Neurochem. Int. [JOURNAL]
Sun
200 papers
Two phosphomimetic sites in the GABA transporter GAT1 C-terminus selectively regulate transporter interactions with distinct types of PDZ domains in vitro.
Koščová I, Baliova M, Jursky F
Neurochem Int · 2025 Nov · PMID 40992571 · Publisher ↗
The GABA transporter GAT1 is a membrane protein that participates in GABA signalling in the brain and certain peripheral tissues. GAT1 contains a C-terminal PDZ motif (-AYI), previously classified as a type II (ΦXΦ) moti...
The GABA transporter GAT1 is a membrane protein that participates in GABA signalling in the brain and certain peripheral tissues. GAT1 contains a C-terminal PDZ motif (-AYI), previously classified as a type II (ΦXΦ) motif, where PDZ interaction should depend on non-phosphorylatable hydrophobic (Φ) residues at PDZ positions 0 (I) and -2 (A). We recently found that a GAT1 C-terminal peptide unconventionally binds to the PDZ1 domain of syntenin-1 and to the PDZ2 domain of PSD95 by using different PDZ interaction schemes, specifically 0,-1 and 0,-3, respectively. In this work, we used phosphomimetic amino acid mutagenesis to investigate the role of phosphorylatable amino acids in the GAT1 C-terminus in binding to these two domains. The mutagenesis and molecular docking experiments suggested that phosphorylation of tyrosine 598 at PDZ position -1 might affect the interaction with the PDZ1 domain of syntenin-1, but it did not affect the interaction with the PDZ2 domain of PSD95. On the other hand, a phosphomimetic but not a neutral mutation of the remote serine residues 592 and 594 at PDZ positions -7 and -5, respectively, affected the interaction of the GAT1 PDZ motif with the PDZ2 domain of PSD95, but not with the PDZ1 domain of syntenin-1. These findings suggest the existence of at least two domain-specific GAT1 PDZ interaction modes regulated by two distinct potentially phosphorylatable serine and tyrosine residues in the GAT1 C-terminus.
The antidepressant venlafaxine induces upregulation of miR-92 and histological alterations in a chicken embryo model.
Kaplan-Arabaci O, Zosen D, Domanska D … +9 more , Bjørnstad S, Santini S, Karaca U, Haeckel JA, Dolva K, Dančišinová Z, Haugen F, Andersen JM, Paulsen RE
Neurochem Int · 2025 Nov · PMID 40983227 · Publisher ↗
Antidepressants are commonly prescribed for treating anxiety disorders and depression, including pregnant patients. These medications influence the absorption and metabolism of key neurotransmitters such as serotonin, no...
Antidepressants are commonly prescribed for treating anxiety disorders and depression, including pregnant patients. These medications influence the absorption and metabolism of key neurotransmitters such as serotonin, norepinephrine, and dopamine. However, many aspects of antidepressant function remain unclear, especially regarding their impact on neurodevelopment when used during pregnancy. To explore this, we employed a 3R-friendly chicken embryo model to investigate the cellular and molecular implications of antidepressants use. We focused on commonly used antidepressants for the study: escitalopram, which is a selective serotonin reuptake inhibitor; and venlafaxine, a serotonin and noradrenaline reuptake inhibitor, both of which are frequently prescribed during pregnancy. Drug distribution analysis showed that both antidepressant drugs reached clinical concentrations in the brain of developing chicken embryos and persisted for several hours. High-throughput miRNA-sequencing showed that venlafaxine upregulated 13 different miRNAs in the chicken cerebellum. Specifically, miR-92 and its human ortholog, miR-363, were significantly upregulated in chicken cerebellum and neuronally differentiated human SH-SY5Y cells, respectively. Neurite metrics showed a significant reduction in neurite outgrowth with venlafaxine, but not with escitalopram. Furthermore, venlafaxine caused histological alterations, such as increased white matter and reduced thickness of the cortical and molecular layer in the cerebellum. Both drugs reduced the thickness of the external granular layer and the number of mitotic events, impacting this crucial germinal zone of the brain. These findings highlight distinct neurodevelopmental effects of escitalopram and venlafaxine and raise awareness for potential adverse neurological effects in offspring exposed to antidepressants in utero.
Further characterisation of the intrastriatal 6-OHDA Parkinson's disease model with non-motor symptom replication and widespread catecholamine dysfunction in male mice.
Braun A, Racz J, Garg S … +1 more , Bobrovskaya L
Neurochem Int · 2025 Nov · PMID 40975293 · Publisher ↗
The 6-OHDA mouse model of Parkinson's disease is not well characterised, with variable dosages, injection sites and timeframes. This study further characterised the unilateral intrastriatal 8 μg 6-OHDA mouse model using...
