Neurochem. Int. [JOURNAL]
Sun
200 papers
Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease.
Fujii K, Takeuchi T, Fujino Y … +5 more , Tanaka N, Fujino N, Takeda A, Minakawa EN, Nagai Y
Neurochem Int · 2025 Dec · PMID 41175945 · Publisher ↗
Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised....
Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an App knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated App knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.
Food restriction and amphetamine exposure synergistically enhance accumbal dopamine D1 receptor-mediated locomotor activity.
Lee S, Yoon HS, Kim JH
Neurochem Int · 2025 Dec · PMID 41161535 · Publisher ↗
Natural rewards such as food and drugs of abuse share the mesolimbic dopamine system, including the nucleus accumbens (NAcc), as a common neural pathway that influences appetite and addictive behavior. Ghrelin, an orexig...
Natural rewards such as food and drugs of abuse share the mesolimbic dopamine system, including the nucleus accumbens (NAcc), as a common neural pathway that influences appetite and addictive behavior. Ghrelin, an orexigenic hormone, acts synergistically with mesolimbic dopamine in this process. In the present study, we examined the effects of food restriction (FR) on plasma ghrelin levels and amphetamine (AMPH)-induced locomotor activity. Chronic FR (cFR) significantly enhanced AMPH-induced locomotor activity compared to normal feeding and acute FR (aFR), which was associated with increased plasma ghrelin and dopamine D1 receptor (D1R) expression levels in the NAcc. These effects were inhibited by either systemic or NAcc-specific administration of D1R or ghrelin receptor antagonists. Furthermore, rats under the aFR condition showed enhanced locomotor activity in response to intra-accumbal microinjection of the D1R agonist when pre-exposed to AMPH, whereas rats in the cFR condition showed these effects regardless of pre-exposures to either AMPH or saline. These results demonstrate that FR conditions interact with drugs of abuse via the accumbal ghrelin and D1R systems, thereby contributing to the expression of addictive behaviors. Notably, these findings suggest that dietary status should be considered during addiction treatment.
LC-MS/MS techniques for the analysis of steroid panel in human cerebrospinal fluid.
Skodova T, Vitku J, Bradac O … +4 more , Skalicky P, Bubenikova A, Kanceva R, Kolatorova L
Neurochem Int · 2025 Dec · PMID 41138917 · Publisher ↗
The metabolic processes within the brain are reflected in the cerebrospinal fluid (CSF). It is in close contact with the nervous system, which is both target and source of multiple steroids. The aim of our study was to d...
The metabolic processes within the brain are reflected in the cerebrospinal fluid (CSF). It is in close contact with the nervous system, which is both target and source of multiple steroids. The aim of our study was to develop and validate robust, sensitive LC-MS/MS methods with and without derivatization step for the analysis of unconjugated steroids from all major steroid classes in CSF. The validation of the method without derivatization was performed for ten C19- steroids (dehydroepiandrosterone (DHEA), 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, testosterone, epitestosterone, dihydrotestosterone, 11-hydroxytestosterone, 11-ketotestosterone and androstenedione), ten C21- steroids (cortisol, 11-deoxycortisol, 21-deoxycortisol, cortisone, corticosterone, 11-deoxycorticosterone, pregnenolone, progesterone, 17-hydroxyprogesterone, aldosterone) and three C18- steroids (estrone, estradiol, estriol). The method with derivatization is validated for determination of eleven C19- steroids (testosterone, 11-ketodihydrotestosterone, 11-hydroxytestosterone, DHEA, 7α-hydroxyDHEA, 7β-hydroxyDHEA, 7-ketoDHEA, androstenedione, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone) and six C21- steroids (cortisol, cortisone, corticosterone, pregnenolone, 17-hydroxypregnenolone, progesterone) in CSF. The method without derivatization is applicable for the determination of the majority of steroids in CSF, except for pregnenolone, 17-hydroxypregnenolone and DHEA, for which the derivatization method provides better sensitivity. When analyzing CSF samples of normal pressure hydrocephalus (NPH) patients, 11-ketodihydrotestosterone, epitestosterone, androsterone, epiandrosterone, 7β-hydroxyepiandrosterone, 7-ketoDHEA and 21-deoxycortisol were found to be below the LLOQ, suggesting that their presence is very limited. 17-hydroxypregnenolone, and 11-deoxycortisol were quantified for the first time, their CSF levels in NPH subjects are presented. We also observed significantly increased CSF levels of testosterone and 17-hydroxyprogesterone in men compared to women, both with NPH.
