Neurochem. Int. [JOURNAL]
Sun
200 papers
BLF stimulates neuronal differentiation via activation of p35/CDK5 signaling and AMPK-mediated mitochondrial regulation.
Cidem A, Oner M, Chang GR … +5 more , Yen CC, Chen KR, Yang SH, Lin H, Chen CM
Neurochem Int · 2026 Jan · PMID 41448275 · Publisher ↗
Lactoferrin (LF) is a multifunctional glycoprotein with established roles in non-neuronal cell growth and differentiation and has underexplored potential in neurodevelopment. Here, we investigated bovine lactoferrin (bLF...
Lactoferrin (LF) is a multifunctional glycoprotein with established roles in non-neuronal cell growth and differentiation and has underexplored potential in neurodevelopment. Here, we investigated bovine lactoferrin (bLF) as a neurotrophic agent, systematically evaluating its effects on neuronal differentiation, morphology, and mitochondrial regulation in PC12 cells. We demonstrated that bLF (50 μg/mL) induces neurite outgrowth comparable to nerve growth factor (NGF) while maintaining >90 % cell viability. Mechanistically, bLF activated TrkA by phosphorylation at Ser490, followed by ERK phosphorylation at Thr202/Tyr204 within 60 min, mirroring canonical NGF signaling. bLF also upregulates p35 (CDK5 activator) and phosphorylates Synapsin-I, driving presynaptic maturation. Structurally predicted to bind TrkA's ligand-binding interface, bLF synergizes with NGF to amplify differentiation outcomes. Furthermore, TMRE staining and AMPK phosphorylation assays revealed that bLF enhances axonal mitochondrial activity, surpassing NGF's effects. These results establish bLF as a multifunctional neurotrophic agent that coordinates TrkA-ERK-p35/CDK5 signaling, synaptic protein activation, and AMPK-driven mitochondrial regulation. Given its safety profile and synergy with endogenous neurotrophic pathways, bLF emerges as a promising candidate for neuroregenerative therapies targeting nerve injury or neurodegeneration.
Butein suppresses depolarization-evoked glutamate release by modulating P/Q-type Ca channels and protein kinase C pathway in rat cortical synaptosomes.
Pai MS, Hsiao MH, Lee MY … +3 more , Chang H, Chiu WC, Wang SJ
Neurochem Int · 2026 Jan · PMID 41448274 · Publisher ↗
This study examined the effects of butein, a natural chalcone, on glutamate release from rat cortical synaptosomes and elucidated the underlying mechanisms. Using 4-aminopyridine (4-AP) to evoke glutamate releases, we fo...
This study examined the effects of butein, a natural chalcone, on glutamate release from rat cortical synaptosomes and elucidated the underlying mechanisms. Using 4-aminopyridine (4-AP) to evoke glutamate releases, we found that butein inhibited evoked glutamate release in a concentration-dependent manner (IC = 11.4 μM) without altering basal release. The inhibition required extracellular Ca, as it was prevented under Ca-free conditions. Butein attenuated 4-AP-induced cytosolic Ca elevation without affecting membrane depolarization. Moreover, the inhibitory effect of butein on evoked glutamate release was prevented by blockade of vesicular glutamate transporters, P/Q-type Ca channels or protein kinase C (PKC), but was unaffected by inhibition of N-type Ca channels, protein kinase A (PKA), Ca/calmodulin-dependent kinase II (CaMKII), or mitogen-activated protein kinase (MAPK). Western blot analysis showed that butein suppressed 4-AP-induced phosphorylation of PKC, PKCα, and the downstream substrates myristoylated alanine-rich C-kinase substrate (MARCKS) and synaptosomal-associated protein-25 (SNAP-25). FM1-43 dye release and synaptotagmin 1 antibody (syt1-L ab) uptake assays further demonstrated that butein inhibits exocytotic vesicle release. Collectively, these findings indicate that butein inhibits evoked glutamate release from cortical nerve terminals by reducing P/Q-type Ca channel-dependent Ca influx and subsequently downregulating the PKC-mediated signaling pathways.
GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice.
Fan B, Liang Y, Zhi T … +5 more , Wu L, Wu Y, Yang Y, Xie Z, Wu X
Neurochem Int · 2026 Jan · PMID 41407043 · Publisher ↗
BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (...
BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD. METHODS: We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55 mice with APP/PS1 transgenic mice (APP/PS1; GPR55). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55 mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55 mice to further observe its effect on cognitive function. RESULTS: Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55 mice. CONCLUSIONS: These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.
