Optic nerve injury often causes irreversible vision loss due to limited self-regeneration capacity, persistent neuroinflammation, and failed remyelination. Current therapies partially promote axonal regeneration but rarely achieve meaningful visual recovery, limited mainly by unstable myelin reconstruction and inadequate injury microenvironment modulation. Here, we developed a photo-crosslinkable bilayer hydrogel system (GO/GI@MPDA-Cle). Its outer layer (GM-Odex) provides strong wet tissue adhesion for optic nerve sheath sealing, while the inner layer (GM-imid) enables sustained local release of drug-loaded nanoparticles (MPDA-Cle) for microenvironment modulation. In Vitro, the system exhibited excellent antioxidant and anti-inflammatory properties and polarized microglia toward an anti‑inflammatory phenotype. In a rat partial optic nerve injury model, the hydrogel protected retinal ganglion cells through local immunomodulation and was associated with improved oligodendrocyte-associated maturation and remyelination-associated repair, accompanied by partial improvement in optic nerve conduction-related function. Transcriptomic analysis further revealed that the treatment downregulated pathways related to inflammation, oxidative stress, and neuronal apoptosis, while upregulating genes involved in neuronal regeneration, axonal growth, and myelination. By integrating physical sealing, immunomodulation, and myelin repair, this study proposes a promising multifunctional strategy for optic nerve injury treatment.

ORAI channels are store-operated Ca[2+] channels, which play important roles in physiology and pathophysiology. ORAI channel modulators are useful for developing pharmacological interventions. Here, we aimed to investigate the benzhydryl-derived analogues as novel ORAI channel blockers. The effects of benzhydryl-derived analogues TH1177, clemastine, cloperastine, and diphenhydramine were investigated in HEK-293 cells overexpressing individual ORAI isoforms and STIM1. The ORAI currents were recorded by patch-clamp, and cytosolic Ca[2+] was measured by a fluorescent Ca[2+] dye. TH1177 inhibited ORAI1, ORAI2, and ORAI3 currents with IC50 values of 18.3 μM, 4.8 μM, and 35.6 μM, respectively. Clemastine inhibited ORAI1 and ORAI2, but showed no effect on ORAI3. Both cloperastine and diphenhydramine, without a pyrrolidine ring structure, only showed minimal inhibition of ORAI1. Intracellular application of TH1177 and outside-out patch demonstrated that TH1177 blocked ORAI3 currents via the extracellular surface. TH1177 did not affect cytosolic STIM1 clustering and movement. Moreover, TH1177 potently inhibited cell proliferation with IC50 values of 2.6 µM for HAEC, 5.2 µM for EA.hy926, and 29.4 µM for HK-2 cells and induced apoptotic cell death. It is concluded that TH1177 is a pan-inhibitor for ORAI1-3 channels, while clemastine inhibits ORAI1 and ORAI2 but shows little effect on ORAI3. The pyrrolidine ring structure in the compounds of TH1177 and clemastine is critical for their inhibitory activity. The two benzhydryl derivatives (cloperastine and diphenhydramine) without the pyrrolidine ring only showed minimal inhibition of ORAI1. Our findings give a new pharmacological profile of ORAI channels.

In this study, a novel cell membrane chromatography (CMC) model was developed to discover Histamine H1 receptors (H1R) targeted anti-allergic drugs for specific screening and ligand-receptor interaction analysis by SNAP-tagged H1R fusion protein conjugation and BG-modified silica gel. Allergic diseases (ADs) are prevalent pathological conditions arising from immune dysregulation, which significantly compromise patient quality of life across multiple domains, while traditional Chinese medicines (TCMs) are widely used to treat ADs. H1R plays a pivotal role in the pathogenesis of allergic diseases and acts as an attractive target for therapeutic intervention. Although antihistamines are the first-line therapy for ADs, their clinical utility is limited by side effects. Consequently, a novel screening method for active components targeting H1R in TCMs is crucial for the research and discovery of novel anti-allergic lead compounds. In the current study, the H1R-SNAP-tag cell membrane chromatography (H1R-SNAP-tag/CMC) column was prepared with outstanding specificity, selectivity, and reproducibility by chemically immobilizing H1R overexpression cell membranes to the BG-silica gel (BG-SiO2) using the SNAP-tag technology. The H1R-SNAP-tag/CMC-HPLC-MS system was investigated using the H1R antagonist Clemastine fumarate and the results showed that the system was a reliable model for screening potential anti-allergic compounds from TCMs. From an Iris tectorum Maxim. (I. tectorum) extract, six H1R-binding compounds were identified: tectoridin, iristectorin A, iridin, tectorigenin, irigenin, and irisflorentin. Frontal analysis and molecular docking confirmed their affinity for H1R, while subsequent in vivo and in vitro pharmacological assays preliminarily validated their anti-allergic efficacy.