Astrocytic HIF-1α/VEGF induces endothelial PI3K/Akt activation to accelerate post-ischemic angiogenesis upon LCN2 inhibition.
Tian N, Li X, Jiang Y … +5 more , Deng J, Wang H, Guo B, Chen M, Liao R
Neurochem Int · 2025 Dec · PMID 41101646 · Publisher ↗
Therapeutic angiogenesis represents a pivotal yet underexplored avenue for functional recovery following cerebral ischemia. Although lipocalin-2 (LCN2) participates in neuropathological processes, its cell-type-specific...
Therapeutic angiogenesis represents a pivotal yet underexplored avenue for functional recovery following cerebral ischemia. Although lipocalin-2 (LCN2) participates in neuropathological processes, its cell-type-specific regulation of post-ischemic vascular remodeling remains unknown. Here, we demonstrate that CRISPR/Cas9-mediated C8D1A astrocyte-like cells-specific LCN2 knockout significantly enhances vascular network formation in endothelial co-cultures under oxygen-glucose deprivation/reperfusion (OGD/R). Clinically, elevated LCN2 (GDS4521 dataset) correlates with poor stroke prognosis. Functional analyses revealed that AAV-shRNA-mediated LCN2 knockdown in photothrombotic stroke mice reduced infarct volume, attenuated peri-infarct neuronal loss, increased peri-infarct vascular density, and improved neurobehavioral outcomes at 7 days post-ischemia. Mechanistically, transcriptomic profiling identified hypoxia-inducible factor 1α (HIF-1α) as the master regulator of ischemia-induced angiogenesis. Molecular docking confirmed LCN2-HIF1α interaction. Furthermore, LCN2 ablation unleashes a HIF-1α/VEGF signaling cascade in C8D1A astrocyte-like cells, which activates endothelial phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) via paracrine mechanisms to drive functional revascularization. These findings not only redefine ischemic pathophysiology but also pioneers LCN2 inhibition as a translational strategy to overcome the limitations of current pro-angiogenic therapies in cerebrovascular disease.
Psychotropic and neurodegenerative drugs modulate platelet activity via the PAF pathway.
Kosidou S, Zannas Z, Ofrydopoulou A … +2 more , Lambropoulou DA, Tsoupras A
Neurochem Int · 2025 Dec · PMID 41093133 · Publisher ↗
Mild psychiatric conditions such as anxiety and depression, as well as severe disorders like schizophrenia and neurodegenerative diseases, are increasingly recognized as systemic inflammatory conditions. Platelets posses...
Mild psychiatric conditions such as anxiety and depression, as well as severe disorders like schizophrenia and neurodegenerative diseases, are increasingly recognized as systemic inflammatory conditions. Platelets possess both hemostatic and immunomodulatory roles in these situations, with sharing key molecular pathways with the central nervous system, offering thus a valuable peripheral model for evaluating psychotropic drug effects. Platelet-activating factor (PAF), a potent thrombo-inflammatory mediator, has emerged as a potential link between the two systems, yet its involvement in drug responses remains understudied. This study systematically investigates the effects of psychotropic drugs (i.e. antidepressants, antipsychotics and anxiolytics), and neuroprotective (anti-Alzheimer's/Anti-Parkinson's) drugs on platelet aggregation, focusing on PAF-pathway in comparison to a control platelet agonist, ADP. Using ex vivo light transmission aggregometry, we determined IC values for each drug and analyzed the impact of selected drug combinations, in which the NSAID diclofenac was also included. Results revealed that most of the compounds assessed inhibited more effectively the PAF-induced aggregation of platelets compared to their effect on the ADP-pathway, with perphenazine showing the greatest anti-PAF potency. Several drug combinations, notably those including alprazolam and diclofenac, demonstrated significant synergistic effects. These findings suggest that commonly prescribed psychotropic drugs and medications for neurodegenerative disorders can influence platelet activity, mostly through the PAF-pathway, and that their interactions with NSAIDs may amplify their efficacy. Nevertheless, some drugs and their combinations induced lysis of platelets at much higher concentrations than their IC50 values, which stems safety concerns for their use.
Neuronal FSTL4 negatively regulates BDNF-mediated neuron-glioma interaction.
Sun Y, Xiao M, Wang X … +5 more , Xu Y, Chen A, Li B, Feng B, Tao B
Neurochem Int · 2025 Dec · PMID 41082941 · Publisher ↗
Gliomas exploit various molecular pathways to promote their survival, proliferation, and invasion. Recent studies reveal the complex neuron-glioma interaction and BDNF plays a major role in this interaction. However, it'...