Assessing the critical role of ceramide in the pathogenesis of Alzheimer's disease and its clinical significance.
Huang YW, Chan HC, Khoo JY … +5 more , Chan ML, Bender D, Ponnusamy VK, Belaidi AA, Ke LY
Neurochem Int · 2026 Jan · PMID 41401852 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polym...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polymorphism and dysregulated ceramide metabolism are critical links among these pathogenic processes. Ceramide accumulation in the brain contributes to Aβ generation, tau phosphorylation, and neuronal apoptosis. Elevated ceramide levels have been observed in plasma, cerebrospinal fluid, and peripheral organs such as the liver, reflecting systemic lipid dysregulation. Lipoproteins-particularly low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)-transport ceramide across the blood-brain barrier, while apoE4 isoforms exacerbate this process by disrupting vascular integrity and lipid homeostasis. In addition, hepatic and gut-derived ceramides may influence neurodegeneration through the liver-gut-brain axis. Therapeutic interventions targeting ceramide synthesis (serine palmitoyltransferase inhibitors), production (neutral sphingomyelinase inhibitors), and the ceramide/sphingosine-1-phosphate (S1P) balance show potential in preclinical models for reducing Aβ pathology, tau aggregation, and neuroinflammation. These findings position ceramide metabolism as a critical mediator of AD pathogenesis and a promising target for diagnosis and treatment. Modulating ceramide and S1P signaling could complement current amyloid- and tau-directed therapies, offering new opportunities for disease modification and early intervention.
Astaxanthin inhibits the aggregation and cytotoxicity of tauΔK280 via possible interaction with the aggregation-prone segments.
Shi H, Zhao Y
Neurochem Int · 2026 Jan · PMID 41389844 · Publisher ↗
Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the...
Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tauΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tauΔK280 cells while reducing the amount of tauΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tauΔK280 in vitro. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tauΔK280 in vitro. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tauΔK280 cells by preventing the formation of tauΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tauΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.
Tricyclic antidepressant amitriptyline potentiates brain-derived neurotrophic factor expression mediated by PKC delta-NF-kappa B signaling in primary cultured astrocytes with connexin43-knockdown.
Tokunaga N, Fujimoto R, Nakamura Y … +2 more , Hisaoka-Nakashima K, Morioka N
Neurochem Int · 2026 Jan · PMID 41389843 · Publisher ↗
Depression is a major mental illness, and its underlying mechanisms remain unclear. Emerging evidence suggests that astrocytes, which play a crucial role in brain function, may be involved in the pathophysiology of depre...
Depression is a major mental illness, and its underlying mechanisms remain unclear. Emerging evidence suggests that astrocytes, which play a crucial role in brain function, may be involved in the pathophysiology of depression. We previously showed that downregulation of astrocytic connexin43 (Cx43) enhances the antidepressant effect of amitriptyline. However, the precise molecular mechanisms underlying this phenomenon remain unknown. In the present study, we investigated the signaling pathways involved in the antidepressant action of amitriptyline using an in vitro model involving Cx43-knockdown astrocytes. We found that amitriptyline potentiated the expression of brain-derived neurotrophic factor (BDNF), a key neurotrophic factor, in Cx43-knockdown astrocytes. This potentiation was mediated by the activation of Gq protein-coupled lysophosphatidic acid (LPA) receptors, a pathway that was sensitized by Cx43 downregulation. We further demonstrated that this signaling cascade involved the activation of Protein Kinase C (PKC) δ and transcription factor NF-κB, but not the conventional BDNF transcription factor CREB. We propose that Cx43 downregulation enhances the antidepressant effect of amitriptyline by specifically engaging the Gq-PKCδ-NF-κB pathway. These findings suggest that Cx43 downregulation in astrocytes, which has been considered a pathological feature of depression, may paradoxically contribute to the therapeutic efficacy of antidepressants by sensitizing a specific signaling pathway. Our study provides new insights into the molecular mechanism of antidepressant action and highlights the potential role of astrocytic Cx43 in modulating therapeutic responses.
SPI1 suppresses YAP phosphorylation in vascular endothelial cells to prevent intracranial aneurysm progression.
Liu Y, Zheng D, Zhao L … +4 more , Leng B, Sun Q, Bian L, Zheng Y
Neurochem Int · 2026 Jan · PMID 41381001 · Publisher ↗
This study aims to elucidate the mechanism by which YAP mediates the activity of vascular endothelial cells (ECs) in the biological process of intracranial aneurysms (IAs) and to provide a novel target for noninvasive IA...