The 6-OHDA mouse model of Parkinson's disease is not well characterised, with variable dosages, injection sites and timeframes. This study further characterised the unilateral intrastriatal 8 μg 6-OHDA mouse model using a four-week protocol, with replication of motor and some non-motor symptoms in male mice. Non-motor symptom replication included cognitive impairment and gastrointestinal dysfunction. Olfactory dysfunction and anxiety-like behaviour were unable to be replicated in this study. Parkinson's disease pathology, particularly non-motor pathology, was also investigated in this study which found the intrastriatal 6-OHDA lesion caused widespread catecholamine dysfunction outside of the nigrostriatal pathway, including the mesocortical and mesolimbic pathway. Proteins involved in neuroinflammation (GFAP), oxidative stress defence (SOD2) and synaptic proteins (SNAP25) were altered, as seen in Parkinson's disease pathology, in the brains of the 6-OHDA lesioned mice.
Schwann cells as a therapeutic target for amyotrophic lateral sclerosis: A TDP-43 focussed review.
Lewis KN, Gonsalvez DG, Turner BJ … +1 more , Barton SK
Neurochem Int · 2025 Nov · PMID 40975292 · Publisher ↗
Amyotrophic lateral sclerosis (ALS) is an incurable, lethal neurodegenerative disease and a proteinopathy with >97 % of cases characterised by pathological accumulation of TDP-43. TDP-43 is ubiquitously expressed and its...
Amyotrophic lateral sclerosis (ALS) is an incurable, lethal neurodegenerative disease and a proteinopathy with >97 % of cases characterised by pathological accumulation of TDP-43. TDP-43 is ubiquitously expressed and its pathological accumulation has now been identified in non-neuronal cells in both the central and peripheral nervous systems. Thus, the expansion to exploring other cells and their contribution to ALS pathogenesis may be the key to finding more effective treatments. Schwann cells are the myelinating cells of the peripheral nervous system, that encase neuronal axons to propagate action potentials, maintain neuronal health, and respond to neuronal activity in the extracellular environment. Despite Schwann cells being identified to exhibit aberrant TDP-43 proteinopathy in ALS patients, their role in disease remains elusive. Here, we review the potential contributions of Schwann cells to ALS as well as the prospective benefits of harnessing Schwann cells treat the disease.
Toxic Tango in Parkinson's Disease: A dance between αSyn and iron import, export and speciation.
Cosson T, Faller P, Pountney DL
Neurochem Int · 2025 Nov · PMID 40967508 · Publisher ↗
The intricate interplay between brain iron homeostasis and pathological α-Synuclein (αSyn) in Parkinson's Disease (PD) is still unclear. αSyn is the primary protein involved in disease progression and promotes cytotoxici...
The intricate interplay between brain iron homeostasis and pathological α-Synuclein (αSyn) in Parkinson's Disease (PD) is still unclear. αSyn is the primary protein involved in disease progression and promotes cytotoxicity by impairing dopamine synthesis, mitochondrial dysfunction and disrupts brain iron homeostasis. Iron has further revealed to induce αSyn aggregation however, the exact mechanism of interaction between iron and αSyn is uncertain. Many studies have demonstrated an imbalance of iron homeostasis in PD pathogenesis, including macroautophagy related to αSyn aggregate and accumulated ferritin degradation. Inducible ferritinophagy has been suggested as a possible therapeutic to combat raised ferritin levels and reinstate iron homeostasis however this may lead to increased ferroptosis. Despite limited knowledge of ferritinophagy induced ferroptosis in PD there is a possible link to neurodegeneration. This review aims to summarise the current understanding of the chemical interactions between iron and αSyn and possible binding affinities in biologically relevant models, while further highlighting αSyn's pathological role in neurodegeneration and aberrant iron homeostasis. Developing knowledge surrounding the complex interactions between αSyn and iron in PD will aid in possible therapeutic strategies to combat PD disease progression.
Clinically relevant infraorbital nerve deflation and chronic constriction injury models of trigeminal neuralgia display unifying mechanisms.
Satti S, Ramteke S, Chaganti S … +3 more , Padhy HP, Samanthula G, Dandekar MP
Neurochem Int · 2025 Nov · PMID 40939756 · Publisher ↗
BACKGROUND: Trigeminal neuralgia is a debilitating pain condition that occurs due to the deflation of trigeminal nerve. Herein, we developed clinically relevant trigeminal neuralgia model using a distal infraorbital trig...
