Neurochem. Res. [JOURNAL]
Sun
200 papers
Centratherin Exhibits Antitumor Activity Against Glioblastoma Cells.
Mafra de Faria B, Leme da Silva Pinheiro F, Medeiros I … +9 more , Lobo JFR, Teixeira AM, Machado Rocha L, Borges RM, Rossi MID, de Andrade LC, Pontes B, Dubois LG, Romão LF
Neurochem Res · 2026 Feb · PMID 41653375 · Full text
Glioblastoma (GB) is the most aggressive and lethal primary brain tumor, characterized by high proliferative, migratory, and invasive capacities, as well as marked resistance to apoptosis. Despite standard therapy with t...
Glioblastoma (GB) is the most aggressive and lethal primary brain tumor, characterized by high proliferative, migratory, and invasive capacities, as well as marked resistance to apoptosis. Despite standard therapy with temozolomide (TMZ), prognosis remains poor, underscoring the need for novel therapeutic strategies. In this study, we investigated the antitumor potential of centratherin, a sesquiterpene lactone, in established GB cell lines and patient-derived GB cells (GBM02, GBM95). Centratherin significantly reduced cell viability in a dose-dependent manner, with IC50 values varying across GB cells, while exhibiting no cytotoxicity to healthy human astrocytes. Functional assays revealed that centratherin impairs cell proliferation, migration, and invasion, and alters cytoskeletal architecture, as evidenced by morphological changes, reduced actin and tubulin organization. Additionally, centratherin induced double-strand DNA breaks, increased γH2AX levels, and triggered cell death predominantly via necrosis, as demonstrated by LIVE/DEAD staining, Annexin V/PI flow cytometry, and ultrastructural analysis. Notably, this cytotoxic effect did not involve necroptosis, as RIP1 expression and Nec-1 sensitivity were unchanged. Furthermore, centratherin failed to sensitize GB cells to TMZ, suggesting distinct mechanisms of action, in spite of its remarked effect on inducing cell death in GB cancer stem-like cells. Overall, our findings highlight centratherin as a promising selective cytotoxic agent against GB, capable of inducing cell death and disrupting key malignant phenotypes, which may be advantageous for GB treatment.
4-Phenylbutyrate Induces Functional Elongation of the Microglial Process Through Activation of Akt.
Dai T, Dai Q, Ding Y … +11 more , Su J, Huang C, Yang R, Peng J, Chen Z, Song R, Fang Y, Wang H, Ye M, Wang J, Lu X
Neurochem Res · 2026 Feb · PMID 41653373 · Publisher ↗
Conversion of microglia to a branching state is considered a potential strategy to ameliorate neuroinflammation. Inhibition of histone deacetylases (HDACs) may convert microglia to a branching state and thus prevent neur...
Conversion of microglia to a branching state is considered a potential strategy to ameliorate neuroinflammation. Inhibition of histone deacetylases (HDACs) may convert microglia to a branching state and thus prevent neuroinflammation. Drugs that inhibit HDACs could be used to alleviate neuroinflammation. Here, we hypothesize that 4-phenylbutyric acid (4-PBA), an HDAC inhibitor, could shift microglia to an anti-inflammatory phenotype by promoting microglial process elongation. As expected, our results showed that 4-PBA induced reversible elongation of branching processes in primary cultured mouse microglia and in microglia in the prefrontal cortex of mice. Pretreatment with 4-PBA also prevented lipopolysaccharide (LPS)-induced shortening of branching processes in microglia under both in vitro and ex vivo conditions, LPS-induced pro-inflammatory responses in cultured microglia and prefrontal cortex, and LPS-induced sickness behavior in mice. Short-term incubation with 4-PBA led to a significant increase in phosphorylation levels of protein kinase B (Akt) in cultured microglia. 4-PBA did not induce microglial process elongation in vitro or ex vivo when cultured microglia or mice were treated with the Akt signaling inhibitor LY294002, suggesting that the pro-elongation effect of 4-PBA on microglial processes require activation of Akt signaling. Moreover, 4-PBA did not prevent LPS-induced inflammatory responses in cultured microglia and prefrontal cortex or LPS-induced sickness behaviors when cultured microglia or mice were treated with LY294002. Altogether, these results indicate that 4-PBA induces microglial process elongation in an Akt-dependent manner, which may underlie the anti-neuroinflammatory properties of 4-PBA.
Decanoic Acid Treatment Alleviates Non-cell Autonomous Transfer of HD Pathology by Secretome of Mutant Huntingtin Expressing Cells.
Mehta R, Dabhi R, Singh S … +2 more , Shah A, Vijayvargia R
Neurochem Res · 2026 Feb · PMID 41653326 · Publisher ↗
Huntington’s disease (HD) is a fatal neurodegenerative disorder marked by progressive neuronal loss with prominent degeneration of the striatum. Although classically viewed as a cell-autonomous disorder, emerging evidenc...