This study aims to elucidate the mechanism by which YAP mediates the activity of vascular endothelial cells (ECs) in the biological process of intracranial aneurysms (IAs) and to provide a novel target for noninvasive IAs treatment. Single-nuclei RNA profiling of aneurysmal cells revealed that ECs within aneurysms exhibit an intermediate identity between arterial and venous/capillary cells, rather than clustering within the normal arterial population. These specific human ECs showed downregulated YAP expression under turbulent flow. Immunostaining of human IA tissues demonstrated reduced YAP and increased phosphorylated YAP (p-YAP) compared with superficial temporal artery walls. Using YAP-knockdown human brain microvascular endothelial cells (HBMECs), we observed elevated expression of senescence markers p21 and p16, accompanied by diminished proliferation and migration capacities. Furthermore, SPI1 (also known as PU.1) overexpression alleviated EC degeneration induced by turbulent flow through suppression of YAP phosphorylation. Collectively, our findings indicate that turbulent flow markedly reduces YAP expression while promoting its phosphorylation, thereby accelerating endothelial senescence. Importantly, SPI1 overexpression effectively mitigated turbulent-flow-induced endothelial senescence, suggesting that SPI1 may serve as a potential therapeutic target for preventing aneurysmal progression.
Investigating the role of GABAergic interneurons in the antidepressant-like mechanism of agomelatine.
Ye S, Xu Q, Amin N … +4 more , Bao L, Yang Y, Abbasi IN, Fang M
Neurochem Int · 2026 Jan · PMID 41381000 · Publisher ↗
Depression is a prevalent and debilitating mental disorder with substantial impacts on global health and socioeconomic costs. Despite various antidepressants targeting monoaminergic neurotransmission, a significant propo...
Depression is a prevalent and debilitating mental disorder with substantial impacts on global health and socioeconomic costs. Despite various antidepressants targeting monoaminergic neurotransmission, a significant proportion of patients fail to achieve remission with existing treatments. Agomelatine (AGO), as a novel antidepressant, has shown promise in treating depression. However, the neural circuits and molecular mechanisms underlying its therapeutic effects remain largely unknown. This study aimed to investigate the role of GABAergic neural circuits on the antidepressant effects of AGO and elucidate the underlying cellular and molecular mechanisms. A chronic unpredictable mild stress (CUMS) mouse model was used to induce depressive-like behaviors. Genetic manipulation was employed to selectively ablate GABAergic neurons, and the effects of AGO treatment on behavioral performance and neuronal morphology were assessed. Additionally, the expression of synaptic and clock genes was analyzed to explore underlying molecular mechanisms. We found that AGO treatment significantly improved the behavioral performance of CUMS mice and rescued the structural integrity and quantity of central neurons. It regulated the protein expressions of VGAT, VGLUT1, and Gad65 in the brain tissues of CUMS mice. Notably, AGO altered the protein and gene expressions in GABAergic neural circuits across different brain regions. Morphological analysis revealed that AGO improved dendritic spine density and length in neurons in the selective ablation of GABAergic interneurons. The antidepressant effects of AGO involve the modulation of GABAergic neural circuits as a critical but non-exclusive target, alongside the restoration of GABAergic-glutamatergic balance, synaptic function, and clock gene expressions. These findings highlight AGO's potential in normalizing disrupted neuronal function in depression and offer insights into novel multi-target therapeutic strategies.
Interplay and intervention of epigenetic dysregulation in traumatic brain injury pathology.
Faasen SG, Arruri V, Alisch RS
Neurochem Int · 2026 Jan · PMID 41318069 · Full text
Traumatic brain injury (TBI) occurs when an external mechanical force damages brain tissue, leading to temporary or lasting disturbances in brain structure and function. The heterogeneous molecular and phenotypic nature...
Traumatic brain injury (TBI) occurs when an external mechanical force damages brain tissue, leading to temporary or lasting disturbances in brain structure and function. The heterogeneous molecular and phenotypic nature of TBI poses a major challenge to translating basic research discoveries into clinically effective interventions. Emerging evidence indicates that epigenetic and epitranscriptomic mechanisms, including histone modifications, DNA methylation, and RNA modifications, play pivotal roles in the molecular response to TBI. In this review, we discuss post-TBI epigenomic alterations with a focus on histone modifications, DNA methylation, and RNA modifications, and we highlight preclinical interventions that modulate these alterations and improve related post-TBI behavioral outcomes.
A novel GSK3β inhibitor ameliorates tau aggregation and neuroinflammation in Alzheimer's disease.
