Neurochem. Res. [JOURNAL]
Sun
200 papers
Reactive Microglia-Mediated Synaptic Engulfment in the Basolateral Amygdala may Contribute to Preoperative Anxiety-Induced Postoperative Hyperalgesia.
Wang F, Liu Q, Li Y … +3 more , Ding Y, Li T, Tian W
Neurochem Res · 2026 Jan · PMID 41484764 · Publisher ↗
Preoperative anxiety is closely associated with postoperative hyperalgesia, but the underlying neural mechanisms remain incompletely understood. The basolateral amygdala (BLA) is a key hub for processing negative emotion...
Preoperative anxiety is closely associated with postoperative hyperalgesia, but the underlying neural mechanisms remain incompletely understood. The basolateral amygdala (BLA) is a key hub for processing negative emotions and pain. Emerging evidence indicates that microglial activation and synaptic engulfment contribute to the pathogenesis of neuropsychiatric and pain-related disorders. However, the role of BLA microglial activation-driven synaptic engulfment in preoperative anxiety-induced postoperative hyperalgesia remains unelucidated. A mouse model of preoperative anxiety-induced postoperative hyperalgesia was established by combining single prolonged stress (SPS) with plantar incision (I) surgery, designated as the SI model. Minocycline, a microglial inhibitor, was administered to investigate the role of microglial activation. The open field test (OFT) and elevated plus maze test (EPMT) were used to assess anxiety-like behaviors. Mechanical allodynia and thermal hyperalgesia tests were conducted to measure pain-related behaviors. Immunofluorescence (IF) staining for ionized calcium-binding adapter molecule 1 (IBA1), IBA1 + cluster of differentiation 68 (CD68), and IBA1 + synaptophysin (SYN) was performed to examine microglial reactivity, phagocytic activation, and synaptic engulfment in the BLA. Golgi staining was employed to quantify dendritic spine density of BLA neurons. Western blotting (WB) was employed to measure the expression levels of synaptic proteins, including postsynaptic density protein 95 (PSD95), SYN, and synapsin 1 (SYN1), in the BLA. SPS induced anxiety-like behaviors and exacerbated postoperative hyperalgesia in mice. Meanwhile, SI model mice exhibited increased microglial activation, phagocytic activity and synaptic engulfment in the BLA, accompanied by decreased dendritic spine density and reduced expression of synaptic proteins. Furthermore, minocycline treatment suppressed microglial activation and phagocytic activity, attenuated excessive synaptic engulfment, reversed the reductions in dendritic spine density and synaptic protein expression in the BLA, and ultimately alleviated both anxiety-like behaviors and postoperative hyperalgesia in SI mice. Our findings indicate that excessive microglial activation-mediated synaptic engulfment in the BLA is closely associated with preoperative anxiety-induced postoperative hyperalgesia. Targeting BLA microglial activation and associated synaptic engulfment may hold potential as a novel therapeutic strategy for mitigating preoperative anxiety-related postoperative hyperalgesia.
Schisanhenol Inhibits MPTP/MPP-Induced Ferroptosis in Dopaminergic Neurons Via Nrf2/TrxR1/GPX4 Pathway against Parkinson's Disease.
Dong G, Fan L, Li C … +10 more , Jiao Y, Li X, Li H, Liang Y, Ren Y, Wang L, Xiao D, Xiao J, Wu T, Li L
Neurochem Res · 2025 Dec · PMID 41460594 · Publisher ↗
Schisanhenol (Sal) is a lignan component derived from the traditional Chinese medicine Schisandra rubrifora (Franch.). Pharmacological research has highlighted that Sal exhibits pronounced neuroprotection against oxidati...
Schisanhenol (Sal) is a lignan component derived from the traditional Chinese medicine Schisandra rubrifora (Franch.). Pharmacological research has highlighted that Sal exhibits pronounced neuroprotection against oxidative stress-triggered damage. An in vivo mice model of Parkinson's disease (PD) was developed using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and in vitro studies employed 1-methyl-4-phenylpyridinium (MPP) as a neurotoxin in SH-SY5Y cells. Behavioral tests, immunohistochemistry, biochemical analyses, cell viability assays, and Western blot were applied. Sal (50 mg/kg and 100 mg/kg) markedly alleviates behavioral disorders in mice. The quantity of tyrosine hydroxylase (TH)-positive cells and TH protein levels in the substantia nigra (SN) were significantly augmented, while alpha-Synuclein (α-Syn) declined. Iron content in SN was reduced, thioredoxin reductase (TrxR) activity was enhanced, and protein Nrf2, TrxR1, and GPX4 were upregulated. In vitro findings showed that Sal (25 µM, 50 µM, 100 µM) significantly restored cell viability, replenished GSH/GSSG ratio, and reduced MDA levels. Molecularly, Sal administration upregulated GPX4, HO-1, Nrf2, and TrxR1 expression, as well as enhanced mitochondrial membrane potential. Particularly, Sal treatment heightened Nrf2 protein entry to the nucleus and upregulated TrxR1 expression. The nuclear translocation of Nrf2 was reversed by Nrf2 inhibitor ML385. Meanwhile, The neuroprotective effect of Sal was reversed by ML385 and TrxR1 inhibitor Auranofin. Sal exhibits significant therapeutic potential in mitigating MPTP-induced PD in mice and MPP-induced Dopaminergic (DA) neuron toxicity in SH-SY5Y cells, as it protects DA neurons while inhibiting ferroptosis. These outcomes are likely associated with the Nrf2/TrxR1/GPX4 pathway.
