanus) is an underexplored venomous elapid of South Asia distributed towards the North-western region of the Indian subcontinent. The cryptic natural history of the snake, geographically variable venom composition, and venom induced neurotoxicity pose a significant challenge for researchers and clinicians. This review integrates current knowledge on the distribution, ecology, and behaviour of the species across its distribution in Pakistan and north-western India. We critically evaluated venom composition studies that suggest plausible mechanisms of neurotoxicity with predominance of β-bungarotoxins or phospholipase A2s (PLA2s), and ancillary role of three-finger toxins (3FTxs), like κ- and α-neurotoxins depending on the region. Neutralization assays and limited clinical reports indicate reduced effectiveness of polyvalent "Big Four" antivenom against B. sindanus envenoming. We explored relevant strategies for the development of effective therapeutics against B. sindanus venom, including conventional, region-specific, next-generation antivenom and/or adjunct therapies. In this context, we explored the potential of recently developed broadly-neutralizing recombinant monoclonal antibodies to bind B. sindanus venom toxins across different populations and geographies using a hypothesis-driven in silico molecular docking and residue-interaction approach. Prioritized research agenda should explore the natural history and venom dynamics of this species to better understand the venom evolution, venom variation, clinical relevance, and antivenom neutralization, and utilize the learning for the development of safer and effective alternative therapeutic approaches.