Ning XY, Liu WJ, Zhou LJ … +10 more , Wang N, Li XZ, Wu LM, Li ZS, Yang AZ, Liu SY, Xu ZH, Xun FH, Xu ZH, Zhao QC
Neurochem Int · 2026 Jan · PMID 41318068 · Publisher ↗
In Alzheimer's disease, increased GSK3β activity drives tau phosphorylation and directly or indirectly triggers neuroinflammation, neuronal damage and cognitive decline. We previously developed a novel GSK3β inhibitor, Z...
In Alzheimer's disease, increased GSK3β activity drives tau phosphorylation and directly or indirectly triggers neuroinflammation, neuronal damage and cognitive decline. We previously developed a novel GSK3β inhibitor, ZLWH-60, which demonstrated inhibitory activity with an IC50 of 11.5 nM. Here, we comprehensively evaluated the therapeutic potential of ZLWH-60 in suppressing tau pathology and neuroinflammation using multiple chemically-induced AD models. Our results demonstrate that ZLWH-60 could reduce the phosphorylation of multiple tau epitopes by inhibiting the activity of GSK3β, thereby ameliorating cognitive impairments in OKA-induced mouse model. In the LPS-induced mouse model, ZLWH-60 also reduced the secretion of inflammatory factors in the brain, exerting a neuroprotective effect. Our data highlight that ZLWH-60, as a GSK3β inhibitor, has a powerful ability to reduce the phosphorylation of tau protein and shift the balance of the inflammatory response from pro-inflammatory to anti-inflammatory, demonstrating the potential for therapeutic use of this drug to control AD.
ERBB4 colocalizes with phosphorylated tau aggregates in multiple tauopathies.
Matsumoto C, Kabuta T, Sano T … +3 more , Murayama S, Saito Y, Takahashi Y
Neurochem Int · 2026 Jan · PMID 41297670 · Publisher ↗
The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4-a receptor tyrosine kinase-triggers multiple cellular responses, including proliferation, apo...
The neuregulin-ERBB4 pathway is essential for maintaining cellular function. Upon stimulation by its ligand, neuregulin, ERBB4-a receptor tyrosine kinase-triggers multiple cellular responses, including proliferation, apoptosis, differentiation, and neuromuscular junction formation. Previous research has implicated dysregulated ERBB4 signaling in the pathophysiology of several neurodegenerative disorders, such as Alzheimer's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, and Parkinson's disease. In this study, we examined ERBB4 expression in diseases characterized by phosphorylated tau (MAPT) pathology. We found that ERBB4 colocalized with neuronal and glial phosphorylated tau-positive inclusions in multiple tauopathies, including Pick's disease, Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutation. Conversely, ERBB4 did not colocalize with α-synuclein aggregates in α-synucleinopathies (Parkinson's disease and multiple system atrophy) or with neuronal intranuclear inclusions in triplet repeat disorders (Huntington's disease and dentatorubral-pallidoluysian atrophy). A co-immunoprecipitation assay indicated that ERBB4 can interact with tau intracellularly. Notably, in corticobasal degeneration, we observed ectopic ERBB4 expression in astrocytes lacking apparent phosphorylated tau aggregates. These findings suggest a potential role for ERBB4 in the pathophysiology of tau-related neurodegenerative diseases.
Essential oils by name and by nature: a review of their antioxidant and neuroprotective potential in Parkinson's disease.
Cannas C, Zoroddu S, Peana AT … +3 more , Rocchitta G, Bagella L, Migheli R
Neurochem Int · 2026 Jan · PMID 41297669 · Publisher ↗
Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) and endogenous antioxidants, plays a central role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease...
Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) and endogenous antioxidants, plays a central role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). The brain's high oxygen demand and abundance of polyunsaturated fatty acids make it particularly vulnerable to ROS-induced damage. Despite major advances in research, no disease-modifying treatments for PD are currently available. Consequently, increasing attention has been directed toward natural bioactive compounds with antioxidant and neuroprotective properties. Among these, essential oils (EOs), volatile plant-derived mixtures with documented antioxidant, anti-inflammatory, and neuroactive effects, are emerging as promising adjuvants for PD management. This review critically examines the antioxidant and neuroprotective effects of well-characterized EOs evaluated in both in vitro and in vivo models of neurodegeneration. Literature searches were conducted in PubMed and Scopus up to March 2025, identifying studies investigating EOs or their major components in PD-related experimental settings. Evidence indicates that essential oils derived from the Citrus and Rosa genus, and the Lamiaceae family, can reduce intracellular ROS accumulation, inhibit lipid peroxidation, enhance endogenous antioxidant enzyme activity, and modulate both apoptotic and inflammatory pathways. These multitarget actions are often attributed to synergistic interactions among EO constituents, such as limonene, linalool, thymol, and carvacrol. Owing to their low toxicity and ability to cross the blood-brain barrier, EOs represent promising natural candidates for the development of complementary therapeutic strategies in PD. Further mechanistic and translational studies are warranted to substantiate their clinical potential.