Gliomas exploit various molecular pathways to promote their survival, proliferation, and invasion. Recent studies reveal the complex neuron-glioma interaction and BDNF plays a major role in this interaction. However, it's unclear whether and how the BDNF-mediated cross-talk between neurons and gliomas is regulated. FSTL4 is reported to negatively regulate BDNF maturation. Here, we hypothesized that neuronal FSTL4 may negatively regulate BDNF-mediated neuron-glioma cross-talk. By using a combination of approaches like chemogenetic activation of primary neurons and CRISPR knockout/activation of endogenous FSTL4, we show that activated primary neurons support the proliferation of co-cultured glioma cells and neuronal BDNF secretion mediates this neuron-glioma interaction via activating TrkB in glioma cells. In addition, this process is negatively regulated by neuronal FSTL4 as its CRISPR KO in primary neurons further supports the proliferation of co-cultured glioma cells. Importantly, CRISPR activation of endogenous FSTL4 expression in primary neurons results in impaired ability to support co-cultured glioma cells, highlighting the therapeutic potential of activating endogenous FSTL4 for glioma treatment. Taken together, our study shows that the FSTL4/BDNF/TrkB axis plays an essential role in fine-tuning the neuron-glioma interaction and targeting this interplay with CRISPR tools may help to develop novel therapeutic strategies.
Reprogramming activated astrocytes into GABAergic neurons to treat trigeminal neuralgia.
Xia S, Chen K, Li X … +3 more , Zou D, Wang M, Wang Y
Neurochem Int · 2025 Dec · PMID 41072852 · Publisher ↗
Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of...
Trigeminal neuralgia (TN) is the most common type of cranial neuralgia. Currently, there remains a significant gap in the availability of effective and safe treatment options in clinical practice. Transdifferentiation of proliferating activated astrocytes into inhibitory neurons is a potential therapeutic strategy for central nervous system diseases. GABAergic neurons are one of the most type of prevalent inhibitory neurons. This study aims to reprogram proliferating astrocytes in the spinal trigeminal subnucleus caudalis (SpVc) into GABAergic neurons, could improve neuronal excitation-inhibition balance, alleviate pain, which serve as a potential treatment for trigeminal neuralgia. A chronic constriction injury of the distal infraorbital nerve (CCI-dION) was induced in the infraorbital branch of the trigeminal nerve to create a rat model of TN. Adeno-associated viruses were used to overexpress transcription factors Sox2 and Mash1 in astrocytes. The changes in astrocytes and GABAergic neurons in the SpVc region were detected by immunofluorescence, Western blotting, qPCR, and electron microscopy. The mechanical pain threshold testing was used to assess rat TN. In the SpVc region of CCI-dION rats, astrocytes showed proliferation and activation, and the number of GABAergic neurons decreased significantly. Overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which - improved the mechanical pain threshold in CCI-dION rats. Furthermore, fluorocitrate-mediated astrocyte deactivation abolished both the neuronal reprogramming and the analgesic effects, underscoring the essential role of astrocytes in this process. These findings suggest that overexpressing Sox2 and Mash1 in astrocytes led to a significant transdifferentiation into GABAergic neurons, which significantly improved the mechanical pain threshold in CCI-dION rats. Thus, this approach has the potential to provide a new treatment for TN.
Regional and cell type-specific activation of the unfolded protein response after kainate injection in mice.
Nguyen LH, Nguyen LD, Dao DX … +4 more , Hattori T, Ishii H, Takarada-Iemata M, Hori O
Neurochem Int · 2025 Dec · PMID 41067391 · Publisher ↗
The unfolded protein response (UPR) is activated under different neuropathological conditions, such as brain ischemia, epilepsy, and neurodegeneration. We previously reported that a UPR transducer, activating transcripti...
The unfolded protein response (UPR) is activated under different neuropathological conditions, such as brain ischemia, epilepsy, and neurodegeneration. We previously reported that a UPR transducer, activating transcription factor 6 (ATF6), and its downstream molecular chaperones in the endoplasmic reticulum (ER) have neuroprotective properties against excitotoxicity. In this study, we examined the temporal and spatial changes in the UPR activation after administration of an excitotoxic reagent, kainate (KA), into mice. RT-qPCR revealed enhanced expression of UPR genes, with peaks either on day 1 or day 3 after intrahippocampal KA injection. The status of the UPR was analyzed using ER stress-activated indicator (ERAI)-transgenic mice, in which the spliced form of XBP-1, downstream of the IRE1 branch of the UPR, can be monitored. ERAI-derived GFP signals were strongly observed in CA3 neurons and moderately observed in dentate gyrus neurons, but not in CA1 neurons, after KA injection. A small portion of the activated astrocytes was also positive for ERAI signals. Further studies revealed that ERAI signals were observed in both the soma and dendrites of neurons in regions with enhanced neuronal activity and resistance to KA toxicity. These results suggest that the UPR may be associated with the neuronal activity and survival after KA injection.