BACKGROUND: Trigeminal neuralgia is a debilitating pain condition that occurs due to the deflation of trigeminal nerve. Herein, we developed clinically relevant trigeminal neuralgia model using a distal infraorbital trigeminal nerve chronic deflation injury (dIoN CDI) in male and female rats. The results were compared with an existing distal infraorbital nerve chronic constriction injury (dIoN CCI) model. METHODS: Pain-related assessments were conducted by von-Frey filaments, orofacial-pain assessment device (OPAD), grooming time and rat-grimace scale (RGS). Anxiodepressive-phenotypes were assessed by elevated-plus maze test (EPM), sucrose-preference test (SPT), forced-swim test (FST), splash test. Brain, trigeminal nerve, faeces and blood samples were collected for molecular analysis. RESULTS: Rats subjected to dIoN CCI and dIoN CDI surgery displayed a decrease in von-Frey threshold and lick number in OPAD. The grooming time and RGS also indicated development of pain. A significant decrease in sucrose consumption in male rats and less exploration of open arms in EPM test by female rats, indicated the development of chronic pain-generated anxiodepressive behaviors. In biomarkers analysis, dIoN CCI and dIoN CDI groups showed elevated expression of calcitonin gene-related peptide and substance P in spinal trigeminal nucleus and/or ganglia. These groups also showed enhanced levels of dopamine, acetylcholine, 5-HT, and corticosterone and decreased concentration of GABA and noradrenaline in frontal and somatosensory cortices, brainstem and plasma. We also noted altered levels of sex hormones, fecal short-chain fatty acids, and occludin expression in the colon. CONCLUSION: These results indicate that both trigeminal neuralgia models display unifying principles in male and female rats.
Developmental neuroplasticity enables recovery from anesthetic-induced synaptic perturbations in the immature brain.
Chen L, Zhang Z, Yang S … +13 more , Tang Y, Wang X, Li W, Yang L, Guo C, Fang S, Xiao W, Yan M, Li Y, Peng T, Li B, Zhang XM, Huang L
Neurochem Int · 2025 Nov · PMID 40930165 · Publisher ↗
General anesthetics are essential in pediatric medicine, yet concerns persist regarding their potential neurotoxic effects on the developing brain. Whether transient synaptic disruptions caused by anesthesia lead to long...
General anesthetics are essential in pediatric medicine, yet concerns persist regarding their potential neurotoxic effects on the developing brain. Whether transient synaptic disruptions caused by anesthesia lead to long-term deficits or are mitigated by endogenous plasticity remains unresolved. Here, we use longitudinal in vivo two-photon imaging in awake mice to investigate the structural and functional consequences of a single, clinically relevant exposure to sevoflurane at postnatal day 20. We find that sevoflurane induces transient behavioral hyperactivity and suppresses filopodia elimination. Remarkably, these effects are fully reversed within 24 h. Across a 10 days follow-up, we observe no persistent alterations in synaptogenesis, neuronal activity, motor learning, or anxiety-like behavior. Electrophysiological recording and calcium imaging further confirm the restoration of normal firing and synaptic transmission in layer 5 pyramidal neurons. These findings reveal a dual-phase recovery mechanism-acute plasticity followed by chronic convergence, highlighting the developing brain's intrinsic resilience to transient anesthetic insults. Our study redefines sevoflurane not as a source of irreversible neurotoxicity but as a temporary challenge that can be effectively buffered by developmental neuroplasticity, offering important reassurance for its continued use in pediatric anesthesia.
Dynamic interaction of oligodendrocyte precursor cells with other cell types in the central nervous system.
Li J, Qin S, Liu H … +4 more , Dai Z, Lan Z, Yuan Y, Su Z
Neurochem Int · 2025 Nov · PMID 40930164 · Publisher ↗
Traditionally, oligodendrocyte precursor cells (OPCs) were primarily regarded for their differentiation potential to mature oligodendrocytes that ensheath central nervous system (CNS) axons through myelin formation. Rece...
Traditionally, oligodendrocyte precursor cells (OPCs) were primarily regarded for their differentiation potential to mature oligodendrocytes that ensheath central nervous system (CNS) axons through myelin formation. Recent breakthroughs in single-cell sequencing and in vivo imaging technologies have revolutionized our understanding, revealing that OPCs engage in extensive dynamic interactions with diverse CNS cell populations during neurodevelopment, tissue homeostasis maintenance, and pathological microenvironment remodeling. Notably, while OPCs exhibit relatively conserved phenotypic signatures, their functional plasticity within heterogeneous microenvironments demonstrates significant spatial specificity and disease-context dependence. In this review, we will systematically sort out the molecular interaction mechanism between OPCs and neurons, astrocytes, microglia, and vascular endothelial cells, deeply analyze their dynamic functional profiles, and focus on discussing: (1) the fine-tuning regulatory model of neuronal circuits mediated by OPCs at the developmental stage (2) the bidirectional regulatory mechanism of OPCs involved in maintaining the metabolic-immune balance under homeostasis; (3) OPC functional reprogramming in the pathological process of multiple sclerosis, cerebral ischemia, etc. This review aims to consolidate current evidence into a cohesive perspective on OPC multimodal functions, evaluate non-myelinating contributions, and discuss promising therapeutic targets for neural regenerative medicine.
Multi-omics reveals changes in astrocyte fatty acid metabolism during early stages of Alzheimer's disease.