GDNF-AS1 mediated LHX2/METTL3/NCOA4 axis inhibits glioma progression via induction of ferroptosis.
Zhou Y, Liu Z, Ma W
Neurochem Int · 2026 Jan · PMID 41275921 · Publisher ↗
Glioma, particularly glioblastoma (GBM), represents the most aggressive primary brain tumor with limited treatment options and poor prognosis. Emerging evidence highlights ferroptosis induction as a promising therapeutic...
Glioma, particularly glioblastoma (GBM), represents the most aggressive primary brain tumor with limited treatment options and poor prognosis. Emerging evidence highlights ferroptosis induction as a promising therapeutic strategy, while long non-coding RNAs (lncRNAs) have gained attention as potential biomarkers and regulators in glioma pathogenesis. This study aimed to investigate the molecular mechanism of lncRNA Glial Cell Line-Derived Neurotrophic Factor Antisense RNA 1 (GDNF-AS1) in glioma cell ferroptosis through the LIM Homeobox 2 (LHX2)/Methyltransferase-Like 3 (METTL3)/Nuclear Receptor Coactivator 4 (NCOA4) pathway using Normal Human Astrocytes (NHA) and glioma cell lines (U87MG, T98G, U251, and A172), along with intracranial and subcutaneous xenotransplantation models established in BALB/c nude mice. Functional experiments demonstrated that GDNF-AS1, LHX2, and NCOA4 were downregulated while METTL3 was upregulated in glioma cells. GDNF-AS1 overexpression promoted mitochondrial damage and oxidative stress by enhancing ferroptosis, ultimately impairing glioma cell biological functions. METTL3 silencing augmented GDNF-AS1's effects, further exacerbating ferroptosis and oxidative stress while inhibiting glioma progression. Mechanistically, GDNF-AS1 recruited transcription factor LHX2 to upregulate its enrichment at the METTL3 promoter, thereby suppressing METTL3 transcription, reducing N6-Methyladenosine (m6A) levels, promoting NCOA4 expression, and inducing ferroautophagy and ferroptosis in glioma cells. These findings demonstrate that GDNF-AS1 inhibits glioma development by activating ferroptosis through the LHX2/METTL3/NCOA4 axis.
Therapeutic potential of K channels in the attenuation of Parkinson's disease pathogenesis and progression - A review.
Gundi B, Ho HL, Zhang X … +6 more , He A, Xin D, Ferreira AFF, Britto LR, Feng ZP, Sun HS
Neurochem Int · 2026 Jan · PMID 41275920 · Publisher ↗
Parkinson's disease (PD) is one of the most prevalent progressive neurodegenerative diseases today. However, existing treatments primarily focus on symptom management rather than attenuating disease progression and patho...
Parkinson's disease (PD) is one of the most prevalent progressive neurodegenerative diseases today. However, existing treatments primarily focus on symptom management rather than attenuating disease progression and pathogenesis. ATP-sensitive potassium (K) ion channels play a significant role in motor control and coordination within the basal ganglia and have been implicated in the dopaminergic depletion mechanisms underlying PD. Recent studies have explored the potential of K channel inhibitors to slow PD pathogenesis and progression. Both pharmacological inhibition and genetic inactivation of these channels have been shown to reduce oxidative stress, dopamine (DA) depletion, and subsequent motor deficits. Contrastingly, alternative evidence suggests that K channel openers (KCOs) may elicit similar effects, highlighting the need for further exploration of K-mediated DA depletion mechanisms in PD. Future studies expanding our understanding of the mechanistic action of K in PD are essential to effectively leverage the channel's potential as a therapeutic target for combating PD pathology.
Transgenerational non-genomic transmission of acquired nervous system Phenotypes: Narrative review and epigenetic insights.
Abou Merhi A, Sivan V, Koueik J … +5 more , Walsh A, Papale LA, Alisch RS, Hogan K, Iskandar BJ
Neurochem Int · 2025 Dec · PMID 41265750 · Publisher ↗
Transgenerational epigenetic inheritance (TEI) refers to the transmission of phenotypic traits across multiple generations independent of changes in DNA sequence that are mediated by epigenetic mechanisms, including DNA...