Crossing the Borders: the amino acid transporter LAT1 (SLC7A5) in the Blood-Brain Barrier.
Scalise M, Scanga R, Console L … +5 more , Galluccio M, Marzano F, Magrì A, Pochini L, Indiveri C
Neurochem Int · 2025 Dec · PMID 41067390 · Publisher ↗
The blood-brain barrier is an anatomical structure responsible for controlling the flux of nutrients, metabolites, and xenobiotics into and out of the brain. This fundamental function is carried out through the coordinat...
The blood-brain barrier is an anatomical structure responsible for controlling the flux of nutrients, metabolites, and xenobiotics into and out of the brain. This fundamental function is carried out through the coordinated action of specific ion channels and membrane transporters belonging to the SLC and ABC superfamilies. Indeed, membrane transporter expression in the BBB is less redundant than in other parts of the body. Therefore, any alteration to one of these proteins may pose a threat to the brain. The fifth member of the SLC7 family, which is expressed at the BBB has been the subject of much research over the years. SLC7A5, also known as LAT1, is a plasma membrane transporter of essential amino acids, whose role in brain development is well recognised. The protein is expressed in the membranes of BBB vessels, neurons, and microglia, creating a connection between different areas of the human brain. LAT1 received significant attention in the context of brain tumor treatment, particularly for glioblastoma multiforme, a malignancy with a poor prognosis characterised by fatal relapses. Since several drugs are also substrates of LAT1, its expression at the BBB could be exploited to deliver drugs that target brain diseases. This review describes the functional, structural, and regulatory features of LAT1, focusing on pharmacology in the context of brain homeostasis.
Histone lactylation is associated with METTL3-dependent LCN2 mA modification and astrocyte activation after intracerebral hemorrhage.
Gao L, Zheng X, Tan C … +7 more , Peng L, Wang C, Zheng Z, Han J, Wang J, Yang Z, Chen W
Neurochem Int · 2025 Dec · PMID 41061931 · Publisher ↗
BACKGROUND: Intracerebral hemorrhage (ICH) is a major cause of secondary brain injury (SBI), which results in severe neurological deficits and poor clinical outcomes. Elevated serum lactate levels have been associated wi...
BACKGROUND: Intracerebral hemorrhage (ICH) is a major cause of secondary brain injury (SBI), which results in severe neurological deficits and poor clinical outcomes. Elevated serum lactate levels have been associated with unfavorable outcome in ICH patients. However, the role of lactate in ICH-induced SBI remain poorly understood. METHOD: An autologous blood injection mouse model of ICH and lactate-treated C8D1A cells were employed as the in vivo and in vitro models, respectively. The establishment of ICH model was validated by behavior tests, and brain injury was assessed by H&E and Nissel staining. qRT-PCR, Western blot and IHC analysis were used to detect the expression of key molecules. Immunofluorescent (IF) staining was employed to evaluate astrocyte activation. Pro-inflammatory cytokine release was monitored by ELISA assay. The interaction between H3K18la and METTL3 was assessed by ChIP assay, and the association between METTL3 and LCN2 mRNA was assessed by RNA immunoprecipitation (RIP) assay. RESULTS: The levels of lactate, METTL3 and LCN2 are elevated in ICH model in mice. The inhibition of lactate decreased METTL3 expression and alleviated ICH-induced SBI. Mechanistically, histone H3K18 lactylation was associated with the upregulated levels of METTL3 and mA in mouse brains. METTL3 regulated the mA modification of LCN2 and upregulated its expression. In ICH mice, silencing of LCN2 inhibited A1 astrocyte activation. Histone lactylation-modulated LCN2 mA modification is involved in astrocyte activation and the regulation of SBI in ICH mice. CONCLUSION: These results suggested a mechanism whereby histone lactylation is implicated in the activation of A1 astrocytes through METTL3-mediated LCN2 mA modification.
Differences in presynaptic hippocampal GABAergic terminals at the early stage of life in female and male mice: effect of an acute early inflammatory challenge.
Benatti C, Roggeri A, Toscano Y … +5 more , Torre V, Brunello N, Tascedda F, Blom JMC, Pittaluga A
Neurochem Int · 2025 Nov · PMID 41052678 · Publisher ↗
GABA dictates the efficiency of synaptic connection, influencing its developmental complexity, but its role is tuned by developmental sex differences which affect the efficiency of its innervation. We investigated the ef...