Peripheral nerve injury (PNI) causes rapid disruption of neuromuscular connectivity, leading to sarcopenia characterized by muscle wasting, mitochondrial dysfunction, and metabolic imbalance. Although calcium dysregulation and aberrant AMPK/mTOR signaling are known contributors, the molecular cascade linking nerve injury to muscle degeneration remains incompletely understood. This review explores pharmacological and molecular strategies to restore neuromuscular integrity after PNI. We focus on agents such as 4-aminopyridine (4-AP), a potassium channel blocker that enhances nerve conduction, and clemastine, an antihistamine that promotes Schwann cell-mediated remyelination. These compounds represent a potential dual approach to accelerating nerve repair while maintaining muscle viability. We also explore muscle-centered molecular strategies, focusing on pathways such as Forkhead box protein O (FOXO), Glycogen synthase kinase 3 beta (GSK-3β), signal transducer and activator of transcription 3 (STAT3), and TGF-β/Smad, which govern the balance between protein synthesis and degradation. Of note, most current studies suggest that phytochemicals derived from marine sources, including seaweed, may attenuate denervation-induced catabolism by modulating FOXO signaling and suppressing E3 ubiquitin ligase activity. Additionally, we highlight the critical crosstalk between motor neurons and skeletal muscle, mediated by neurotrophic factors such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and Neurotrophin-3 (NT-3), which support both neuromuscular junction stability and axonal regrowth. By integrating insights from nerve biology and muscle physiology, this review outlines a therapeutic framework that targets both nerve regeneration and muscle preservation, an approach that effectively addresses nerve injury-induced sarcopenia effectively.

Severe traumatic brain injury (TBI) remains difficult to treat because successful control of mass lesions, intracranial pressure, cerebral perfusion, oxygenation, and systemic instability does not ensure that secondary cellular injury has stopped. PubMed/MEDLINE and ClinicalTrials.gov were searched through July 28, 2026, and representative candidates were organized across five overlapping pathophysiological nodes. Evidence was described by study source, purpose, and result direction rather than assigned a formal quality grade. Human evidence was heterogeneous. Glibenclamide/glyburide and hypertonic sodium lactate produced preliminary imaging or physiological signals without demonstrated functional benefit. Riluzole was neutral in an adult randomized trial, whereas a small study in chronic TBI found that minocycline reduced a neuroinflammatory imaging signal but increased plasma neurofilament light. Metformin and N-acetylcysteine plus probenecid provided exploratory pharmacokinetic, biomarker, or safety data. Amantadine provided phenotype-specific clinical proof of principle in traumatic disorders of consciousness. Cerebrolysin showed mixed human evidence, including a favorable day-90 multidimensional ensemble signal that requires independent replication. Deferoxamine and clemastine remain preclinical. We therefore propose a modular pharmacological framework composed of separable investigational modules rather than simultaneous multidrug treatment. Module activation should require optimized foundational care, a matching phenotype, measurable target activation or engagement, and acceptable systemic safety. This framework prioritizes phenotype-enriched, single-module development before any sequential or combination design and does not support routine off-label polypharmacy.