HAT1 Protects Against Cerebral Ischemia Injury by Inhibiting TFRC-Mediated Ferroptosis.
Dou Y, Deng C, Yue H … +1 more , Xie X
Neurochem Res · 2025 Dec · PMID 41460540 · Publisher ↗
Ferroptosis is a pathogenesis of stroke. Succinylation is a promising therapeutic target for stroke. This study aimed to investigate the impact of succinyltransferase HAT1 in the progression of ischemic stroke and the un...
Ferroptosis is a pathogenesis of stroke. Succinylation is a promising therapeutic target for stroke. This study aimed to investigate the impact of succinyltransferase HAT1 in the progression of ischemic stroke and the underlying mechanism. HT-22 cells were stimulated by oxygen glucose deprivation to induce cell death. Mice received middle cerebral artery occlusion (MCAO) to generate a model. Ferroptosis was evaluated using propidium iodide staining and by measuring key indicators, including glutathione (GSH) levels, intracellular Fe²⁺ concentration, reactive oxygen species (ROS) levels, and ferroptosis-related protein levels. Brain infarction was observed using 2,3,5-Triphenyltetrazolium staining. The succinylation of transferrin receptor (TFRC) was measured using immunoprecipitation and western blotting. The results showed that HAT1 expression was downregulated in OGD-related HT-22 cell ferroptosis. Overexpression of HAT1 promoted the viability, as well as inhibited inflammatory response and ferroptosis of OGD-induced cells. Moreover, HAT1 ameliorated neurological dysfunction, brain infarction, and ferroptosis in the brain of MCAO mice. Additionally, we identified a novel mechanism whereby HAT1 interacted with TFRC and promoted its succinylation at K384 and K626 sites, establishing a previously unrecognized post-translational regulatory axis. Overexpression of TFRC or mutants of TFRC at succinylation sites abrogated the effect on cell phenotype induced by HAT1. In conclusion, HAT1 suppresses ferroptosis by promoting TFRC succinylation, thereby attenuating ischemic brain injury. These findings provide a potential therapeutic target for ischemic stroke.
The LINC00968/miR-194-5p Axis Exacerbates Neurological Dysfunction After Intracerebral Hemorrhage by Regulating Oxidative Stress and Neuroinflammation.
Wu J, Sun S, Ren L … +1 more , Hu Q
Neurochem Res · 2025 Dec · PMID 41460533 · Publisher ↗
This study aims to investigate the regulatory role and molecular mechanism of the LINC00968/miR-194-5p axis in secondary neurological injury after intracerebral hemorrhage (ICH). A rat ICH model was established by inject...
This study aims to investigate the regulatory role and molecular mechanism of the LINC00968/miR-194-5p axis in secondary neurological injury after intracerebral hemorrhage (ICH). A rat ICH model was established by injecting collagenase IV. In vitro, PC12 cells were treated with hemin to mimic the ICH environment. RT-qPCR was used to detect the levels of LINC00968 and miR-194-5p. Assessment of cell proliferation and apoptosis was performed with the CCK-8 assay and flow cytometry. The levels of SOD, MDA, ROS, and inflammatory factors (IL-6, TNF-α, IL-10) were measured using commercially available detection kits. To assess neurological deficits, the mNSS, corner turn, and forelimb placement tests were employed. To evaluate brain edema, the dry-wet weight method was utilized. The direct binding between LINC00968 and miR-194-5p was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. In both in vivo and in vitro ICH models, LINC00968 expression was significantly upregulated. Knockdown of LINC00968 significantly enhanced cell proliferation, inhibited apoptosis, and reduced oxidative stress and inflammation in vitro. In rats, it significantly improved neurological deficits and reduced brain edema. Mechanistically, LINC00968 acts as a competing endogenous RNA (ceRNA) that sponges miR-194-5p. Suppressing miR-194-5p eliminated the neuroprotection resulting from LINC00968 silencing. LINC00968 aggravates neurological deficits, neuroinflammation, and oxidative stress after ICH by competitively binding to miR-194-5p.
Cerebrolysin Ameliorates Age-Induced Dendritic Spine Degeneration and Memory Decline in C57BL6 Mice.
Aguilar-Hernández L, Flores-Gómez GD, Nacher J … +2 more , Morales-Medina JC, Flores G
Neurochem Res · 2025 Dec · PMID 41460391 · Full text
Aging is associated with progressive synaptic deterioration and cognitive decline; however, therapeutic strategies capable of restoring both structural and functional deficits remain limited. This study evaluated the eff...