GABA dictates the efficiency of synaptic connection, influencing its developmental complexity, but its role is tuned by developmental sex differences which affect the efficiency of its innervation. We investigated the efficiency of mechanisms of GABA storage and exocytosis in hippocampal terminals of male and female mice during the juvenile period (PND21), adolescence (PND36) or adulthood (PND90). The expression of mRNA encoding for the presynaptic GABA transporter type 1, (GAT1) and the vesicular GABA transporter (VGAT1) was analysed. A significant scaling-down in the GAT1 mRNA levels (SLC6A1) was detected at PND21 in both sexes until adulthood, while the SLC32A1-VGAT mRNA level was conserved. We also analysed the density of GAT1 and VGAT proteins. Western blot analysis unveiled the presence of a monomeric and an oligomeric form of GAT1. The density of the monomeric form was conserved at the different stages of development in both sexes. Differently, the oligomeric assembly was significantly overexpressed in hippocampal synaptosomal lysates from PND21 male and female mice, but recovered at PND36. VGAT density was largely conserved in PND21 and PND36 male hippocampal synaptosomal lysates when compared to adult particles, but significantly lower in PND21 female particles. Notably, these changes are consistent and support the altered vesicular storage of newly taken-up [H]GABA detected in PND21 male and female hippocampal synaptosomes as well as the different responsiveness of GABAergic male and female synaptosomes to increasing depolarizing stimuli (12, 20 and 30 mM KCl-enriched solutions) measured as efficiency of the [H]GABA exocytosis. Interstingly, an acute LPS treatment affects the efficiency of GABA exocytosis at PND36 in a sex-dependent manner. These results add new knowledge on the role of GABA as effector of central inhibitory plasticity at the early stage of development and its relevance in dimorphic adaptation in physio pathological conditions.
TREM2 deficiency aggravates neuroinflammatory response and cognitive impairment via disease-associated microglia in Parkinson's disease models.
Zhang P, Zhu B, Feng J … +7 more , Liang X, Huang P, He C, Deng Y, Lu J, Wang L, Zhang Y
Neurochem Int · 2025 Dec · PMID 41047022 · Publisher ↗
This study explores whether Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) regulates the distinct disease-related microglia (DAM) phenotype and exerts a protective role in cognitive impairment in Parkinson's di...
This study explores whether Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) regulates the distinct disease-related microglia (DAM) phenotype and exerts a protective role in cognitive impairment in Parkinson's disease (PD). Adeno-associated virus carrying TREM2 shRNA (AAV-TREM2-shRNA) was injected into the bilateral hippocampus of the A53T α-Synuclein (α-Syn) transgenic PD mouse model; Additionally, lentivirus was transduced into BV2 microglial cells to knock out the expression of TREM2, which were subsequently stimulated with α-Syn preformed fibrils (PFF). Furthermore, cognitive status of mice, α-Syn aggregation, microglia status, expression of inflammatory factors, pro-inflammatory and anti-inflammatory DAM markers, MAPK and NF- κB pathway activation status and neuron apoptosis were evaluated. TREM2 deficiency induced cognitive impairment in A53T α-Syn PD mice by decreased performance in the novel objective recognition and Morris water maze tests. TREM2 knockdown resulted in synaptic loss, microglial activation, increased inflammatory factors, and MAPK and NF- κB pathway activation in the hippocampus of mice. In vitro, TREM2 deficiency exacerbated the inflammatory response of BV2 cells stimulated by α-Syn PFF by inhibiting anti-inflammatory DAM, and promoting neuronal apoptosis and Ser129-phosphorylation of α-Syn. TREM2 knockdown also promoted pro-inflammatory DAM activation and increased inflammatory factors expression via the ERK1/2 signaling pathway. Our findings suggest that TREM2 plays a protective role in cognitive impairment and promotes anti-inflammatory DAM activation via the ERK1/2 signaling pathway in PD mice, providing novel insight into the immunopathogenesis of cognitive impairments in PD.
Functional effects of heavy metal exposures on N6-methyladenosine (m6A) methylation and other Epitranscriptomic modifications in the central nervous system.
Lodhi N, Powell L, Schneider JS
Neurochem Int · 2025 Nov · PMID 41046059 · Full text
Among different RNA methylations, N6-methyladenosine (m6A) is the most abundant in the brain and determines the fate of RNA through reversible processes using methyltransferases, demethylases, and methyl-binding proteins...