Clemastine (CLE), an H1R antagonist widely used for the treatment of allergic rhinitis, has recently been investigated for its positive modulatory effects on P2X7, a receptor for extracellular ATP (eATP) involved in the regulation of inflammation, immune responses, and the composition of the tumor microenvironment (TME). Here, we further examined the effects of CLE on P2X7-mediated responses to clarify the pharmacological significance of P2X7 potentiation. First, in murine and human cells expressing (B16F10 WT and HEK293-hP2X7) or lacking (B16F10 P2X7[-/-] and HEK293 WT) the P2X7 receptor, we measured intracellular Ca[2+] influx, ethidium bromide (EB) and daunorubicin (DN) uptake, mitochondrial morphology, and LDH and ATP release following P2X7 agonism or antagonism in the presence of CLE. We found that CLE increased Bz-ATP-induced P2X7-mediated channel opening, pore formation, mitochondrial remodeling, eATP release, and cell death, effects absent in P2X7-null cells and abolished by P2X7 antagonists. As a readout of activation of NLRP3 inflammasome, a known downstream effector of the P2X7 receptor, we also assessed the effect of CLE on IL-1β release from peritoneal macrophages from wild-type (WT) or P2X7 knockout (KO) mice, LPS-primed and treated with ATP and/or CLE. We found that the combined treatment significantly increased IL-1β release from P2X7-WT macrophages compared to the two stimuli administered separately. On the whole, our results demonstrate that CLE can effectively positively modulate P2X7 function, suggesting new opportunities for its therapeutic exploitation.

Multiple sclerosis is a chronic demyelinating disorder of the central nervous system characterized by neuroinflammation, oxidative stress, axonal injury, and progressive loss of myelin. Although currently available disease-modifying therapies effectively suppress immune activity, their ability to promote remyelination and neurological recovery remains limited. Clemastine fumarate (CMF), a first-generation antihistamine, has demonstrated remyelinating potential through the promotion of oligodendrocyte maturation, whereas selenomethionine (SLM), a selenium-containing antioxidant, may attenuate oxidative stress and inflammatory injury. As these agents target distinct yet complementary pathological mechanisms, their combined therapeutic potential in MS remains unexplored. Therefore, the present study investigated the neuroprotective and remyelinating effects of CMF and SLM, administered individually or in combination, in an ethidium bromide (EMBE)-induced demyelination model in adult Wistar rats (n = 8/group). Following ICP EMBE administration, animals received CMF (20 or 40 mg/kg, i.p.), SLM (5 mg/kg, i.p.), or combination treatment for 28 days. Behavioral, neurochemical, inflammatory, oxidative stress, apoptotic, and histopathological parameters were evaluated together with PI3K, Akt, and mTOR protein expression. EMBE administration produced marked motor and cognitive deficits, neurotransmitter imbalance, oxidative stress, neuroinflammation, apoptotic alterations, altered PI3K, Akt, and mTOR protein expression and extensive demyelination. Treatment with CMF and SLM significantly attenuated these pathological changes, with combination therapy producing the greatest overall benefit. Treatment was further associated with normalization of altered PI3K, Akt, and mTOR protein expression and substantial preservation of myelin integrity. CMF and SLM thus appear to exert complementary neuroprotective and remyelinating effects, CMF principally promoting oligodendrocyte-mediated remyelination and SLM limiting oxidative and inflammatory injury that together converge on the PI3K/Akt/mTOR axis, supporting simultaneous dual-target intervention as a rational strategy for MS.

Depression is one of the most prevalent mental disorders worldwide. The limited clinical efficacy of current antidepressants highlights identifying new therapeutic targets. Emerging evidence suggests that dysfunction of oligodendrocyte lineage cells contributes to the pathophysiology of depression. Teneurin-4 (Tenm4), a transmembrane protein that promotes oligodendrocyte differentiation and myelination, has been implicated in psychiatric disorders in genome-wide association studies; however, its causal role remains unclear. To determine whether Tenm4 contributes to depressive-like behavioral phenotypes, we examined Tenm4 protein expression in mice exposed to repeated forced swimming stress and generated hippocampal Tenm4 knockdown (Tenm4KD) mice. Chronic stress reduced Tenm4 expression levels in the hippocampus. Mice with hippocampus-specific Tenm4KD exhibited depressive-like behaviors, accompanied by reduced hippocampal myelin basic protein. Importantly, administration of clemastine, a myelin formation promoter, inhibited the reduction of myelin and attenuated depression-like behavioral phenotypes. Immunohistochemical analysis showed that Tenm4KD significantly decreased the number of mature oligodendrocyte cells and increased in the number of oligodendrocyte precursor cells, without changes in the total number of oligodendrocyte lineage cells. This study provides the first evidence that hippocampal Tenm4 deficiency induces depression-like behavior phenotypes through impaired oligodendrocyte differentiation and promoting demyelination. Our results identify Tenm4 as a molecular regulator of stress-induced behavioral phenotypes and suggest that it might represent a potential therapeutic target for mood disorders associated with demyelination.