Transgenerational epigenetic inheritance (TEI) refers to the transmission of phenotypic traits across multiple generations independent of changes in DNA sequence that are mediated by epigenetic mechanisms, including DNA methylation, histone modifications, chromatin morphology, and non-coding RNAs. This review focuses on manuscripts that report epigenetic mechanisms in the transgenerational inheritance of nervous system phenotypes in both mammalian and non-mammalian experimental models. Non-mammalian organisms such as C. elegans and Drosophila have been instrumental in disclosing TEI pathways comprising small RNA networks, histone-based modifications, and N6-methyladenine modifications that balance limited cytosine methylation. Authenticating TEI in mammals is complex due to extensive elimination of epigenetic factors and pathways essential for mitosis that do not participate in meiosis, germline development, and early embryogenesis, termed epigenetic "erasure" or "reprogramming". Specific epigenetic pathways that guide neural development, including DNA methylation at metastable epialleles and gamete-derived small RNAs, escape erasure, and have been linked to altered neurodevelopment and behavior in offspring. Together, these data indicate a role for epigenetic regulation in tuning neural circuits during neurodevelopment with enduring impacts on brain organization and behavior. This perspective situates neural TEI within a mechanistic framework that links early environmental exposures to long-lived neuronal circuit properties and behavioral outcomes. Accordingly, elucidating neural-specific TEI mechanisms alone and in combination will enhance our understanding of how ancestral environmental exposures shape neurological structures, functions, behaviors, and susceptibilities to disease across generations. The present review synthesizes current evidence, identifies key interpretative challenges, and details directions for future research in neural TEI.
Esketamine attenuates post-traumatic stress disorder via suppressing neuroinflammation and abnormal myelination.
Gu Z, Song R, Liu G … +7 more , Yu H, Ju L, Su Y, Bi J, Qiu J, Dong Y, Liu A
Neurochem Int · 2025 Dec · PMID 41265749 · Publisher ↗
BACKGROUND: Post-traumatic stress disorder (PTSD) is a chronic psychological disorder that is induced by traumatic events. The pathophysiological mechanism of PTSD involves complex neurobiological processes. However, the...
BACKGROUND: Post-traumatic stress disorder (PTSD) is a chronic psychological disorder that is induced by traumatic events. The pathophysiological mechanism of PTSD involves complex neurobiological processes. However, the underlying mechanism is not clear, leading to lack of effective therapeutic interventions. METHODS: Mice were exposed to the electric foot shocks using the contextual fear memory paradigm. A subanesthetic dose (30 mg/kg) of esketamine or saline was administered via intraperitoneal (i.p.) injection 1 h after the electric foot shocks. Fear retrieval was tested on day 1 and day 7 after fear conditioning. Anxiety-like and depressive-like behaviors were evaluated using the open field test and elevated plus maze on day 1 and day 2, respectively, after the foot-shocks. The medial prefrontal cortex (mPFC) was freshly collected 1 h after esketamine administration following the foot-shocks for RNA sequencing. Additionally, the mPFC were collected 4 days after fear conditioning and subjected to quantitative real-time PCR (qPCR) analysis and immunofluorescence staining. RESULTS: A single subanesthetic dose of esketamine significantly alleviated PTSD-like symptoms in mice induced by electric foot-shocks. RNA sequencing revealed the involvement of neuroinflammation and aberrant myelination in the pathogenesis of PTSD. Subsequently, we observed a significant increase in the number of ionized calcium binding adaptor molecule 1 (Iba1)-positive microglial cells and transcriptional upregulation of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), in the mPFC of mice subjected electric foot shocks, indicating elevated neuroinflammation. Subanesthetic esketamine administration significantly attenuated this neuroinflammatory response. Furthermore, electric foot shocks caused significantly increased the expression of myelin basic protein (MBP), myelin-associated glycoprotein (MAG), oligodendrocyte transcription factor 2 (Olig2) and platelet-derived growth factor receptor-α (PDGFRα), suggesting increased myelination associated with PTSD. Esketamine treatment also rescued this abnormal myelination. CONCLUSION: Our study demonstrates the contribution of neuroinflammation and abnormal myelination are closely related to the development of PTSD. Moreover, a subanesthetic dose of esketamine alleviated the PTSD-like symptoms in mice by suppressing foot-shock-induced increases in neuroinflammation and myelination. These results highlight the therapeutic potential of subanesthetic esketamine in mitigating PTSD.
Transcription factor EB inhibition in response to genotoxic stress promotes apoptosis of glioblastoma cells.