Among different RNA methylations, N6-methyladenosine (m6A) is the most abundant in the brain and determines the fate of RNA through reversible processes using methyltransferases, demethylases, and methyl-binding proteins. The reversibility of m6A is an emerging regulatory mechanism for gene expression, regulating many aspects of RNA metabolism and influencing learning and memory processes. Global m6A profiles are dynamically modified via the activity of various writers, readers, and erasers. However, m6A alterations from exposure to heavy metals, including the metals lead (Pb), cadmium (Cd), cobalt (Co), and manganese (Mn) and the metalloid arsenic (As), and the impact on brain function, are not fully understood. This paper reviews recent work that may begin to shed light on how heavy metal exposures may affect m6A methylation and how this might impact central nervous system functioning.
Manganese stimulates ferroptosis to trigger neurotoxicity in mice and HT22 cells: the role of NCOA4-mediated ferritinophagy.
Tao Z, Zhang X, Chen J … +12 more , Hu J, Wang S, Xing G, Ngeng NA, Malik A, Appiah-Kubi K, Farina M, Skalny AV, Tinkov AA, Aschner M, Yang B, Lu R
Neurochem Int · 2025 Nov · PMID 41043778 · Publisher ↗
Manganese (Mn), an essential trace element for physiological functions, can induce neurotoxicity through iron-dependent oxidative stress mechanisms when present in excess. This study reveals that Mn triggers ferroptosis...
Manganese (Mn), an essential trace element for physiological functions, can induce neurotoxicity through iron-dependent oxidative stress mechanisms when present in excess. This study reveals that Mn triggers ferroptosis in neural cells via nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Using in vivo (Mn-exposed mice) and in vitro (hippocampal HT22 cells) models, we demonstrated that Mn exposure disrupts iron homeostasis, elevating brain iron accumulation and downregulating ferroptosis-protective proteins (SLC7A11 and GPX4). The ferroptosis inhibitor ferrostatin-1 effectively counteracted Mn-induced cell death, whereas the extracellular iron chelator deferoxamine showed limited protection. Crucially, NCOA4 knockdown significantly mitigated Mn-induced iron overload and cell viability loss, outperforming deferoxamine. These findings establish ferritinophagy as a central mechanism in Mn neurotoxicity and highlight the therapeutic potential of targeting intracellular iron regulation over extracellular chelation. Our work provides a mechanistic foundation for developing interventions against Mn-associated neurodegenerative disorders.
MUSASHI1 promotes tau phosphorylation by activating the p38 MAPK pathway.
Li W, Ma B, Tian X … +4 more , Xiong Q, Zhou M, Liu W, Shu X
Neurochem Int · 2025 Nov · PMID 41038390 · Publisher ↗
Aberrant phosphorylation of the Tau protein represents a critical event in the pathogenesis of Alzheimer's disease (AD); however, therapeutic interventions specifically targeting this modification remain limited. Therefo...
Aberrant phosphorylation of the Tau protein represents a critical event in the pathogenesis of Alzheimer's disease (AD); however, therapeutic interventions specifically targeting this modification remain limited. Therefore, a thorough understanding of the molecular mechanisms underlying Tau hyperphosphorylation is essential for the development of effective preventive and therapeutic strategies against AD. The RNA-binding protein MUSASHI1 (MSI1) is recognized for its significant role in neurodevelopment, and previous studies have reported its dysregulated overexpression in the brains of AD patients. In the current investigation, we demonstrate that MSI1 expression progressively increases in parallel with the advancement of Tau pathology in P301S transgenic mouse models. Furthermore, our findings suggest that MSI1 activates the p38 mitogen-activated protein kinase (MAPK) signaling pathway, thereby promoting Tau phosphorylation. Additionally, we have identified two microtubule-associated proteins as novel potential interaction partners of MSI1 within neuronal cells. Collectively, these results reveal a previously uncharacterized mechanism that may contribute to aberrant Tau phosphorylation in AD, offering new directions for future research in this field.
Spinal p38 MAPK/PGC-1α/SIRT3 signaling pathway mediates remifentanil-induced hyperalgesia in rats via ROS release and NR2B activation.
Feng G, Song F, Wang A … +6 more , Wang L, Zhang H, Wang S, Hou H, Zhang L, Deng L
Neurochem Int · 2025 Nov · PMID 41016638 · Publisher ↗
Remifentanil-induced hyperalgesia (RIH) poses a significant clinical challenge. Our research group has previously confirmed that abnormal activation of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal dorsal...