Chronic stress induces psychiatric disorders, including depression and anxiety, yet effective therapies remain limited. Myelin in adult brains undergoes dynamic remodeling through oligodendrocyte precursor cells (OPCs) differentiation into oligodendrocytes (OLs) and the degeneration of pre-existing myelin. However, how chronic stress alters myelin dynamics and whether this represents a therapeutic target remains unclear. Here, adult mice subjected to 4-h daily restraint for 2 weeks exhibited significant anxiety, depression, and social deficits. Histological examinations revealed reduced OPC and OL density, decreased c-Fos-positive neurons, and loss of synaptic proteins in the brains exposed to chronic stress. To understand the dynamic changes of myelin, cell-lineage labeling and tracing demonstrated that chronic stress exposure remarkably inhibited oligodendrogenesis in the medial prefrontal cortex (mPFC), motor cortex, hippocampus, and amygdala, as revealed by the NG2[CreERT]; Tau-mGFP line, but did not significantly change pre-existing myelin as revealed by a newly generated line for mature OLs and myelin. To explore the role of myelinogenesis changes, adult myelin formation was inhibited by Olig2 conditional knockout in OPCs, resulting in decreased neuronal synaptic proteins and activity, accompanied by anxiety and depressive-like behaviors. Conversely, enhancing myelinogenesis through conditional deletion of the M1R in OPCs of stressed mice resulted in higher number of c-Fos-positive neurons, elevated synaptic protein expression, and a partial reversal of the behavioral deficits. Importantly, treating the stressed animal with the pro-myelination drug clemastine phenocopied the effects of M1R deletion on histological and behavioral disorders. Together, our findings demonstrate that enhancing oligodendrogenesis represents a promising strategy to rescue CRS-caused behavioral disorders.

This narrative review synthesizes emerging evidence on experience-dependent myelin plasticity and its relevance for neurorehabilitation in persons with multiple sclerosis (MS). Building on foundational work demonstrating motor learning-induced neuroplasticity, we highlight growing recognition that myelination remains adaptable across the lifespan and may be harnessed to support motor relearning, neuroprotection, and remyelination in MS.

Medication burden in older patients with chronic kidney disease (CKD) is substantial, and simple medication counts are insufficient for identifying those at elevated risk of inappropriate prescribing. This study characterized medication burden by assessing the number of medications, potentially inappropriate medications (PIMs) and anticholinergic burden in dialysis and non-dialysis patients with CKD aged ≥ 65 years. This retrospective study included patients with a CKD diagnosis who had hospital contact at the Department of Nephrology, Aalborg University Hospital, Denmark, between January and December 2022. Patients were classified as receiving dialysis or not, and polypharmacy and hyper-polypharmacy were defined as ≥ 5 and ≥ 10 medications, respectively. PIMs were identified using the EU(7)-PIM list, and anticholinergic burden was evaluated using the ACB scale with a cut-off of ≥ 3 points. In total, 140 dialysis patients and 534 non-dialysis patients were included. Polypharmacy was present in all dialysis patients and in 83% of non-dialysis patients, whereas hyper-polypharmacy affected 89% and 56%, respectively. Dialysis patients had a higher median number of PIMs (3 vs. 2) and a greater proportion with an ACB score ≥ 3 (44% vs. 27%). Proton pump inhibitors (PPIs), opioids and non-benzodiazepine hypnotics (Z-drugs) were identified as common PIMs, whereas bladder antimuscarinics (tolterodine and solifenacin), sedating antihistamines (clemastine and promethazine) and antipsychotics with anticholinergic properties (quetiapine) were the most frequently used medications with strong anticholinergic properties. In conclusion, medication burden in patients with CKD is high, and incorporating PIMs and ACB scores may identify prescribing risks not captured by medication counts alone.