Park SH, Jeong M, Kong MJ … +1 more , Choi KC
Neurochem Int · 2025 Dec · PMID 41248831 · Publisher ↗
Glioblastoma multiforme (GBM), one of the most malignant brain cancers, responds poorly to chemotherapy and surgery. Transcription factor EB (TFEB) is markedly overexpressed in GBM cells. We investigated whether TFEB con...
Glioblastoma multiforme (GBM), one of the most malignant brain cancers, responds poorly to chemotherapy and surgery. Transcription factor EB (TFEB) is markedly overexpressed in GBM cells. We investigated whether TFEB contributes to resistance to genotoxic stress and whether its inhibition promotes apoptosis of GBM cells and glioma stem cells (GSCs). Specifically, we examined whether combined treatment with etoposide and SAHA overcomes TFEB-mediated resistance and enhances apoptotic cell death. We examined the effects of etoposide, a topoisomerase II inhibitor, and SAHA, a histone deacetylase inhibitor, on TFEB expression and apoptotic signaling in human GBM cells and GSCs. To assess TFEB-mediated drug resistance, we measured cell viability, proliferation, and tumorsphere formation following single or combined treatments. Apoptotic signaling was analyzed by western blotting, MTT assays, and tumorsphere formation assays. Functional roles of TFEB were further investigated using overexpression and shRNA knockdown approaches. Treatment with etoposide induced apoptosis and reduced TFEB expression in GBM cells. Co-treatment with etoposide and SAHA synergistically increased cleaved PARP and phosphorylated H2AX levels, indicating enhanced apoptotic activity. In TFEB-overexpressing and knockdown GBM cells, apoptosis sensitivity varied according to TFEB expression levels. In GSCs, combination treatment significantly suppressed cell proliferation and tumorsphere formation, accompanied by reduced TFEB expression and oligomerization, and increased apoptosis. Our findings suggest that TFEB promotes the chemoresistance of GBM tumors and GSCs by suppressing apoptosis. Co-treatment with etoposide and SAHA inhibits TFEB activity and enhances apoptotic cell death, representing a promising therapeutic strategy for treating malignant brain tumors.
Characterizing stroke-related cellular changes in the surviving neurons of mouse ischemic stroke.
Ikegami T, Sasaki T, Shimbo T … +12 more , Kitayama T, Yamamoto Y, Ouchi Y, Yamazaki S, Sugiyama S, Nishiyama K, Gon Y, Okazaki S, Todo K, Matsumura S, Tamai K, Mochizuki H
Neurochem Int · 2025 Dec · PMID 41223896 · Publisher ↗
Rapid restoration of cerebral blood flow through endovascular therapy is crucial for minimizing neuronal injury in ischemic stroke. This study characterized cellular and molecular alterations during the acute and subacut...
Rapid restoration of cerebral blood flow through endovascular therapy is crucial for minimizing neuronal injury in ischemic stroke. This study characterized cellular and molecular alterations during the acute and subacute phases of distal middle cerebral artery occlusion (dMCAO) in mice using single-nucleus (snRNA-seq) and single-cell (scRNA-seq) RNA sequencing. C57BL/6 mice were assigned to control, sham, dMCAO 3-day, and dMCAO 14-day groups. snRNA-seq identified diverse cell populations, including neurons (glutamatergic and GABAergic), fibroblast-like cells, astrocytes, oligodendrocytes, microglia, endothelial cells, and pericytes. Microglia shifted from homeostatic (Siglech, P2ry12) to acute-phase (Lgals1, Top2a, Mki67) and disease-associated states, consistent with previous evidence confirming that our dataset captured stroke-related dynamics. snRNA-seq enabled efficient recovery and analysis of neurons, revealing stroke-induced cell state changes.; notably, glutamatergic neurons declined on day 3, while endothelial cells increased. Gene ontology analysis indicated neuronal death, autophagy, and cAMP biosynthesis pathways. Elevated Syngap1, Ikbkb, and Rock1 expression across glutamatergic subclusters suggested roles in cell death-related mechanisms and vulnerability to ischemic injury. Dissociation of SynGAP1 from PSD-95 after ischemia may enhance ERK1/2 phosphorylation, whereas ischemic preconditioning suppresses this dissociation and prevents ERK1/2 overactivation. Immunohistochemistry confirmed Syngap1 and cAMP response element-binding (CREB) pathway activation at 3 and 14 days post-ischemia, aligning with sequencing results. Suppressing CREB with pAAV-A-CREB reduced neuronal survival, underscoring its role in autophagy and neuroprotection. These findings provide mechanistic insight into stroke-induced molecular alterations and identify autophagy and cAMP pathways within the penumbra as promising therapeutic targets.