Remifentanil-induced hyperalgesia (RIH) poses a significant clinical challenge. Our research group has previously confirmed that abnormal activation of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal dorsal horn contributes to RIH, but the specific regulatory pathway remains unclear. It is known that p38 MAPK can regulate the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and the PGC-1α/Sirtuin 3 (SIRT3) pathway plays an important role in various pain models. However, whether this pathway is involved in RIH remains to be elucidated. In this study, an RIH model was established using male Sprague-Dawley (SD) rats, and significant hyperalgesia was observed in the RIH group. Intrathecal injection of the p38 MAPK inhibitor SB203580 or the PGC-1α agonist ZLN005 significantly alleviated this hyperalgesic response. Mechanistic analysis further revealed that in the RIH model group, activation of p38 MAPK was increased in spinal dorsal horn microglia, while the expression of PGC-1α and SIRT3 were decreased. In neurons, reactive oxygen species (ROS) levels were increased, accompanied by increased expression of the N-methyl-d-aspartate receptor (NMDAR) subunit NR2B, synaptic structural remodeling, and an increase in the amplitude and frequency of NMDAR-mediated spontaneous excitatory postsynaptic currents (sEPSCs). All these pathological changes could be reversed by intervention with either SB203580 or ZLN005. In conclusion, this study demonstrates that remifentanil activates p38 MAPK in spinal dorsal horn microglia, inhibits the PGC-1α/SIRT3 signaling pathway, promotes ROS release, subsequently activates the neuronal NR2B subunit, and ultimately induces RIH. This mechanism provides a new potential target for the treatment of RIH.
SPP1 expression after spinal cord compression injury and its effects on glial cell activation.
Lei L, Wang X, Zhao J
Neurochem Int · 2025 Nov · PMID 41015119 · Publisher ↗
PURPOSE: To study the role and mechanism of SPP1 in spinal cord injury. METHODS: We created a rat model of spinal cord compression injury (SCI) and examined the expression of SPP1 in spinal cord tissue using western blot...
PURPOSE: To study the role and mechanism of SPP1 in spinal cord injury. METHODS: We created a rat model of spinal cord compression injury (SCI) and examined the expression of SPP1 in spinal cord tissue using western blotting and immunofluorescence staining. We assessed motor function and pathological repair in SCI rats using the BBB locomotor scale, swimming tests, HE staining, Nissl staining, myelin staining, immunofluorescence, and western blot experiments. Additionally, we examined microglial activation and inflammatory phenotypes to analyze underlying mechanisms. To determine if SPP1's effects are linked to MK2, we used the MK2 inhibitor PF-364402. RESULTS: After spinal cord injury, the expression level of SPP1 exhibited a significant increase, peaking on the third day post-injury. A co-localization relationship was noted with Iba-1-labeled microglia. Reduced SPP1 expression enhanced motor function recovery and aided in spinal cord tissue repair after injury in mice. Low SPP1 expression modulated glial cell inflammation, reducing the iNOS-labeled pro-inflammatory phenotype and increasing the Arg-1-labeled anti-inflammatory phenotype. This modulation subsequently inhibited the activation of microglia. Furthermore, we validated the inhibitory effect of low SPP1 expression on the activation of the MK2 signaling pathway, which was associated with a reduction in the phosphorylation levels of MK2, p38, and NF-κB. CONCLUSION: This study found that SPP1 was highly expressed in rats with spinal cord injury and was associated with microglial activation and inflammatory phenotype transformation. Low levels of SPP1 promoted neural repair and motor function recovery, which may be related to the MK2 pathway.
Genetic and epigenetic architectures of stroke: Insights from GWAS to precision medicine.
Shehjar F, Mahajan R, Shahnaz S … +1 more , Shah ZA
Neurochem Int · 2025 Nov · PMID 41005670 · Full text
Stroke remains a leading cause of death and disability, driven by complex interactions among genetic, epigenetic, and environmental factors. Advances in genomic technologies have elucidated the role of common polygenic v...
Stroke remains a leading cause of death and disability, driven by complex interactions among genetic, epigenetic, and environmental factors. Advances in genomic technologies have elucidated the role of common polygenic variants and rare monogenic mutations in determining susceptibility to stroke subtypes. Genome-wide association studies have identified key loci, including Histone Deacetylase 9 (HDAC9), Paired-like Homeodomain Transcription Factor 2 (PITX2), Zinc Finger Homeobox 3 (ZFHX3), and Collagen Type IV Alpha 1 Chain (COL4A1), associated with vascular inflammation, atrial fibrillation, and small vessel dysfunction. Monogenic disorders such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL; NOTCH3), Fabry disease (GLA), and Sickle Cell Disease (SCD; HBB) illustrate the impact of single-gene mutations on early-onset or familial stroke. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) regulate pathways related to apoptosis, inflammation, angiogenesis, and blood-brain barrier dysfunction. Pharmacogenomic profiling, involving genes such as CYP2C19, VKORC1, and SLCO1B1, can guide individualized therapy with antiplatelets, anticoagulants, and statins. Collectively, these advances are steering stroke care toward precision medicine, integrating multi-omics data and gene-targeted strategies for improved prevention, diagnosis, and treatment.