Aging is associated with progressive synaptic deterioration and cognitive decline; however, therapeutic strategies capable of restoring both structural and functional deficits remain limited. This study evaluated the effects of aging on dendritic spine dynamics and recognition memory across multiple brain regions, and evaluated whether chronic treatment with cerebrolysin (CBL) could ameliorate age-related alterations (3, 6, 12 and 18 months of age). We additionally assessed the effects of CBL on key molecular markers of synaptic plasticity in aged (18-month) C57BL6 mice. Aging impaired locomotor activity (12- and 18-month groups) and produced deficits in short- and long-term recognition memory relative to young controls. Notably, CBL selectively enhanced locomotion in 18-month group and improved short-term memory in the 12-month group. At the structural level, aging reduced spine density and decreased the proportion of thin and mushroom spines in the prefrontal cortex and dorsal hippocampus, whereas CBL treatment increased spine density in the dorsal hippocampus and basolateral amygdala, and promoted the formation of mature mushroom spines in a region and age-dependent manner. Importantly, CBL elevated β-actin, synaptophysin and brain-derived nerve factor expression across multiple regions in the 18-month group. This study provides the first integrated demonstration that CBL enhances dendritic spine maturation and dendritic structural remodeling while concurrently improving cognitive outcomes within the same cohort of aged animals. Collectively, our findings position CBL as a promising therapeutic candidate to counteract age-related synaptic loss and cognitive decline, advancing current understanding of neuroprotective interventions in aging.
Regulatory Landscapes of Protein Acylations in Neuroinflammation: From Molecular Mechanisms to Therapeutic Targets.
Han J, Han J, Duan S … +2 more , Xin C, Jiang P
Neurochem Res · 2025 Dec · PMID 41460381 · Publisher ↗
In recent years, the role of novel protein acylation modifications in neuroinflammation has gradually become a hot research topic. In this paper, we reviewed the molecular mechanisms of five types of acylation modificati...
In recent years, the role of novel protein acylation modifications in neuroinflammation has gradually become a hot research topic. In this paper, we reviewed the molecular mechanisms of five types of acylation modifications, namely lactylation (Kla), succinylation (Ksucc), crotonylation (Kcr), β-hydroxybutyrylation (Kbhb) and palmitoylation, and their association with neuroinflammation. To clarify the roles of these acylation modifications in neuroinflammation, we summarized the acyl donors, key regulatory enzymes (acyltransferases and deacylases), and dynamic regulatory networks for each modification type. On the one hand, they are directly involved in the inflammatory response by regulating microglial activation and pro-inflammatory factor release; on the other hand, they can indirectly affect the neurodegenerative disease process through metabolic reprogramming. This article also discusses drug development for novel acylases, including strategies based on enzyme activity inhibition or metabolic intervention, and points out the limitations of current studies. Future studies need to explore the spatial and temporal dynamics of acylation modifications, cross-regulatory networks and their functions in the neuroimmune microenvironment to provide new targets for the development of precise anti-neuroinflammatory therapies. The discovery of novel acylation modifications not only expands the theoretical framework of protein post-translational modification (PTM), but also opens up a multi-dimensional intervention pathway for the treatment of neuroinflammation-related diseases.
Correction: Electroacupuncture Alleviates Cerebral Ischemia-Reperfusion Injury by Downregulating IL-17 A and Inhibiting Neurotoxic Astrocyte Activation.
Zhao MM, Song Q, Xie QY … +4 more , Sun WQ, Zhang Y, Tang W, Li MX
Neurochem Res · 2025 Dec · PMID 41422476 · Full text
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Ectomesenchymal Stem Cell Transplantation Induces Microglial Polarization and Anti-inflammatory IL-10 Secretion via NF-κB and MAPK Pathways to Mitigate Brain Injury Post-cerebral Hemorrhage.
Li Y, Yang W, Tang Y … +6 more , Du S, Ye Y, Xu B, Shi W, Zhao X, Lu X
Neurochem Res · 2025 Dec · PMID 41420699 · Publisher ↗
Intracerebral hemorrhage (ICH) has poor clinical outcomes, with microglia-induced neuroinflammation being a key pathological process. This study investigated the therapeutic potential of ectomesenchymal stem cells (EMSCs...
Intracerebral hemorrhage (ICH) has poor clinical outcomes, with microglia-induced neuroinflammation being a key pathological process. This study investigated the therapeutic potential of ectomesenchymal stem cells (EMSCs) from the nasal mucosa in ICH. Using a mouse ICH model, we transplanted EMSCs intracranially. We assessed neurological function, neuronal survival, microglial polarization, and inflammatory responses. In vitro, we co-cultured EMSCs with hemin-stimulated microglia and performed transcriptomic analysis. Key proteins in the NF-κB and MAPK pathways were evaluated in vivo based on in vitro findings. EMSC transplantation significantly improved neurological deficits and reduced neuronal injury. It promoted microglial polarization towards the anti-inflammatory M2 phenotype and increased levels of the anti-inflammatory cytokine IL-10. Mechanistically, EMSCs suppressed the activation of the NF-κB and MAPK signaling pathways in microglia. Our findings demonstrate that EMSCs alleviate neuroinflammation and neural injury after ICH by modulating microglial polarization, potentially via inhibiting the NF-κB and MAPK pathways. This suggests EMSCs as a promising novel therapy for hemorrhagic stroke.