Huntington’s disease (HD) is a fatal neurodegenerative disorder marked by progressive neuronal loss with prominent degeneration of the striatum. Although classically viewed as a cell-autonomous disorder, emerging evidence suggest non-cell-autonomous spread of the pathology but without clear mechanistic details. In this study, we demonstrate that the secretome of a truncated mHTT expressing HD150Q cells contains soluble, aggregated, and exosome-associated mHTT species that are efficiently internalized by wild-type striatal neuronal cells. This led to hallmark HD-like dysfunctions including suppressed mitochondrial biogenesis regulators (Bdnf, Nrf1), depleted ATP, and elevated mitochondrial and cytosolic ROS, consistent with bioenergetic collapse and redox stress. Further, secretome exposure activated the unfolded protein response, repressed DRD1α/DRD2–BDNF transcriptional circuitry and reduced neuronal viability. Fractionation experiments demonstrated that both aggregated and vesicle associated mHTT species were pathogenic, exerting independent yet additive bioenergetic toxicity. Strikingly, peripheral immune cells exposed to the same secretome exhibited a robust pro-inflammatory response, mirroring systemic immune activation seen in HD patients. These findings establish mHTT-containing secretome as a transmissible pathogenic entity capable of reprogramming both neuronal and immune cells. Importantly, we show that treatment of donor HD cells with decanoic acid (C10:0)—a medium-chain fatty acid, abolishes the secretome’s pathogenic effect on both neuronal and immune cells. Together, our results establish extracellular mHTT as a mechanistically sufficient and pharmacologically targetable driver of disease spread. Importantly, this work provides proof-of-concept that pharmacological modulation of the secretome using decanoic acid represents a promising strategy for limiting propagation and progression of Huntington’s disease.
HCG18 is a Potential Pathogenic Factor and Diagnostic Biomarker Alzheimer's Disease.
Chen P, Li G, Cheng L … +2 more , Liu Y, Liu Y
Neurochem Res · 2026 Feb · PMID 41653257 · Publisher ↗
Alzheimer's disease (AD), a major neurodegenerative disorder, lacks effective early diagnostic and therapeutic strategies. This study aimed to investigate the diagnostic utility of Long non-coding RNAs HLA Complex Group...
Alzheimer's disease (AD), a major neurodegenerative disorder, lacks effective early diagnostic and therapeutic strategies. This study aimed to investigate the diagnostic utility of Long non-coding RNAs HLA Complex Group 18 ( HCG18) in AD and elucidate its molecular mechanisms in neuronal injury. Eighty-three AD patients and 83 healthy controls (HC) were enrolled. Serum samples were analyzed for HCG18 expression using qRT-PCR and cerebrospinal fluid (CSF) samples were analyzed for AD biomarkers by ELISA. Diagnostic performance was assessed using ROC analysis. Aβ1-42-treated HT22 cells (Immortalized murine hippocampal neuronal-like cell line) were employed to model neuronal injury, with HCG18 knockdown and miR-425-3p inhibition experiments conducted to validate functional interactions. HT22 cell apoptosis, oxidative stress markers (SOD, GSH-Px, MDA, ROS), and HCG18/miR-425-3p interactions were evaluated through flow cytometry, biochemical assays, and dual-luciferase reporter systems. Serum HCG18 levels were significantly elevated in AD patients compared to HC (P < 0.001), exhibiting strong diagnostic accuracy (AUC = 0.889). HCG18 expression correlated negatively with CSF Aβ1-42 (r=-0.709) and MMSE scores (r=-0.657), but positively with t-tau (r = 0.591) and p-tau181 (r = 0.582). In Aβ1-42-treated HT22 cells, HCG18 knockdown reduced apoptosis, suppressed ROS, and normalized oxidative stress markers. Mechanistically, HCG18 directly bound to and acted as a molecular sponge for miR-425-3p, sequestering its function; the downregulation of miR-425-3p mediated by a synthetic inhibitor reversed the protective effects of HCG18 silencing. HCG18 serves as a potential non-invasive biomarker for AD, exacerbating neuronal injury via sponging miR-425-3p to disrupt redox balance. Targeting the HCG18/miR-425-3p axis may offer new therapeutic strategies for AD.
G9a Targeting by miR-122 Ameliorates Ischemic Brain Injury via Enhanced Microglial Autophagy and Suppressed Ferroptosis.
Wu Y, Shan W, Lan H … +5 more , Xu Q, Duan G, Zhong G, Li X, Wu J
Neurochem Res · 2026 Feb · PMID 41632357 · Publisher ↗
Microglia are crucial in ischemic brain injury (IBI). Modulating microglial autophagy and inhibiting ferroptosis via miR-122 targeting G9a may mitigate disease progression. This study investigated whether miR-122 attenua...