Zhong J, Li M, Dai Z … +1 more , Wan J
Neurochem Int · 2025 Nov · PMID 40889558 · Publisher ↗
BACKGROUND: Although astrocytes are known to contribute to Alzheimer's disease (AD) progression, their dynamic molecular alterations remain poorly characterized, particularly in early stages of the disease. METHODS: We p...
BACKGROUND: Although astrocytes are known to contribute to Alzheimer's disease (AD) progression, their dynamic molecular alterations remain poorly characterized, particularly in early stages of the disease. METHODS: We performed multi-omics profiling (transcriptomics, proteomics, spatial metabolomics) of astrocytes from APP/PS1 and WT mice to characterize dynamic changes during AD progression. To assess similar changes in early human AD, we analyzed single-nucleus RNA sequencing data from human samples. RESULTS: Transcriptomic analysis of astrocytes from APP/PS1 and WT mice at five time points (2, 4, 6, 9, and 12 months of age) showed notable gene expression differences at 6 months, with reduced activity in fatty acid metabolism pathways (e.g., PPAR signaling, biosynthesis of unsaturated fatty acids). An astrocyte-specific metabolic model confirmed these disruptions. Proteomic analysis corroborated this by showing decreased activity in pathways like butanoate metabolism and PPAR signaling. Spatial metabolomics of brain slices from APP/PS1 and WT mice highlighted fatty acid enrichment in the hippocampus and cortex, alongside differential metabolites specific to the AD mouse model. Single-cell RNA sequencing analysis of human brain samples further showed fatty acid metabolism abnormalities in astrocytes from early AD cases versus controls, emphasizing its role in AD progression. CONCLUSION: Our study identified abnormal fatty acid metabolism as an early feature of astrocytes in AD, suggesting an association between dysregulated fatty acid metabolism and disease progression.
Impaired lysosomal proteolysis in developing neurons induces protein aggregation and disrupts morphogenesis and neuromaturation.
Zhou Y, Fujiwara Y, Shirazaki M … +7 more , Tian X, Igarashi G, Yamauchi H, Imaizumi K, Hayakawa H, Miyoshi K, Katayama T
Neurochem Int · 2025 Nov · PMID 40889557 · Publisher ↗
Lysosomes play a central role in the degradation of intracellular substances. Through this degradative capacity, lysosomes contribute to biological homeostasis and are particularly critical for the maintenance and functi...
Lysosomes play a central role in the degradation of intracellular substances. Through this degradative capacity, lysosomes contribute to biological homeostasis and are particularly critical for the maintenance and function of neurons. Deficiencies in various lysosomal proteins cause a group of conditions known as lysosomal storage disorders, which often present with developmental delay and other neurological symptoms. In addition, defects in lysosomal function and the autophagic pathways that deliver intracellular substrates to lysosomes have been linked to neurodevelopmental disorders. However, the contribution of lysosomal degradative capacity to neurodevelopment has not been well appreciated. In this study, we aimed to examine the relationship between overall lysosomal proteolytic capacity and neuronal development using primary cultured neurons at early developmental stages. We found that lysosomal protein expression and proteolytic activity increased with neuronal maturation, suggesting that lysosomal proteolysis may play an important role in neuronal development. Treatment of cultured neurons with specific inhibitors of lysosomal proteases during development impaired morphogenesis, as indicated by a significant decrease in neurite length and complexity, along with decreased expression of neuronal lineage marker proteins. Furthermore, we observed that neurons with development impaired by lysosomal protease inhibition accumulated aggregated proteins-some of which were ubiquitinated-in the cytoplasm. These aggregates were enriched with various proteins related to neurodevelopment. These findings provide new insights into the previously underappreciated role of lysosomes in neuronal development.
Imbalance of NKCC1/KCC2 contributes to the pathogenesis of primary focal hyperhidrosis.
Zheng RJ, Lin NL, Zhang ML … +4 more , Qiu RQ, Yu FQ, Li X, Lin JB
Neurochem Int · 2025 Nov · PMID 40882919 · Publisher ↗
BACKGROUND: Primary focal hyperhidrosis (PFH) is characterized by excessive sweating in localized regions, significantly impacting patients' quality of life. The imbalance between sodium-potassium-chloride cotransporter...