Neuroprotective Effect of Marine-Derived Nacre Extract against Aβ-Induced Toxicity via Preservation of Mitochondrial Function and Biogenesis.
Yan Z, Yotsuya Y, Hasegawa Y
Neurochem Res · 2025 Dec · PMID 41420698 · Publisher ↗
Pearls, formed from the nacreous layers of marine mollusks, have long been used in traditional medicine, yet the molecular basis of their bioactivity remains insufficiently characterized. Mitochondrial dysfunction is a c...
Pearls, formed from the nacreous layers of marine mollusks, have long been used in traditional medicine, yet the molecular basis of their bioactivity remains insufficiently characterized. Mitochondrial dysfunction is a central feature of Alzheimer's disease (AD) pathology and represents a critical therapeutic target. Although nacre extract has been reported to improve cognitive impairment, its effects on mitochondrial function and biogenesis under amyloid-β (Aβ)-induced toxicity remain unclear. In this study, we examined the impact of nacre extract on mitochondrial activity in PC12 cells and in an Aβ-injected mouse model. Treatment with nacre extract significantly alleviated Aβ-induced mitochondrial dysfunction in PC12 cells, restoring membrane potential, ATP production, and the expression of mitochondrial biogenesis-related genes, including PPARγ and Nrf1. MitoBright LT staining demonstrated recovery of mitochondrial mass following extract administration. In vivo, we first isolated and identified a sulfated polysaccharide fraction from nacre extract, which significantly improved Aβ-induced memory impairment. In parallel, this fraction preserved mitochondrial function in the brains of Aβ-injected mice, as evidenced by maintained membrane potential, ATP levels, and hippocampal succinate dehydrogenase expression. Together, these findings demonstrate that nacre extract exerts neuroprotective effects through its sulfated polysaccharide fraction, highlighting its potential as a marine-derived therapeutic resource against AD-related neurodegeneration.
Fasted-State Aerobic Exercise Enhances Cognition and Hippocampal BDNF Signaling in an Alzheimer's Disease Rat Model.
Kirkbir F, Atasoy T, Khodadadai D … +3 more , Sajedi H, Keskin O, Babaie M
Neurochem Res · 2025 Dec · PMID 41420669 · Publisher ↗
Alzheimer's disease (AD) is a multifactorial disorder that demands a comprehensive management strategy. Both aerobic exercise training and intermittent fasting (IF) have been shown to ameliorate AD symptoms, yet the impa...
Alzheimer's disease (AD) is a multifactorial disorder that demands a comprehensive management strategy. Both aerobic exercise training and intermittent fasting (IF) have been shown to ameliorate AD symptoms, yet the impact of exercise in the fasted state remains understudied. This study compared the effects of four weeks of moderate‑intensity treadmill running in either a fasted or a normal fed state on cognitive function and hippocampal BDNF signaling in an amyloid-β (Aβ)-injected rat model of AD. Twenty‑month‑old male Wistar rats were allocated into five groups (n = 12 each): AD, AD plus IF (ADIF), AD plus exercise training (ADET), AD plus IF plus exercise training (ADIFET), and control. AD was induced by bilateral intra‑hippocampal Aβ injection. Exercise interventions (fasted or fed) were conducted 5 days/week for 4 weeks. Aβ injection significantly impaired learning and memory and reduced hippocampal levels of PKA, CREB, and BDNF (p < 0.001). Both fasting and exercise independently elevated plasma and hippocampal β-hydroxybutyrate (βHB) (p < 0.001), with the highest βHB increase observed in the fasted-exercise group (p < 0.01). All intervention groups (ADIF, ADET, and ADIFET) demonstrated significant improvements in cognitive performance and hippocampal levels of PKA, CREB, and BDNF (p < 0.001). The combined fasting plus exercise group produced greater benefits than either IF or exercise alone (p < 0.05), and exercise alone outperformed fasting alone (p < 0.05). These findings indicate that aerobic exercise in the fasted state offers superior neuroprotective and cognitive benefits, likely via upregulation of βHB/PKA/CREB/BDNF signaling, highlighting fasted‑state exercise as a promising therapeutic approach for AD.
Biochemical Role of the Endocannabinoid System in the Pathophysiology of Attention Deficit Hyperactivity Disorder: A Narrative Review and Future Directions.
Özmeral Erarkadaş K, Erarkadaş M, Yıldız Gündoğdu Ö
Neurochem Res · 2025 Dec · PMID 41410830 · Publisher ↗
The endocannabinoid system (ECS) is a lipid-derived signaling network composed of cannabinoid receptors, endogenous ligands, and metabolic enzymes. Through its widespread neuromodulatory functions, the ECS regulates dopa...