Microglia are crucial in ischemic brain injury (IBI). Modulating microglial autophagy and inhibiting ferroptosis via miR-122 targeting G9a may mitigate disease progression. This study investigated whether miR-122 attenuates IBI progression by targeting G9a to promote microglial autophagy and inhibit ferroptosis. In vivo, a transient middle cerebral artery occlusion (tMCAO) rat model received intracerebroventricular injections of agomiR-122 for miR-122 overexpression or AAV-G9a for G9a overexpression to assess miR-122/G9a roles in autophagy and ferroptosis. In vitro, oxygen-glucose deprivation/reperfusion (OGD/R)-treated BV2 cells were transfected with miR-122 mimic, oe-G9a, and treated with rapamycin (RA) or ferrostatin-1 (Fer-1) to delineate the miR-122/G9a-autophagy-ferroptosis axis. A microglia-hippocampal neuronal cell transwell co-culture system assessed HT22 viability to confirm miR-122-mediated neuroprotection via G9a inhibition. In vivo, miR-122 ameliorated neurological deficits and attenuated brain injury in tMCAO rats by negatively regulating G9a. This was accompanied by enhanced autophagy (e.g., increased LC3-II/I ratio) and suppression of ferroptosis (e.g., upregulation of GPX4) and inflammatory responses. In vitro, agomiR-122 in OGD/R-injured BV2 cells promoted cell viability and autophagy, while inhibiting ferroptosis. These effects were reversed by AAV-G9a but rescued upon treatment with RA or Fer-1. Moreover, in a BV2-HT22 co-culture system, agomiR-122 in microglia conferred neuroprotection, an effect that was abolished by G9a upregulation. MiR-122 ameliorates IBI by targeting G9a to enhance microglial autophagy and suppress ferroptosis, offering mechanistic insights and novel therapeutic targets.
Ciprofol Promotes SIRT1-Mediated Raf Regulation of ERK1/2 Hyperphosphorylation.
Wang J, Lin J, Liu L … +4 more , Liu S, Xie Z, Jiang S, Huang H
Neurochem Res · 2026 Jan · PMID 41591531 · Publisher ↗
Epilepsy (EP) is characterized by sudden abnormal discharges of neurons in the brain. Its complex pathological mechanisms limit effective treatment strategies. In recent years, Ciprofol, as a novel 2,6-disubstituted phen...
Epilepsy (EP) is characterized by sudden abnormal discharges of neurons in the brain. Its complex pathological mechanisms limit effective treatment strategies. In recent years, Ciprofol, as a novel 2,6-disubstituted phenol derivative, has attracted extensive attention due to its unique molecular structure and diverse biological functions. This study aims to investigate the mechanism by which Ciprofol exerts anti-temporal lobe epilepsy (TLE) effects: specifically, Ciprofol upregulates SIRT1 (a NAD+-dependent deacetylase) expression to trigger its deacetylase activity, thereby downregulating Raf (an upstream factor of MAPK/ERK pathway) and further modulating ERK phosphorylation in the MAPK/ERK signaling pathway. Behavioral analysis showed that Ciprofol significantly reduced the severity of acute seizures in kainic acid (KA)- and pentylenetetrazol (PTZ)-induced acute TLE mouse models. Further molecular biology experiments, using techniques such as electrophysiological recordings, Western blotting, metabolomics, transcriptome sequencing, and qPCR, revealed that Ciprofol decreased the amplitude of induced excitatory postsynaptic currents (EPSCs) in the hippocampus and significantly downregulated the expression levels of postsynaptic NMDA2B and NMDA2A receptor proteins; transcriptome sequencing indicated prominent enrichment of MAPK/ERK pathway-related genes; LC-MS (metabolomics) showed GABA release remained unchanged while glutamate (Glu) levels were significantly reduced. LC-MS measurements demonstrated that GABA release remained unchanged following Ciprofol treatment, while glutamate (Glu) levels were significantly reduced. In addition, bubble plot analysis indicated that the MAPK/ERK signaling pathway was prominently involved in Ciprofol’s anti-epileptic effects.Further pharmacological interventions confirmed the critical role of the MAPK/ERK signaling pathway. Administration of the ERK1/2 inhibitor Ulixertinib and experiments using ERK1/2-specific knockout mice significantly enhanced the anti-epileptic effects of Ciprofol. In contrast, treatment with the broad-spectrum ERK1/2 activator Okadaic Acid markedly weakened these effects. These results further validated the key role of ERK1/2 in the MAPK/ERK signaling pathway in mediating the anti-temporal lobe epilepsy effects of Ciprofol. Moreover, this study identified that SIRT1 regulates the expression of the upstream factor Raf through its deacetylation activity, thereby influencing the phosphorylation state of ERK1/2 in the MAPK/ERK signaling pathway. Therefore, for the first time, this study elucidated that Ciprofol exerts anti-TLE effects by upregulating SIRT1 to mediate Raf deacetylation and inhibit ERK1/2 hyperphosphorylation in the MAPK/ERK pathway—directly linking Ciprofol, SIRT1, and anti-epileptic action. Ciprofol exerts its antiepileptic effects on temporal lobe epilepsy by mediating the downregulation of Raf expression through SIRT1, thereby modulating the excessive phosphorylation of ERK1/2 in the MAPK/ERK signaling pathway. This, in turn, reduces neuronal eEPSCs and the release of excitatory neurotransmitters.
Noninvasive Focused Ultrasound as a Safe Modulator of Calcium-Dependent Neurochemical Signalling in Primary Cortical Cultures.
Bano I, Jorratt P, Kútna V … +2 more , Pala J, Tsenov G
Neurochem Res · 2026 Jan · PMID 41579319 · Full text
Focused ultrasound stimulation (FUS) is a promising non-invasive neuromodulation technique that can influence neuronal activity through mechanical stimulation. In this study, primary cortical neurons were isolated from e...