Striatal injection of aminochrome in Wistar rats induces early-stage behavioral changes of Parkinson's disease and dopaminergic degeneration in the caudal and medial regions of the nigra pars compacta.
Teles-Souza J, Oliveira JVR, Araújo FM … +12 more , Sanches FS, Jesus LB, Souza SL, Brito ADPS, Oliveira Leite CM, Ferrolho GJ, Fernandez-Villalba E, Vilas Bôas DS, Santana RC, Costa SL, Herrero MT, Silva VDA
Neurochem Int · 2025 Dec · PMID 41205817 · Publisher ↗
Most preclinical Parkinson's disease (PD) models use neurotoxic agents to cause rapid dopaminergic neuron degeneration, mimicking the late stage of PD. That creates a gap in understanding early-stage pathophysiology, cri...
Most preclinical Parkinson's disease (PD) models use neurotoxic agents to cause rapid dopaminergic neuron degeneration, mimicking the late stage of PD. That creates a gap in understanding early-stage pathophysiology, critical for neuroprotective therapies and early diagnosis. To replicate the prodromal stage of PD, it is pivotal that preclinical study models promote a slow and selective death of dopaminergic neurons, triggering degenerative processes and early symptoms. In this context, we investigated behavioral and neuronal changes using a model of unilateral aminochrome injection (6 nmol/6 μL) in the striatum of adult male Wistar rats (CEUA-ICS, Protocol 3006070223), focusing on subtle changes representative of the early stages of PD. On the fourteenth day after the stereotaxic injection, we observed behavioral impairments marked by a reduction of frequency of entries, time spent and distance traveled in the central quadrants in the open field test, reduction of frequency of rearing and grooming in the open field, as well as an increase in the rate of motor asymmetry in the cylinder test. In addition, we observed a decrease in the transition of animals through the elevated plus maze, with a reduction in the number of entries into the open arm. Immunohistochemical analyses indicated that aminochrome induces cytotoxicity for tyrosine hydroxylase-positive (TH) cells and induces astrogliosis and microgliosis. Our findings show that striatal injection of aminochrome induces a reduction in the density of TH fibers in the striatum, a slight reduction in the number of dopaminergic neurons in the caudal and medial regions of the nigra pars compacta (SNpc), and subtle motor deficits typical of an early stage of PD. Here, we provided evidence that aminochrome can induce a rodent model of the prodromal stages of PD.
Functional impact of CYFIP2 RNA editing on actin regulation, axon growth, and spinogenesis.
La Via L, Ndoj E, Bertoli M … +10 more , Mutti V, Carini G, Filippini A, Bono F, Fiorentini C, Ribaudo G, Gianoncelli A, Borsani G, Russo I, Barbon A
Neurochem Int · 2025 Dec · PMID 41203017 · Publisher ↗
Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a component of the wave regulatory complex (WRC), one of the most important players in regulating cellular actin dynamics. Interestingly, the CYFIP2 transcript undergoes...
Cytoplasmic FMRP-interacting protein 2 (CYFIP2) is a component of the wave regulatory complex (WRC), one of the most important players in regulating cellular actin dynamics. Interestingly, the CYFIP2 transcript undergoes RNA editing, an epitranscriptomic modification catalyzed by ADAR enzymes, which leads to adenosine (A) to inosine (I) deamination. CYFIP2 editing in the coding sequence results in a K/E substitution at amino acid 320. The functional meaning of this regulation is still unknown. In this study, we aimed to investigate the potential implications of CYFIP2 RNA editing related to actin dynamics during cell differentiation, axon development and synaptogenesis in neural cells. We generated SH-SY5Y neuroblastoma cell lines in which the CYFIP2 gene has been functionally inactivated via CRISPR-Cas9 technology. CYFIP2 KO cells exhibited profound actin filament disorganization and loss of the ability to differentiate into a neuron-like phenotype. The overexpression of both the unedited (K) and edited (E) CYFIP2 isoforms restored normal abilities. Finally, we used primary neuronal cultures in which endogenous CYFIP2 was knocked down via short hairpin RNA (shRNA) technology and CYFIP2 editing variants were overexpressed. While CYFIP2-KD cells presented a decrease in axon development and spine frequency, CYFIP2-E variants increased the number of axon branches, total axon length and dendritic spine frequency compared with both CYFIP2-KD cells and CYFIP-K variants. Overall, our work reveals for the first time the functional significance of the CYFIP2 K/E RNA editing process in regulating the spread of neuronal axons during the initial stages of in vitro development and spinogenesis.
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