The endocannabinoid system (ECS) is a lipid-derived signaling network composed of cannabinoid receptors, endogenous ligands, and metabolic enzymes. Through its widespread neuromodulatory functions, the ECS regulates dopaminergic, noradrenergic, and glutamatergic pathways that are critical for attention and behavioral control. Emerging evidence indicates that dysregulation of ECS components may contribute to the pathophysiology of attention deficit hyperactivity disorder (ADHD). This review synthesizes current biochemical evidence on ECS involvement in ADHD pathophysiology, with a focus on receptor signaling, ligand levels, and enzyme activity. By evaluating emerging molecular targets and highlighting gaps in mechanistic knowledge, it aims to guide future studies toward novel therapeutic strategies. A total of 11 preclinical and 2 clinical studies evaluating ECS-related biochemical alterations in ADHD were included. Preclinical research demonstrates alterations in ECS components linked to hyperactivity and impaired cognitive regulation. Although clinical research in this area remains limited, preliminary results are promising, supporting ECS-targeted approaches as novel therapeutic strategies for ADHD. Overall, current evidence suggests that dysregulation of the endocannabinoid system contributes to ADHD pathophysiology. Clarifying ECS-related biochemical mechanisms in ADHD may identify novel molecular targets, while advancing translational efforts toward ECS-based therapeutic strategies.
L-Theanine Uptake via Solute Carrier Family 38 Member 1 Inhibits Neuroblastoma Cell Growth.
Kawada K, Matsushima Y, Nakamura R … +14 more , Nishio M, Watanabe Y, Araki S, Sudo T, Yoshikawa S, Shibata M, Kinjo T, Uno K, Higashiura Y, Yamamuro A, Ishimaru Y, Yoshioka Y, Maeda S, Kuramoto N
Neurochem Res · 2025 Dec · PMID 41410739 · Publisher ↗
L-gamma-glutamylethylamide (L-theanine, theanine) is an amino acid and an umami component found in green tea. According to previous reports, theanine acts on the central nervous system by alleviating stress and maintaini...
L-gamma-glutamylethylamide (L-theanine, theanine) is an amino acid and an umami component found in green tea. According to previous reports, theanine acts on the central nervous system by alleviating stress and maintaining natural sleep. Furthermore, theanine has been reported to have a mild cancer-suppressing effect. However, the molecular mechanism of theanine's potential central nervous system (CNS) activity remains unclear. We evaluated the inhibitory effect of theanine on the proliferation of neural cell lines and found that theanine most effectively inhibited the proliferation of NSC-34 mouse motor neuron-like hybrid cells compared to other neural cells. NSC-34 cell proliferation inhibition by theanine was completely alleviated by co-administration of α-(methylamino) isobutyric acid or leucine, a substrate of solute carrier family 38 member 1 (Slc38a1, the glutamine transporter) or Slc7a5 (the glutamine/leucine exchanger) respectively. This suggests that theanine uptake into cells occurs via Slc38a1 and excretion from cells occurs via Slc7a5. However, inhibition was observed even in the absence of glutamine and did not correlate with changes in mammalian target of rapamycin phosphorylation levels. These results suggest that theanine inhibits proliferation in a manner that is still unclear after it is taken up into cells. Based on these findings, we propose that theanine may exert an inhibitory effect on the proliferation of neural cells that have abnormally proliferating Slc38a1, namely neuroblastoma.
Myrtenal Ameliorates Ischemic Brain Injury Diabetic and Non-Diabetic Rats.
Korkmaz E, Beytur A, Erden Y … +3 more , Tanbek K, Tekin Ç, Tekin S
Neurochem Res · 2025 Dec · PMID 41405769 · Publisher ↗
Ischemic stroke (IS) is a leading cause of death and permanent disability worldwide. Diabetes is a major risk factor for IS and independently increases mortality. This study investigated the neuroprotective effects of My...
Ischemic stroke (IS) is a leading cause of death and permanent disability worldwide. Diabetes is a major risk factor for IS and independently increases mortality. This study investigated the neuroprotective effects of Myrtenal (Myrt) in a rat model of IS under both diabetic and non-diabetic conditions. Sprague Dawley rats received Myrt (40 mg/kg, intraperitoneally) for 28 days before undergoing 60-minute middle cerebral artery occlusion followed by 24 h of reperfusion. Neurological outcomes were assessed using behavioral tests, infarct volume was measured by TTC staining, and biochemical analyses evaluated oxidative stress (MDA, SOD, CAT, GSH-Px) and inflammatory markers (NLRP3, TNF-α, IL-6, IL-1β). Western blotting was performed to examine BDNF/TrkB, p-PI3K/p-Akt signaling, and apoptosis-related proteins (Caspase-3, Bcl-2, Bax). IS impaired neurological function and increased infarct size, apoptosis, inflammation, and lipid peroxidation, while reducing antioxidant enzymes and BDNF/TrkB and p-PI3K/p-Akt levels (p < 0.05). These pathological changes were more severe in diabetic rats. Pretreatment with Myrt significantly ameliorated these effects in both diabetic and non-diabetic groups (p < 0.05). These findings suggest that Myrt exerts neuroprotective effects against IS by suppressing inflammation, oxidative stress, and apoptosis, possibly through modulation of BDNF/TrkB and p-PI3K/p-Akt pathways. These findings indicate that Myrt may possess neuroprotective potential in IS under both hyperglycemic and normoglycemic conditions.