Focused ultrasound stimulation (FUS) is a promising non-invasive neuromodulation technique that can influence neuronal activity through mechanical stimulation. In this study, primary cortical neurons were isolated from embryonic rat brains and cultured for 14 days in vitro before being divided into Control, FUS 5 V, and FUS 10 V groups. Cells were exposed to low-intensity pulsed FUS (300 kHz, 10 min) using a vertically mounted transducer positioned 5 mm above the culture dish. Post-exposure analyses included cell viability using the MTS assay, total protein quantification by the Bradford method, morphological assessment by Trypan Blue staining, and Fluo-3 AM-based confocal calcium imaging. FUS treatment produced no significant differences in viability or total protein concentration compared with the Control group. Morphological observations confirmed healthy neuronal somata and intact neuritic networks across all groups, with no evidence of cell death or structural damage compared with controls. In contrast, calcium imaging revealed a robust transient elevation in intracellular Ca²⁺ responsiveness when assessed 24 h after FUS exposure, with a significantly higher integrated area under the curve relative to Control. These findings demonstrate that low-intensity FUS safely enhances intracellular calcium signalling while preserving neuronal viability, protein integrity, and morphology, defining a safe acoustic window for non-destructive neuromodulation and providing a framework for mechanistic studies in neurodegenerative disease models.
Plasma-Derived Exosomal hsa-miR-3677-3p Induces Ferroptosis in Neurons by Targeting ABCB8 in Perioperative Neurocognitive Disorders After Prostate Surgery.
Sun Y, Zuo Y, Zhang J … +3 more , Wu Y, Xia X, Liu J
Neurochem Res · 2026 Jan · PMID 41578037 · Full text
Perioperative neurocognitive disorders (PND) are prevalent complications in elderly patients following surgery, characterized by cognitive decline and memory impairment. This study investigates the contribution of plasma...
Perioperative neurocognitive disorders (PND) are prevalent complications in elderly patients following surgery, characterized by cognitive decline and memory impairment. This study investigates the contribution of plasma-derived exosomal microRNA hsa-miR-3677-3p to PND pathogenesis via ABCB8 regulation and subsequent induction of neuronal ferroptosis. Exosomes were isolated from plasma of patients with delayed neurocognitive recovery (dNCR) and non-dNCR patients. Characterization confirmed successful exosome isolation, revealing distinct microRNA profiles between the two groups. MicroRNA sequencing identified 69 differentially expressed microRNAs, with hsa-miR-3677-3p significantly upregulated in dNCR patients. Functional enrichment analysis implicated these microRNAs in mitochondrial function and nervous system development. In vitro overexpression of hsa-miR-3677-3p mimicked the pathological phenotype, leading to downregulation of ABCB8, which resulted in iron dyshomeostasis and oxidative stress, marked by reduced antioxidant capacity, intracellular iron accumulation, elevated malondialdehyde (MDA), a decreased glutathione/glutathione disulfide (GSH/GSSG) ratio, and increased mitochondrial lipid peroxidation (MitoPerOx). Treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) attenuated these alterations, restoring mitochondrial function and reducing oxidative damage. Taken together, our findings indicate that exosomal hsa-miR-3677-3p modulates ABCB8-mediated ferroptosis in neurons, highlighting a novel insight into PND pathogenesis and potential therapeutic strategies.
Metformin Ameliorates Cognitive Deficits and Neuroinflammation in a Mouse Model of Familial Hypercholesterolemia.
do Nascimento NB, Farias HR, Schons T … +13 more , Padilha APZ, Costa MV, Peres AM, da Silva LDS, Dantas RM, Ramos JMO, Rodrigues MS, Telles F, Guma FTCR, Moreira JCF, Bast RKSS, de Bem AF, de Oliveira J
Neurochem Res · 2026 Jan · PMID 41578026 · Full text
Familial hypercholesterolemia (FH), caused by mutations in the low-density lipoprotein receptor (LDLr) gene, has been increasingly associated with neurodegenerative and mood disorders. Studies with LDLR knockout mice (LD...
Familial hypercholesterolemia (FH), caused by mutations in the low-density lipoprotein receptor (LDLr) gene, has been increasingly associated with neurodegenerative and mood disorders. Studies with LDLR knockout mice (LDLr) showed that neuroinflammation is a key event in FH-related brain dysfunction. Because mTOR inhibition has been shown to mitigate brain alterations in this model, we hypothesized that metformin, a drug reported to influence cellular energy metabolism, could attenuate FH-associated brain changes. To test this, adult LDLr mice received daily oral doses of metformin (200 mg/Kg) or vehicle for 30 days. During the final week, behavioral assessments were conducted, including the open-field test, novel object recognition and object reallocation tasks, and the tail suspension test (depressive-like behavior). Body weight, total cholesterol and glucose plasma levels were analyzed. Hippocampal astrocyte and microglial density, as well as the expression of genes related to neuroinflammation and synaptic plasticity, were evaluated. Metformin did not alter total cholesterol levels but significantly improved cognitive performance and reduced depressive-like behavior. The treatment also attenuated hippocampal astrogliosis without affecting microglial reactivity. Molecular analysis revealed reduced hippocampal TGF-β gene expression and increased PSD-95 gene expression and protein content in metformin-treated LDLr mice. Although a slight, non-significant reduction in the phosphorylated-to-total mTOR ratio was detected, no clear evidence of AMPK/mTOR pathway modulation was observed. Overall, metformin improved memory function and astrocyte reactivity in LDLr mice independently of cholesterol reduction and without demonstrable involvement of the AMPK/mTOR pathway, suggesting its potential as a therapeutic strategy for FH-associated brain dysfunction.