Constant light exposure promotes pathogenic tau hyperphosphorylation and phenotypic manifestations in Drosophila disease models.
Aggarwal P, Virender, Sarkar S
Neurochem Int · 2025 Nov · PMID 41005669 · Publisher ↗
Chronic sleep disruption caused by constant artificial light exposure has emerged as both a comorbidity and a precursor of several neurodegenerative disorders, including tauopathies. Tauopathies, a group of neurodegenera...
Chronic sleep disruption caused by constant artificial light exposure has emerged as both a comorbidity and a precursor of several neurodegenerative disorders, including tauopathies. Tauopathies, a group of neurodegenerative disorders, are characterised by the toxic accumulation of hyperphosphorylated tau in brain neurons. While disturbance in the sleep/wake cycle is an inherent clinical feature of tauopathies, the impact of prolonged light exposure on disease progression and severity has been inadequately investigated. We utilized Drosophila models of human tauopathies to examine the impact of uninterrupted exposure to light on tau-induced phenotypic markers during pathogenesis over a short period of aging. We observed that constant light exposure causes an earlier onset and increased severity of disease-associated phenotypes in an age-dependent manner. We further noted that these aggravated phenotypes are associated with increased pathogenic hyperphosphorylation of tau, leading to the rapid accumulation of relatively larger neurotoxic aggregates in neuronal cells and their subsequent degeneration. Overall, our study demonstrates that unhealthy light exposure accelerates the early onset and severity of tauopathy-related phenotypes, highlighting its potential relevance in developing management strategies for these devastating neurodegenerative disorders.
Neuronutritional enhancement of antioxidant defense system through Nrf2/HO1/NQO1 axis in fibromyalgia.
Inferrera F, Tranchida N, Fusco R … +10 more , Cuzzocrea S, Impellizzeri D, Siracusa R, D'Amico R, Rashan L, Badaeva A, Danilov A, Calabrese V, Di Paola R, Cordaro M
Neurochem Int · 2025 Nov · PMID 40997946 · Publisher ↗
Fibromyalgia (FM) is a disorder characterized by chronic widespread musculoskeletal pain, and it is often accompanied by fatigue, sleep disturbance, and cognitive dysfunction. Although pathophysiology is multifactorial,...
Fibromyalgia (FM) is a disorder characterized by chronic widespread musculoskeletal pain, and it is often accompanied by fatigue, sleep disturbance, and cognitive dysfunction. Although pathophysiology is multifactorial, increasing evidence highlights the pivotal role of oxidative stress and mitochondrial dysfunction in the development of this condition. In particular, the Nrf2/HO-1/NQO1 antioxidant axis plays a crucial role in counteracting oxidative damage and maintaining cellular homeostasis. Boswellia (BS) is a genus of plants in the Burseraceae family, which includes around twenty species found across sub-Saharan Africa, the Arabian Peninsula, and the Indian subcontinent. In Ayurvedic medicine, it has traditionally been used in the treatment of diabetes, fever, as well as certain cardiovascular, dermatological, and neurological conditions. Boswellic acids are thought to possess anti-inflammatory, anti-rheumatic, and pain-relieving properties. The purpose of this study was to investigate the beneficial effects of BS extract in a murine model of reserpine-induced FM. Following reserpine administration, markers of oxidative stress, neuroinflammation, and behavioral changes including mechanical allodynia, hyperalgesia, anxiety, and depression-like behaviors were significantly increased. Daily oral administration of BS at a dose of 100 mg/kg effectively restored these pathological changes. BS oral supplementation, by preventing microglia and astrocyte activation, as demonstrated by decreased GFAP and Iba-1 expression, BS decreased neurological inflammation and restored neurotransmitter levels such as norepinephrine, dopamine and serotonin. Futhermore, improved antioxidant defenses by increasing nuclear translocation of Nrf2 and subsequent expression of its downstream targets, HO-1 and NQO1, limiting lipid peroxidation and ROS production. According to behavioral tests, BS significantly reduced the emotional deficit and mechanical sensitivity linked to FM. Our findings indicate that BS integration has neuroprotective effects, acting on oxidative stress and neuroinflammation, and suggesting that it is a viable natural strategy for managing FM symptoms.
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