NEXN-AS1 Predicts the Occurrence of Post-Stroke Cognitive Impairment and Alleviates Inflammation and Oxidative Stress by Targeting the miR-92a-3p/NRF1 Axis : NEXN-AS1 Alleviates Inflammation and Oxidative Stress in PSCI.
Wang K, Yang L, Zhang C … +4 more , Xing X, Su Z, Gao P, Han B
Neurochem Res · 2025 Dec · PMID 41398486 · Publisher ↗
Post-stroke cognitive impairment (PSCI) is a prevalent cerebrovascular condition resulting from ischemic stroke. This study aimed to determine the expression levels of NEXN-AS1 in PSCI, evaluate its clinical significance...
Post-stroke cognitive impairment (PSCI) is a prevalent cerebrovascular condition resulting from ischemic stroke. This study aimed to determine the expression levels of NEXN-AS1 in PSCI, evaluate its clinical significance, and further uncover the molecular mechanisms through which it contributes to the initiation and progression of PSCI. The quantification of NEXN-AS1, miR-92a-3p, and NRF1 expression was performed using qRT-PCR. The diagnostic utility of serum NEXN-AS1 was assessed through ROC analysis. Risk factors associated with cognitive impairment following stroke were identified using both univariate and multivariate logistic regression. A cellular model of cognitive dysfunction was established via oxygen-glucose deprivation/reperfusion (OGD/R). The PSCI animal model was established through the Middle cerebral artery occlusion (MCAO) surgery. Inflammatory status was determined by measuring cytokine levels, including IL-6, IL-1β, and IL-10, while oxidative stress was evaluated by quantifying ROS, MDA, and CAT. In stroke patients, NEXN-AS1 expression was notably downregulated and further decreased in cases with PSCI. It served as a reliable biomarker for distinguishing stroke patients from healthy individuals and PSCI from post-stroke cognitive normality (PSCN) groups. Upregulation of NEXN-AS1 in BV2 cells following OGD/R stimulation led to increased proliferation, decreased inflammatory response, and reduced oxidative stress. Moreover, miR-92a-3p expression reversed the protective effects of NEXN-AS1 under OGD/R conditions. Overexpression of NEXN-AS1 alleviated cognitive dysfunction, inflammatory response and oxidative stress in PSCI rats, while overexpression of miR-92a-3p counteracted the protective effect of NEXN-AS1 on PSCI rats. Further analysis identified NRF1 as a downstream target of miR-92a-3p. NEXN-AS1 exerts protective effect against ischemic brain injury in both in vitro and in vivo models by regulating miR-92a-3p. Therefore, NEXN-AS1 may predict the occurrence of PSCI, and NEXN-AS1 may contribute to PSCI pathogenesis via regulation of the miR-92a-3p/NRF1 axis.
PRMT5 Aggravates Parkinson's Disease Progression Through the Inhibition of Neuronal Autophagy Through DKK1.
Zhou H, Fan H, Bian H … +3 more , Zou Y, Pang A, Geng X
Neurochem Res · 2025 Dec · PMID 41379372 · Publisher ↗
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and severely affects the physical and mental health of patients. The protein arginine methyltransferase 5 (PRMT5) has been shown to b...
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and severely affects the physical and mental health of patients. The protein arginine methyltransferase 5 (PRMT5) has been shown to be associated with neuronal degeneration in PD, but its specific mechanism of mediating PD remains unclear. The purpose of this study was to investigate the role of PRMT5 in PD and its potential mechanism. PD models in rats and MN9D cells were induced by 6-hydroxydopamine (6-OHDA). Key genes and proteins were identified through real-time quantitative polymerase chain reaction (RT‒qPCR), Western blotting, and immunofluorescence staining; apoptosis levels were measured using flow cytometry; autophagosome formation was observed via monodansylcadaverine (MDC) staining; and neuronal damage in PD rats was evaluated using hematoxylin‒eosin (H&E) and Nissl staining. In this study, we found that PRMT5 levels were elevated in the peripheral blood of PD patients and in 6-OHDA-induced rat brain tissue and MN9D cells and that the expression of PRMT5 was positively correlated with the level of α-Syn. After PRMT5 was knocked down, α-Syn levels in PD rats decreased, neuronal damage was inhibited, and motor disorders improved. In addition, knockdown of PRMT5 promoted 6-OHDA-induced MN9D cell proliferation, inhibited apoptosis, and upregulated autophagy. Mechanistically, PRMT5 inhibits the activation of the Wnt/β-catenin signaling pathway through H3R8me2s modification to stabilize the expression of DKK1, thus inhibiting neuronal autophagy and promoting the development of PD. Our study suggests that PRMT5 may be a potential intervention target for improving PD progression.