Harnessing Endogenous Neural Stem Cells: A New Frontier in Spinal Cord Injury Repair.
Jia M, Wu W, Zhang H … +6 more , Fu Q, Liu Y, Lin X, Huang K, Teng H, Huang Z
Neurochem Res · 2026 Jan · PMID 41577872 · Publisher ↗
Spinal cord injury (SCI), a serious neurological condition caused by trauma, inflammation, infection, or vascular diseases, potentially causing partial or complete loss of sensory and motor function, and in severe cases,...
Spinal cord injury (SCI), a serious neurological condition caused by trauma, inflammation, infection, or vascular diseases, potentially causing partial or complete loss of sensory and motor function, and in severe cases, may lead to paralysis. The global incidence of SCI is rising annually, with a significant increase observed in China. The ependymal region of the spinal cord, containing endogenous neural stem cells (ENSCs), is recognized for its potential in neural regeneration and functional recovery after SCI. Cells lining the central canal of the spinal cord can develop into neurons, astrocytes, and oligodendrocytes, which are essential for repairing SCI. The present manuscript delves into the cellular origins, distribution, heterogeneity, and the potential therapeutic applications of ENSCs, offering insights into novel clinical interventions for SCI based on endogenous regenerative capabilities.
The Cell-Specific Effects of the Human Remyelination-Promoting rHIgM22 on Sphingolipid Metabolism in Cultured Glial Cells.
Grassi S, Prioni S, Marchesini A … +2 more , Cappelletti G, Prinetti A
Neurochem Res · 2026 Jan · PMID 41577839 · Publisher ↗
Demyelinating diseases are heterogeneous in their etiology, clinical course, and manifestations. In the long run, however, they lead to irreversible dysfunction of the nervous system. Although myelin regeneration occurs...
Demyelinating diseases are heterogeneous in their etiology, clinical course, and manifestations. In the long run, however, they lead to irreversible dysfunction of the nervous system. Although myelin regeneration occurs in response to myelin damage in both animal models of demyelination and human patients, the outcome is usually less favorable in humans. This explains the interest in treatments that could improve the effectiveness of myelin regeneration. Among these, treatment with the monoclonal antibody rHIgM22 has been shown to effectively enhance myelin regeneration in both immune and non-immune mouse models of demyelination. Its administration to patients with multiple sclerosis was well tolerated, and it was detected in the cerebrospinal fluid, suggesting penetration of the central nervous system. Previously, we demonstrated that administering rHIgM22 to rat mixed glial cultures alters the balance between ceramide and sphingosine 1-phosphate (S1P), thereby inducing S1P release and astrocyte and oligodendrocyte precursor cell (OPC) proliferation. In this paper, we studied the effects of rHIgM22 treatment on the lipid composition of purified glial cultures from the rat brain, including astrocytes, OPC, and oligodendrocytes (OL) at various stages of in vitro differentiation. rHIgM22 did not affect the phospholipid composition of any of the analyzed cell types. A steady-state metabolic labeling procedure revealed that sphingolipid patterns were unaffected by rHIgM22 treatment in astrocytes. However, rHIgM22 treatment significantly increased the levels of GM3 and GD3 gangliosides in oligodendroglial cells. The increase in GM3 and GD3 versus controls was highest in fully differentiated OL. We also detected a slight but significant reduction in cholesterol levels and in vitro acid sphingomyelinase activity in these cells. Acid sphingomyelinase is a key enzyme in sphingolipid metabolism. Thus, the effect of rHIgM22 on lipid metabolism is cell-specific among different glial populations. We hypothesize that the myelin regeneration effects of rHIgM22 could result from alterations in lipid-dependent membrane organization in oligodendroglial cells.
Exploring the Therapeutic Potential of N-(3,4-dimethoxy phenyl)-6,7-dimethoxyquinazoline-4-amine (TKM01) in Aluminium-Induced Alzheimer's Disease-Like Model of Zebrafish.
Kashif M, Chandrabose K, Pandurangan AK
Neurochem Res · 2026 Jan · PMID 41563627 · Publisher ↗
Aluminum (Al), a pervasive environmental neurotoxicant, has been strongly implicated in the onset and progression of Alzheimer's disease (AD)-like pathology. Chronic and sub-chronic exposure to aluminum chloride (AlCl) i...