BACKGROUND: Primary focal hyperhidrosis (PFH) is characterized by excessive sweating in localized regions, significantly impacting patients' quality of life. The imbalance between sodium-potassium-chloride cotransporter 1 (NKCC1) and potassium-chloride cotransporter 2 (KCC2) disrupts chloride ion homeostasis, potentially contributing to the pathogenesis of PFH. METHODS: Sweat gland tissues from 76 healthy controls and 76 PFH patients were collected. Expression levels of NKCC1 and KCC2 were assessed using quantitative real-time PCR and Western blotting. Primary sweat gland cells isolated from PFH patients (PFH-SG) and controls (NPFH-SG) were subjected to NKCC1 knockdown via lentiviral shRNA transfection. A hyperhidrosis mouse model was induced by intraperitoneal injection of pilocarpine hydrochloride, and mice were pretreated with the NKCC1 inhibitor bumetanide for one week. Sweat secretion, serum acetylcholine, and chloride ion concentrations were measured. Expression levels of aquaporin 5 (AQP5), brain-derived neurotrophic factor (BDNF), and neuregulin-1 (NRG-1) proteins were analyzed. RESULTS: PFH tissues showed significantly elevated NKCC1 and decreased KCC2 expression compared to controls, correlating with lower sweat chloride levels. NKCC1 knockdown in PFH-SG cells reduced elevated AQP5 expression. In vivo, bumetanide treatment markedly reduced sweat secretion, lowered serum acetylcholine, and restored chloride ion concentrations in hyperhidrosis mice. Furthermore, bumetanide treatment significantly decreased expressions of BDNF and NRG-1 in sympathetic ganglia axons, indicating attenuation of sympathetic hyperactivity associated with hyperhidrosis. NKCC1/KCC2 imbalance contributes significantly to PFH pathology. CONCLUSIONS: Bumetanide effectively improves this imbalance, reducing excessive sweating and modulating related neurotransmitter signaling, offering potential therapeutic avenues for PFH.
Transcranial direct current stimulation attenuates cerebral ischemia-reperfusion injury by inhibiting neuronal pyroptosis via Netrin-1.
Wang Y, Liu H, Li P … +9 more , Zhang Z, He Y, Chen Y, Peng Y, Wang B, Jiang L, Li C, Zhu Q, Niu L
Neurochem Int · 2025 Nov · PMID 40876786 · Publisher ↗
The significant role of pyroptosis in the early pathogenesis of ischemic stroke underscores the urgent need for effective management strategies. Transcranial direct current stimulation (tDCS), a noninvasive modality for...
The significant role of pyroptosis in the early pathogenesis of ischemic stroke underscores the urgent need for effective management strategies. Transcranial direct current stimulation (tDCS), a noninvasive modality for modulating brain activity, has been shown to confer neuroprotection by inhibiting neuroinflammation during the acute phase of stroke. However, the specific mechanisms underlying the effect of tDCS on neuronal pyroptosis remain largely unexplored. We established brain I/R injury in adult male Sprague Dawley rats through a middle artery occlusion (MCAO) model. tDCS treatment began 24 h after MCAO and lasts for 6 consecutive days. Evaluate neurobehavioral deficits through an improved Neurological Severity Score (mNSS), Western blot, immunofluorescence staining, TUNEL staining, transmission electron microscopy (TEM), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the expression of pyroptosis related proteins, cell morphology, and levels of inflammatory factors. The results showed that tDCS markedly reduced the levels of NLRP3 inflammasome-dependent pyroptosis proteins (NLRP3, ASC, cleaved-Caspase-1, and GSDMD-N), accompanied by a reduction in the number of cell membrane perforation and cell death related to pyroptosis. Moreover, tDCS increased the expression of NTN-1, which inhibited the activation of NLRP3 inflammasome through the peroxisome proliferator-activated receptor gamma (PPAR-γ)/nuclear factor kappa-B (NF-κB) signaling pathway. Knockdown of NTN-1 reversed the anti-pyroptosis and neuroprotective effect of tDCS. In conclusion, tDCS exerted neuroprotection by curbing neuronal pyroptosis through the NTN-1-mediated PPAR-γ/NF- κB pathway, and could be a useful strategy for ischemic stroke recovery.
Activation of the β-adrenoceptor by formoterol induces calcium-dependent exocytosis of synaptic vesicles at the neuromuscular junction in a sex-specific manner.
Santos KBS, de Castro Fonseca M, Teixeira GHM … +10 more , Sanches B, Guatimosim S, Rossi L, Verly PW, Pereira ES, Cavalcante W, Birbrair A, Bloise E, Tapia JC, Guatimosim C
Neurochem Int · 2025 Nov · PMID 40876785 · Publisher ↗
Increasing evidence suggests that the sympathetic nervous system profoundly interacts with skeletal muscle, influencing both muscle fiber function and composition. β-ARs, the predominant adrenergic receptor subtype in mu...