The Role of Insular Cortex and Prefrontal Cortex in the Pathogenesis of Fibromyalgia: Biochemical and Electrophysiological Rodent Study.
Abouelnaga AF, Hussein AM, Abass M … +4 more , Shafiek MZ, Zaki HF, Mohamed AF, Ibrahim WW
Neurochem Res · 2025 Dec · PMID 41379252 · Full text
Neuroimaging implicates the medial prefrontal cortex (mPFC) and insula in fibromyalgia (FM), but synaptic and network mechanisms are unclear. To verify mPFC hypersynapticity in a reserpine-induced FM model and test wheth...
Neuroimaging implicates the medial prefrontal cortex (mPFC) and insula in fibromyalgia (FM), but synaptic and network mechanisms are unclear. To verify mPFC hypersynapticity in a reserpine-induced FM model and test whether anterior insular deep brain stimulation (DBS) restores mPFC oscillations and pain behavior. Thirty-six male Sprague-Dawley rats received reserpine (1 mg·kg⁻¹ i.p., days 1-3) or vehicle. For Objective 1, mPFC tissue was analyzed by ELISA for glutamate, γ-aminobutyric acid (GABA), C-FOS, nerve growth factor (NGF), synaptophysin, and postsynaptic density protein-95 (PSD-95). For Objective 2, rats were assigned to control-sham, control-DBS, FM-sham, or FM-DBS. Monopolar DBS (130 Hz, 60 µs, 100 µA; 15 min·day⁻¹ for 3 days) targeted the anterior insula; local field potentials were recorded from mPFC, and thermal nociception was assessed by tail immersion and hot-plate tests. Reserpine increased glutamate, C-FOS, NGF, synaptophysin, and PSD-95 and reduced GABA (all p < 0.001), confirming hypersynapticity. Insular DBS increased delta-band normalized ratios (NR) in FM and controls (p < 0.0001), normalized FM-associated theta reductions, decreased alpha/beta NR in controls, and suppressed elevated gamma NR in FM (p < 0.0001). DBS increased withdrawal latencies in FM, indicating improved pain thresholds (p < 0.001). Reserpine induces biochemical hypersynapticity in mPFC, and brief anterior insular DBS rebalances mPFC oscillations and alleviates hyperalgesia. Insular DBS may correct cortical network dysfunction in FM.
Saracatinib Promotes Hippocampal Myelin Regeneration and Oligodendrocyte Precursor Cell Maturation by Inhibiting the NOTCH1 Signaling Pathway in Epileptic Mice.
Luo X, Wu W, Yu B … +4 more , Chen S, Zhao J, Min J, Gu X
Neurochem Res · 2025 Dec · PMID 41364203 · Publisher ↗
Epilepsy is a common neurological disorder often accompanied by hippocampal myelin damage and impaired differentiation of oligodendrocyte precursor cells (OPCs). This study aimed to investigate the regulatory effects of...
Epilepsy is a common neurological disorder often accompanied by hippocampal myelin damage and impaired differentiation of oligodendrocyte precursor cells (OPCs). This study aimed to investigate the regulatory effects of Saracatinib on myelin regeneration and OPC maturation in a mouse model of epilepsy, as well as its underlying mechanisms, to provide new strategies for the treatment of epilepsy-related myelin damage. Changes in hippocampal myelin structure were observed using Fast Blue staining and transmission electron microscopy. Immunofluorescence was used to detect the number of oligodendrocyte precursor cell (OPCs, PDGFRα) and mature oligodendrocytes (ODCs, MBP+). Cell culture experiments verified the effects of Saracatinib on OPC differentiation, and SwissTargetPrediction and GSEA were used to predict its targets. Western blot and immunofluorescence further validated the role of the NOTCH1 signaling pathway in Saracatinib-mediated OPC differentiation. Saracatinib Reduced the Racine Score, Prolonged Seizure Latency, and Decreased Seizure Duration in an Epileptic Mouse Model. Epileptic model mice exhibited significant hippocampal myelin damage, characterized by thinning of myelin sheaths, reduced myelin quantity, and increased axonal exposure. Saracatinib treatment significantly improved myelin structure, restored myelin thickness and continuity, and alleviated axonal atrophy. Immunofluorescence showed that Saracatinib increased MBP expression and decreased PDGFRα expression, promoting the differentiation of OPCs into ODCs. Bioinformatics analysis and experimental validation demonstrated that Saracatinib promoted OPC maturation by inhibiting the NOTCH1 signaling pathway, and this effect could be reversed by the NOTCH1 agonist JAG1. Saracatinib significantly promotes hippocampal myelin regeneration and OPC maturation in epileptic mice by inhibiting the NOTCH1 signaling pathway, providing a potential molecular target and therapeutic strategy for the treatment of epilepsy-related myelin damage.
Genistein Exerts Neuroprotective Effects in an Ouabain-Induced Model of Bipolar Disorder: Behavioral and Molecular Insights.