Aluminum (Al), a pervasive environmental neurotoxicant, has been strongly implicated in the onset and progression of Alzheimer's disease (AD)-like pathology. Chronic and sub-chronic exposure to aluminum chloride (AlCl) induces cognitive deficits, oxidative stress, cholinergic dysfunction, neuroinflammation, and neuronal damage, making it a widely used agent for modeling AD in preclinical research. This study aimed to evaluate the neuroprotective efficacy of TKM01, a novel 4-anilinoquinazoline derivative, in an AlCl-induced AD-like zebrafish model. Adult zebrafish were exposed to AlCl (11 mg/L for 15 days) and pre-treated with TKM01 at two concentrations (240 and 480 µg/mL). Behavioral assessments, including the T-maze, novel object recognition (NOR), and open field test (OFT), demonstrated significant improvements in spatial learning, recognition memory, and reduced anxiety-like behavior in TKM01-treated groups. Biochemical analyses revealed decreased acetylcholinesterase (AChE) activity and lipid peroxidation (LPO), alongside elevated antioxidant enzyme activities, including superoxide dismutase (SOD) and catalase (CAT). ELISA showed a reduction in pro-inflammatory cytokines (TNF-α and IL-1β), and RT-PCR analysis confirmed downregulation of NLRP3, ASC, and caspase A gene expression. Furthermore, histopathological examination revealed that TKM01 mitigated AlCl-induced neuronal degeneration, edema, and cellular disorganization in brain telencephalon. Additionally, molecular docking and 200 ns molecular dynamics simulations supported stable and favorable binding interactions between TKM01 and IL-1β/ASC. Collectively, these findings suggest that TKM01 attenuates AlCl-induced neurotoxicity via antioxidant, anti-inflammatory, anticholinesterase, and neuroprotective mechanisms. TKM01 emerges as a promising multifunctional therapeutic candidate for AD, warranting further investigation in mammalian models.
Nuclear and Cytoplasmic Mouse ID Associated 1 (MIDA1) Protein Varies in Neurons and Astrocytes Across the Different Hippocampal Regions and Exhibits Age-Related Changes.
Cuellar-Santoyo AO, Ruiz-Rodríguez VM, Patrón-Soberano A … +6 more , Hernández-Balderas K, Galindo-Martínez CA, Vargas-Antillón AB, Niño SA, Jiménez-Capdeville ME, Estrada-Sánchez AM
Neurochem Res · 2026 Jan · PMID 41563529 · Publisher ↗
Nuclear Mouse ID Associated 1 (MIDA1), also known as Hsp40/DNAJC2 and ZRF1, plays a key role in the establishment of neural progenitors in the brain. In the cytoplasm, MIDA1 ensures proper protein folding, which, if disr...
Nuclear Mouse ID Associated 1 (MIDA1), also known as Hsp40/DNAJC2 and ZRF1, plays a key role in the establishment of neural progenitors in the brain. In the cytoplasm, MIDA1 ensures proper protein folding, which, if disrupted, can lead to protein misfolding and ultimately neurodegeneration. Thus, MIDA1 is crucial for maintaining brain cell homeostasis. However, it remains unclear whether neurons and astrocytes express MIDA1 equally, whether the distribution of MIDA1 between the nucleus and cytoplasm differs, and if this difference changes with age. Therefore, we evaluated MIDA1 content and distribution in neurons and astrocytes of the CA1, CA3, and dentate gyrus (DG) in 3- and 12-month-old mice. The results indicated that, relative to the nucleus, cytoplasmic MIDA1 content is higher in neurons and astrocytes at both ages. An overall reduction of MIDA1 in the nucleus of neurons was noted with age, while the three-month-old mice displayed increased cytoplasmic MIDA1. In contrast, astrocytes exhibited similar levels of MIDA1 in the nucleus across the hippocampal regions analyzed. However, astrocytes from the CA1 and CA3 regions in the 12-month-old group showed increased cytoplasmic MIDA1 content. Lastly, a comparison of MIDA1 immunofluorescence between neurons and astrocytes revealed that astrocytes exhibit lower nuclear MIDA1 levels at both ages. Notably, at 12 months, cytoplasmic MIDA1 levels were higher in astrocytes than in neurons. Given that MIDA1 function depends on its subcellular location, our results suggest that MIDA1 undergoes more dynamic changes in the cytoplasm across different hippocampal areas, becoming more pronounced in astrocytes at 12 months. Thus, the chaperone role of MIDA1 may be particularly crucial as astrocytes and neurons age, coinciding with the appearance of age-related cognitive deficits detected in the novel object recognition test.
Metabolic Alterations Induced by a Seizure-Causing Sodium Channel Mutation and their Partial Normalization by Dietary α-Linolenic Acid in Drosophila.
Kruth K, Kasuya J, Hand V … +2 more , Iyengar A, Kitamoto T
Neurochem Res · 2026 Jan · PMID 41557249 · Full text
Epilepsy is increasingly recognized as a disorder with prominent metabolic disturbances, but how defined epilepsy-causing mutations reshape metabolism under controlled genetic and environmental conditions remains poorly...