Increasing evidence suggests that the sympathetic nervous system profoundly interacts with skeletal muscle, influencing both muscle fiber function and composition. β-ARs, the predominant adrenergic receptor subtype in muscle fibers, have been shown to enhance protein synthesis, reduce protein degradation, facilitate muscle contraction and relaxation, and improve neuromuscular junction (NMJ) transmission upon activation. In this study, we investigated the effects of Formoterol, a highly selective β-adrenoceptors (β-AR) agonist, on the presynaptic terminal of motor neurons. We used myography, FM1-43 fluorescent dye assays, and transmission electron microscopy (TEM) to evaluate the NMJ following β-AR activation. We demonstrated that β-AR activation by Formoterol enhances muscle contractility and both spontaneous and evoked exocytosis of acetylcholine (ACh)-containing synaptic vesicles at the mouse diaphragm NMJ. Formoterol-induced morphological changes in diaphragmatic NMJs were consistent with increased exo-endocytic activity. Notably, Formoterol-evoked exocytosis displayed sexual dimorphism, with females showing a significantly milder response compared to males. In females, Formoterol-induced synaptic vesicles exocytosis was mediated solely by P/Q-type voltage-activated Ca channels, whereas in males, it involved both P/Q-type channels, transient receptor potential channel of the vanilloid subtype (TRPV) 1 calcium channels, and an additional, yet unidentified, component. Orchiectomized males exhibited responses to Formoterol similar to the females, whereas ovariectomy did not modify female drug responses, indicating that male hormonal environment orchestrates the sex-differences herein described. These findings not only highlight the importance of sex-specific mechanisms but also reveal a novel effect of β-AR activation directly on presynaptic terminals by Formoterol, enhancing exocytosis at the NMJ and thereby increasing neuromuscular transmission.
Decoding the role of mA RNA methylation regulators in psychiatric and substance use disorders.
Koo JS, Zhang H
Neurochem Int · 2025 Nov · PMID 40876784 · Full text
N6-methyladenosine (mA) is the most prevalent internal modification of eukaryotic mRNA and plays a crucial role in regulating gene expression. This dynamic and reversible epitranscriptomic mark responses to both environm...
N6-methyladenosine (mA) is the most prevalent internal modification of eukaryotic mRNA and plays a crucial role in regulating gene expression. This dynamic and reversible epitranscriptomic mark responses to both environmental and internal cues and influences RNA stability, splicing, translation, and localization. In the central nervous system, mA modifications are tightly regulated and critically involved in neural development, synaptic plasticity, learning, memory, and stress responses. These modifications are governed by a complex and responsive network of regulatory proteins, including writers (methyltransferases), erasers (demethylases), and readers (RNA-binding proteins). Emerging evidence indicates that dysregulation of mA regulators contributes to the pathophysiology of various psychiatric disorders. Altered expression or function of mA-related genes has been associated with neuroadaptive changes underlying conditions such as schizophrenia, depression, bipolar disorder, and substance use disorder. This review provides an overview of the molecular mechanisms of mA modification, highlights the roles of mA regulators in psychiatric disorders, summarizes recent findings, and discusses potential therapeutic strategies targeting m6A pathways. A better understanding of mA-mediated mechanisms may advance the diagnosis and treatment of neuropsychiatric conditions.
In vitro pharmacological activity of twenty-eight synthetic cannabinoid receptor agonists at the type 1 and 2 cannabinoid receptors.
Mercier G, Mohamed KA, Zagzoog A … +5 more , Cropper L, Ritchie B, Jin Z, Patel M, Laprairie RB
Neurochem Int · 2025 Nov · PMID 40876783 · Publisher ↗
Synthetic cannabinoid receptor agonists (SCRAs) are a class of novel psychoactive substances whose prevalence in illegal markets continues to grow. Δ-tetrahydrocannabinol (THC) is the primary intoxicating compound presen...
Synthetic cannabinoid receptor agonists (SCRAs) are a class of novel psychoactive substances whose prevalence in illegal markets continues to grow. Δ-tetrahydrocannabinol (THC) is the primary intoxicating compound present in cannabis and is well-known to behave as a partial agonist at both the type 1 and 2 cannabinoid receptors (CB1R, CB2R). Unlike THC, the SCRAs characterized to date generally behave as CB1R and/or CB2R full agonists. The high potency and full agonism of these ligands are thought to drive the toxicity of SCRAs, including psychoses, emesis, and tachycardia. In this study, twenty-eight compounds (including the reference ligands CP55,940 and THC) were evaluated for binding affinity, Gi protein-dependent inhibition of cAMP, and βarrestin2 recruitment in Chinese hamster ovary (CHO-K1) cells stably expressing either receptor. Radioligand binding results demonstrate a general lack of selectivity between cannabinoid receptor subtypes. In signaling assays, most compounds displayed the anticipated full agonism with low nanomolar potency characteristic of SCRAs. Many compounds displayed bias for the inhibition of cAMP over the recruitment of βarrestin2, and this was especially true at CB2R, where several compounds were inactive in the βarrestin2 recruitment assay. However, no clear structure-activity relationship emerged among the tested SCRAs that could account for their selectivity, potency, efficacy, or bias, although potential patterns are discussed herein. Overall, our data support growing evidence that the cannabinoid receptors accommodate a diverse range of ligands, and that compound function may be dictated by factors that are not yet well characterized, such as binding kinetics.
The potential of mulberry (Morus alba L.) leaf extract against pro-aggregant tau-mediated inflammation and mitochondrial dysfunction.