Arafat MT, Ghaiad HR, Elbaz EM
Neurochem Res · 2025 Dec · PMID 41354896 · Full text
Bipolar disorder (BD) is a chronic and prevalent psychiatric disease that has been considered a leading cause of disability among psychiatric conditions. Taking into account that there is yet no satisfactory disease-modi...
Bipolar disorder (BD) is a chronic and prevalent psychiatric disease that has been considered a leading cause of disability among psychiatric conditions. Taking into account that there is yet no satisfactory disease-modifying treatment, we investigated the effect of genistein on ouabain-induced BD in male C57BL/6 mice. Animals were categorized into control, genistein control, ouabain model, lithium (Li)-treated, and genistein-treated groups. BD was induced by bilateral intracerebroventricular injection of 0.625 nmol ouabain. Genistein (10 mg/kg/day) was orally administered for 2 weeks following a single dose of ouabain. Open field test, sucrose preference test, and forced swim test were performed. Na⁺/K⁺-ATPase activity was evaluated through measuring the hippocampal levels of phosphorylated epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase, extracellular signal-regulated kinase, and cAMP response element-binding protein (p-CREB) by western blot analysis. The levels of brain-derived neurotrophic factor (BDNF), serotonin, oxidative stress, and inflammatory markers were quantified by ELISA. The BCL-2-associated X protein (BAX) to B-cell Lymphoma/Leukemia (BCL2) ratio was assessed by qRT-PCR. Genistein reduced manic and anxious behaviors during the manic phase and showed an antidepressant effect during the depression phase, all while maintaining an effective metabolic balance on body weight. Additionally, genistein increased serotonin, p-CREB, and BDNF levels while decreasing inflammation and apoptosis produced by ouabain. Furthermore, genistein restored the normal architecture in both hippocampal and cortical H&E-stained sections. Taken together, genistein was able to activate the Na⁺/K⁺-ATPase signalosome via a multifaceted mode of action, exerting a neuroprotective effect in an animal model of BD, promoting genistein as a therapeutic candidate for BD.
Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.
Li X, Liu Y, Hu H … +1 more , Li S
Neurochem Res · 2025 Dec · PMID 41342958 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, marked by cognitive decline and memory loss. Its multifactorial etiology involves genetic, environmental, and cellul...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, marked by cognitive decline and memory loss. Its multifactorial etiology involves genetic, environmental, and cellular factors, with key pathological features including amyloid-beta (Aβ) plaques and tau tangles. Recent studies have highlighted the roles of liquid-liquid phase separation (LLPS) and autophagy in AD onset and progression. LLPS, an emerging biophysical phenomenon, facilitates protein aggregation and may contribute to early disease stages. Dysregulated autophagy results in the accumulation of toxic proteins, such as Aβ and tau, exacerbating neurodegeneration. This review explores the interplay between LLPS and autophagy in AD, a relationship often overlooked in the literature. It examines their biological mechanisms, synergistic effects on AD pathology, and potential therapeutic strategies. Additionally, we discuss the therapeutic potential of both natural and non-natural compounds in modulating LLPS and autophagy. While compounds like curcumin show promise, a comprehensive framework for their targeted use remains under development. This review provides theoretical support for the advancement of more precise AD therapies.
Molecular Mechanisms Underlying Chronic High-Dose Ketamine-Induced Apoptosis in the Hippocampus: A Narrative Review.
Azadbakht AA, Mashayekhi-Sardoo H, Baghcheghi Y
Neurochem Res · 2025 Dec · PMID 41324812 · Publisher ↗
Chronic high-dose ketamine, widely recognized for its rapid antidepressant effects, poses significant risks to brain health, particularly in the hippocampus, a region critical for learning, memory, and emotional regulati...
Chronic high-dose ketamine, widely recognized for its rapid antidepressant effects, poses significant risks to brain health, particularly in the hippocampus, a region critical for learning, memory, and emotional regulation. This narrative review aims to elucidate the molecular mechanisms underlying ketamine-induced apoptosis in hippocampal neurons, providing a comprehensive synthesis of current research findings. We examine how chronic exposure to high doses of ketamine disrupts glutamatergic signaling through NMDA receptor antagonism, leading to an imbalance in excitatory neurotransmission that triggers apoptotic pathways. Additionally, we explore the roles of neuroinflammation and oxidative stress in exacerbating neuronal vulnerability, highlighting the interplay between these mechanisms. The review discusses how chronic ketamine use activates glial cells, resulting in the release of pro-inflammatory cytokines and increased oxidative damage, further promoting neuronal cell death. Furthermore, we consider the implications of altered neurotrophic factor signaling and mitochondrial dysfunction in the context of ketamine’s neurotoxic effects. By integrating these molecular pathways, we provide insights into the critical factors contributing to ketamine-induced apoptosis. Finally, we highlight the need for further research to clarify the dose-response relationship, individual variability in treatment outcomes, and potential neuroprotective strategies. Ultimately, this review emphasizes the importance of balancing the therapeutic benefits of ketamine with its associated risks, advocating for a nuanced understanding of its long-term effects on brain health to inform clinical practices and optimize patient care.
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