Epilepsy is increasingly recognized as a disorder with prominent metabolic disturbances, but how defined epilepsy-causing mutations reshape metabolism under controlled genetic and environmental conditions remains poorly understood. Here, we used the Drosophila melanogaster gain-of-function voltage-gated sodium channel (VGSC) mutant para, a well-established model of neuronal and behavioral hyperexcitability, to characterize whole-body metabolic alterations and their modulation by dietary supplementation with the ω-3 polyunsaturated fatty acid α-linolenic acid (ALA), which strongly and specifically suppresses para seizure phenotypes. Adult wild-type and para females were reared on control or ALA-supplemented diets, and 172 metabolites were quantified using GC-MS and LC-MS. The para mutation induced broad metabolic alterations, including enhanced glycolysis, reduced tricarboxylic acid cycle and pentose phosphate pathway intermediates, and depletion of nicotinamide riboside and nicotinic acid adenine dinucleotide, suggesting metabolic stress, mitochondrial dysfunction, and impaired redox balance. Amino acid and nucleotide metabolism were extensively reorganized, with prominent changes in tryptophan pathways, as well as imbalances in purine and pyrimidine nucleotides and cyclic nucleotides (cAMP, cGMP). Levels of microbially derived short-chain fatty acids and indole derivatives were elevated, implicating altered gut-brain metabolic interactions. Dietary ALA partially normalized key metabolites, including succinate, 6-phosphogluconate, glycine, proline, and short-chain fatty acids, and increased N-methylnicotinamide, consistent with improved redox homeostasis and attenuated inflammation. These findings demonstrate that VGSC-driven hyperexcitability elicits coordinated metabolic and microbiota-related changes, and that ALA can mitigate these disturbances, highlighting testable metabolic targets for mechanism-based interventions in epilepsy.
Melatonin Promotes Neurogenesis via the JAK2/STAT3 Pathway in Hypoxic-Ischemic Neonatal Rats.
Wang Y, Yu M, Liu C … +8 more , Zhang X, Qin Y, Meng N, Xue N, Li Y, Liu D, Jiang J, Wang X
Neurochem Res · 2026 Jan · PMID 41557248 · Publisher ↗
Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of neurological dysfunction and long-term disability in newborns. Lactate accumulation and metabolic disturbances after brain injury inhibit neurogenesis,...
Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of neurological dysfunction and long-term disability in newborns. Lactate accumulation and metabolic disturbances after brain injury inhibit neurogenesis, while the restorative capacity of endogenous neural stem cells (NSCs) is essential for neural reconstruction. Melatonin (Mel) alleviates neonatal brain injury, but its effects on NSCs proliferation and migration remain unclear, and the visualization methods for dynamic monitoring of metabolic changes are inadequate. In this study, a neonatal rat model of HIBD was established, and multimodal MRI combined with histological techniques was employed to evaluate the effects of Mel on NSCs regeneration and metabolic conditions in the hippocampal dentate gyrus. Using these techniques, the potential neuroprotective effects of Mel via the JAK2/STAT3 pathway were investigated. Multimodal MRI revealed that Mel increased cerebral blood flow and oxygen saturation, reduced lactate levels, improved brain metabolic microenvironment, and alleviated brain damage caused by HIBD. EdU/Nestin and EdU/DCX staining revealed that Mel promoted the proliferation and migration of endogenous NSCs, thereby enhancing neurogenesis. In addition, the use of a JAK2 inhibitor (WP1066) and agonist (C-A1) verified that Mel exerted its protective effects by down-regulating the JAK2/STAT3 pathway. Morris water maze further confirmed that Mel improved spatial learning and memory function in neonatal rats with HIBD. Multimodal MRI offers a visual basis for monitoring metabolic changes and therapeutic effects, while Mel enhances neurogenesis and mitigates brain injury through inhibition of the JAK2/STAT3 pathway, thus providing a theoretical basis for the clinical application of Mel in HIBD in neonates.
Correction: Modulation of the Levels of NMDA Receptor Subunit mRNA and the Bindings of [H]MK-801 in Rat Brain by Chronic Infusion of Subtoxic Dose of MK-801.
Oh S, Kim YH, Hann HJ … +4 more , Lee HL, Choi HS, Kim HS, Ho IK
Neurochem Res · 2026 Jan · PMID 41557205 · Publisher ↗
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EVADR lncRNA Mitigates Neonatal Hypoxic-Ischemic Brain Injury via the miR-145→WNT/β-Catenin Axis and Exhibits Biomarker Potential.
Lu S, Bao M, Hu J
Neurochem Res · 2026 Jan · PMID 41557190 · Publisher ↗
Perinatal hypoxic-ischemic injury (HI) upregulated an endogenous retrovirus-derived lncRNA, EVADR, via HIF-1α/NF-κB. EVADR bound and repressed miR-145, thereby activating WNT/β-catenin signaling. Binding specificity was...
Perinatal hypoxic-ischemic injury (HI) upregulated an endogenous retrovirus-derived lncRNA, EVADR, via HIF-1α/NF-κB. EVADR bound and repressed miR-145, thereby activating WNT/β-catenin signaling. Binding specificity was confirmed by biotin-miRNA pull-down and mutant-seed luciferase reporters. Genetic (si-CTNNB1/si-WNT3A) and pharmacologic (XAV939/CHIR99021) cross-validation demonstrated pathway necessity and rescue. EVADR gain-of-function reduced neuronal death and inflammation and improved behavioral outcomes following HI. Circulating EVADR levels in plasma/CSF correlated with injury severity; ROC analyses indicated diagnostic potential alone and combined with S100B/NSE. These data support EVADR-miR-145→WNT/β-catenin as a mechanistic axis with translational relevance.