Lin TH, Tseng PH, Chen IC … +5 more , Lin CY, Lee MC, Chang KH, Lee-Chen GJ, Chen CM
Neurochem Int · 2025 Nov · PMID 40876782 · Publisher ↗
In Alzheimer's disease (AD), Tau aggregates trigger microglial activation to release inflammatory factors and cause mitochondrial dysfunction, oxidative stress, and neuronal damage. With abundant potent antioxidants, mul...
In Alzheimer's disease (AD), Tau aggregates trigger microglial activation to release inflammatory factors and cause mitochondrial dysfunction, oxidative stress, and neuronal damage. With abundant potent antioxidants, mulberry (Morus alba L.) leaf extract has the potential to treat diseases associated with neuroinflammation, mitochondrial dysfunction, and oxidative stress. This study examined the neuroprotective effects of a mulberry leaf extract against pro-aggregant Tau-mediated inflammation and mitochondrial dysfunction in SH-SY5Y cells expressing the ΔK280 Tau repeat domain (Tau). His-tagged ΔK280 Tau fibrils prepared from E. coli activated BV-2 microglia, as revealed by their altered morphology, increased nitric oxide production, and elevated ionized calcium binding adaptor molecule 1 (IBA1) and major histocompatibility complex 2 (MHCII) expression. The mulberry leaf extract suppressed the production of pro-inflammatory mediators, including NO, IL-1β, IL-6, and TNF-α, and the expression of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 (CASP1) in ΔK280 Tau fibril-stimulated BV-2 cells. Application of conditioned media collected from ΔK280 Tau fibril-activated BV-2 cells induced cellular inflammation in ΔK280 Tau-DsRed-expressing SH-SY5Y cells. The mulberry leaf extract protected these cells by suppressing lactate dehydrogenase (LDH) release, caspase-3 activity, NLR family pyrin domain-containing 1 (NLRP1), CASP1, IL-1β, IL-6, TNF-α, and reactive oxygen species as well as by enhancing neurite outgrowth. In addition, mulberry leaf extract increased mitochondrial membrane potential, lowered mitochondrial superoxide levels, and increased superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), and nuclear factor erythroid 2-related factor 2 (NRF2) levels in SH-SY5Y cells. In conclusion, mulberry leaf extract displayed neuroprotective effects by exerting anti-inflammatory and antioxidative activities to ameliorate pathological Tau-mediated mitochondrial dysfunction in a human Tau cell model. The results of this study support the notion that the mulberry leaf extract is a potential disease-modifying therapeutic agent for AD.
Targeting ferroptosis by electroacupuncture offers a therapeutic regimen for brain injury after ischemic stroke.
Li W, Li Q
Neurochem Int · 2025 Nov · PMID 40850332 · Publisher ↗
Ischemic stroke (IS), the most prevalent form of stroke, remains a significant healthcare challenge and imposes a considerable burden on affected individuals. Ferroptosis, a form of regulated cell death (RCD) characteriz...
Ischemic stroke (IS), the most prevalent form of stroke, remains a significant healthcare challenge and imposes a considerable burden on affected individuals. Ferroptosis, a form of regulated cell death (RCD) characterized by iron overload -induced lipid peroxidation, was identified as a contributor to induce cell death following brain injury after ischemic stroke. Targeting ferroptosis is a novel therapy regimen for IS. And seeking novel therapy is unmet need for IS. Electroacupuncture (EA) has been revealed to have neuroprotective effect against IS and recommended to treat IS by World Health Organization (WHO) for years, but the specific mechanism underlying EA-mediated neuroprotection is still elusive. Emerging evidences have shown that EA alleviates brain injury after ischemic stroke by inhibiting ferroptosis; however, the mechanism by which EA suppresses ferroptosis against IS has not been sufficiently clarified. In this review, we first summarizes the core molecular mechanism of ferroptosis, with an focus on interpret how ferroptosis leads to the genesis of brain injury after ischemic stroke and the novel regulation of ferroptosis during the brain injury after ischemic stroke. We then highlights our emphasize on the emerging evidences that have revealed EA inhibit ferroptosis and review their pharmacological mechanisms against brain injury after ischemic stroke. This review highlights EA as a novel therapeutic regimen for ischemic stroke by suppressing ferroptosis, synthesizing mechanistic insights into iron-dependent lipid peroxidation pathways, evaluating emerging experimental evidence of EA's neuroprotection, and proposing targeted clinical strategies to mitigate post-stroke brain injury.
Epitranscriptomic dysregulation in neurodegenerative diseases and its implications for disease pathology and mechanisms.
Shafik AM, Jin P
Neurochem Int · 2025 Nov · PMID 40845970 · Publisher ↗
RNA modifications, collectively referred to as the epitranscriptome, play a crucial role in regulating RNA metabolism, influencing key processes such as splicing, stability, localization, and translation. Increasing evid...