1,3,4-Oxadiazole Derivative: A Potential Anti-inflammatory and Antioxidant Agent in Experimental Autoimmune Encephalomyelitis.
Zainab SR, Khan JZ, Batool SA … +6 more , Nadeem H, Tipu MK, Fatima H, Ahmad N, Ul-Haq Z, Irshad N
Neurochem Res · 2026 Jan · PMID 41557188 · Publisher ↗
1,3,4-Oxadiazole derivatives have attracted substantial attention as promising therapeutic agents for neurodegenerative disorders due to their anti-inflammatory and neuroprotective properties. This study specifically exa...
1,3,4-Oxadiazole derivatives have attracted substantial attention as promising therapeutic agents for neurodegenerative disorders due to their anti-inflammatory and neuroprotective properties. This study specifically examined a 1,3,4-oxadiazole derivative, i.e.,-{[5-(3-bromophenyl)-1, 3, 4-oxadiazol-2-yl] sulfanyl} ethan-1-ol (abbreviated as OX-1), in the context of multiple sclerosis (MS). Currently, approximately 2.8 million individuals worldwide are living with MS. The study demonstrates the therapeutic potential of OX-1 using the experimental autoimmune encephalomyelitis (EAE) model of MS. Neurobehavioral assessments indicate significant improvements in clinical scoring, motor deficits, muscular strength, and locomotor activity in EAE subjects. Imaging test reveal notable improvements in spinal deformity, further supporting the efficacy of the compound. Comprehensive analyses, including antioxidant assays, RT-PCR, and comet assays, confirm that OX-1 effectively reduces oxidative stress, accompanied by a significant decrease in cytokine expression. Histological examinations reveal critical pathological changes in the hippocampus, cortex, eyes, spinal cord, and optic nerve. The data demonstrate that this compound exhibits neuroprotective effects by activating the Nrf2/HO-1 pathway, thereby reducing oxidative stress and enhancing the antioxidant defense system. Additionally, it suppresses the TLR4/NF-κB pathway, significantly lowering pro-inflammatory cytokine production and immune cell infiltration. Furthermore, molecular docking and simulation studies demonstrate the binding interactions and potential modulatory effects of OX-1 on HO-1 and NF-κB. These results emphasize the therapeutic promise of OX-1 in effectively alleviating the clinical signs and symptoms associated with EAE-induced MS.
Exploring the Anticonvulsant and Neuropreventive Effects of Ganoderma lucidum Extract in the Pentylenetetrazole-Kindling Model: Analysis of Cognitive Comorbidities Associated with Epilepsy.
Abdessamad IR, Youssef B, Ayoub R … +5 more , Youssef ELM, Fatima A, Sara R, Aboubaker EH, Abdelhalem M
Neurochem Res · 2026 Jan · PMID 41557102 · Publisher ↗
Oxidative stress associated with neuronal death resulting from excitotoxicity represents a key pathophysiological mechanism contributing to the genesis and progression of neurofunctional alterations in epilepsy. Here, we...
Oxidative stress associated with neuronal death resulting from excitotoxicity represents a key pathophysiological mechanism contributing to the genesis and progression of neurofunctional alterations in epilepsy. Here, we evaluated the neuroprotective properties of GLE (300 mg/kg; i.g.) in the PTZ-induced Kindling model. Four groups of male Wistar rats were randomly assigned: control, PTZ, GLE-300, and Diazepam, each consisting of 8 rats. During the kindling process, 11 injections of PTZ (35 mg/kg; i.p.) were given every 48 h (21 consecutive days) to create a model of epilepsy. The 5-stage Racine scale was used to assess the severity of seizures. Moris water maze, Y maze test and novel object recognition was used to determine cognitive comorbidities. An assessment of oxidative stress biomarkers in the hippocampus was performed. Histological evaluation was also performed to quantify neuronal death in CA1 and CA3 using nissl staining. Our results show that supplementing animals with GLE attenuates PTZ-induced cognitive impairment and improves memory and learning deficits. In addition, GLE attenuated seizure severity and oxidative stress by decreasing lipid peroxidation and nitric oxide levels, and increasing superoxide dismutase and catalase activities in the hippocampus. Histopathological analysis also confirmed these results. These results indicate that GLE supplementation has therapeutic impacts on cognitive comorbidities and decreases PTZ damage, which may be associated with reduced oxidative stress in the hippocampus.
Correction: Deep Brain Stimulation of Lateral Habenula Ameliorates Depression-like Symptoms in Rats: Involvement of Mesolimbic Circuit.
Kanhere HS, Kokare DM, Jogdand YR … +2 more , Dudhabhate BB, Subhedar NK
Neurochem Res · 2026 Jan · PMID 41557042 · Publisher ↗
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