RNA modifications, collectively referred to as the epitranscriptome, play a crucial role in regulating RNA metabolism, influencing key processes such as splicing, stability, localization, and translation. Increasing evidence now links dysregulation of the epitranscriptome to neurodegenerative diseases. In this review, we focus on four RNA modifications and their influence on neurodegenerative pathways, including synaptic function, neuroinflammatory signaling, and stress granule formation. These findings highlight the complex and multifaceted roles that RNA modifications play in neurodegeneration, emphasizing their emerging potential as biomarkers and therapeutic targets.
Opioids induce constipation by prompting alpha-Synuclein hyperphosphorylation in the colonic myenteric plexus.
Jia B, Zhao Y, Ren X … +5 more , Zhang D, Jia H, Wang D, Wang L, Li J
Neurochem Int · 2025 Nov · PMID 40835100 · Publisher ↗
Opioid-induced constipation (OIC) is the most common gastrointestinal disorder associated with opioid use. It is linked to impaired neurotransmitter release. Alpha-Synuclein (α-Syn) plays a crucial role in maintaining ne...
Opioid-induced constipation (OIC) is the most common gastrointestinal disorder associated with opioid use. It is linked to impaired neurotransmitter release. Alpha-Synuclein (α-Syn) plays a crucial role in maintaining neurotransmitter homeostasis and regulating synaptic plasticity in the nervous system. However, its role in the disease progression remains unclear. In the present study, we investigated the impact of α-Syn hyperphosphorylation on colonic dysmotility and constipation symptoms using a Sprague-Dawley rat model of OIC. Our results suggest that α-Syn expression at the Ser129 phosphorylation site (pS129-α-Syn) is significantly increased in the colonic myenteric layer of OIC rats. Conversely, inhibiting pS129-α-Syn reversed the colonic dysmotility and increased the expression of synaptic functional proteins, such as Synapsin-1, Synaptotagmin-1, vesicle-associated membrane protein 2 (VAMP-2), and Syntaxin-1, as well as enteric neurotransmitter synthases, including neuronal nitric oxide synthase (nNOS) and adenosine triphosphate synthase (ATPB). Additionally, we found that opioids downregulate GSK3β protein expression at the Ser9 site by activating the μ-opioid receptors (MOR). This increases GSK3β kinase activity, ultimately inducing pS129-α-Syn overexpression. In summary, the development of OIC correlates with α-Syn hyperphosphorylation in myenteric plexus neurons in the colon. Opioids can inhibit synaptic vesicle trafficking and enteric neurotransmitter release via the GSK3β/α-Syn hyperphosphorylation signaling axis, ultimately leading to colonic dysmotility and constipation.
Combined supplementation of short-chain fatty acids reduces hyperphosphorylation of Tau at T181,T231 and S396 sites and improves cognitive impairment in a chemically induced AD mouse model via regulation of HDAC and Keap1.
Pu D, Jin Y, Wang L … +4 more , Wang R, Li L, Song Y, Han X
Neurochem Int · 2025 Oct · PMID 40812734 · Publisher ↗
Alzheimer's disease (AD) is characterized by the pathological hallmarks of β-amyloid deposition and Tau protein hyperphosphorylation, with memory loss and cognitive dysfunction as its primary clinical manifestations. The...
Alzheimer's disease (AD) is characterized by the pathological hallmarks of β-amyloid deposition and Tau protein hyperphosphorylation, with memory loss and cognitive dysfunction as its primary clinical manifestations. The incidence of AD has been progressively increasing in recent years. Short-chain fatty acids (SCFAs), key effector molecules in host-gut microbial interactions, play a crucial role in maintaining central nervous system homeostasis. In this study, AD mouse model was established via AlCl/D-gal induction. The effects of mixed SCFA intervention on spatial learning and memory in AD model mice were assessed using behavioral tests, including the Morris Water Maze. Levels of pro-inflammatory cytokines and activities of oxidative stress-related enzymes in brain and colon tissues were quantified using ELISA and commercial kits. Key protein expression levels were analyzed by Western blot, immunohistochemistry, and immunofluorescence. Results demonstrated that SCFAs significantly alleviated cognitive dysfunction in AD model, reduced Tau hyperphosphorylation at T181, T231 and S396 sites, suppressed pro-inflammatory cytokine release, and enhanced antioxidant capacity, but with no reversal in elevated Aβ levels in AD model. Mechanistically, SCFAs inhibited glial cell activation, upregulated MCT-1 and tight junction proteins in the blood-brain barrier and strengthened gut-brain barrier integrity, potentially regulating small molecule trans-barrier transport. Furthermore, examination of relevant protein expressions revealed that SCFAs activated HDAC1 and inhibited overexpressed HDAC3 and Keap-1 in AD mice model. These findings suggest that SCFAs may regulate epigenetic modifications in the brain of AD to exert neuroprotective effects. This study provides novel evidence supporting the potential of symbiotic microbe-derived SCFAs in alleviating AD.
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