Neurochem. Int. [JOURNAL]
Sun
200 papers
Mitofusin 2 in central nervous system disorders: Roles in mitochondrial dynamics and therapeutic Implications.
Tang L, Huang J, Xia R … +3 more , Xu W, Li J, Zhang M
Neurochem Int · 2026 Jun · PMID 42035797 · Publisher ↗
Mitochondrial dynamics have been increasingly recognized as a central determinant in the pathogenesis of central nervous system (CNS) disorders. Mitofusin 2 (MFN2), a critical mitochondrial fusion protein, preserves mito...
Mitochondrial dynamics have been increasingly recognized as a central determinant in the pathogenesis of central nervous system (CNS) disorders. Mitofusin 2 (MFN2), a critical mitochondrial fusion protein, preserves mitochondrial network integrity and participates in fission, mitophagy, and axonal transport, thereby maintaining neuronal function and energy homeostasis. Structural features of MFN2 underpin its diverse regulatory roles, whereas MFN2 deficiency leads to mitochondrial fragmentation, metabolic dysfunction, oxidative stress, and neuronal impairment. This review summarizes the molecular mechanisms of MFN2 in the CNS and its impact on neuronal survival, synaptic function, and signaling pathways. In addition, we highlight potential MFN2-targeted interventions, including natural compounds, pharmacological agents, and emerging small-molecule activators, while also discussing disease-specific mechanisms and translational challenges such as endoplasmic reticulum (ER)-mitochondria communication abnormalities and blood-brain barrier permeability.
Therapeutic potential of biased μ-opioid receptor agonists for delaying opioid tolerance in chronic pain management.
Liu X, Song Q, Wang S … +4 more , Hou R, Jia H, Zhang Z, Liang Y
Neurochem Int · 2026 Jun · PMID 42031206 · Publisher ↗
Opioid tolerance presents a significant challenge in the treatment of chronic pain, leading to reduced responsiveness following prolonged activation of the μ-opioid receptor (MOR). This necessitates escalating doses, the...
Opioid tolerance presents a significant challenge in the treatment of chronic pain, leading to reduced responsiveness following prolonged activation of the μ-opioid receptor (MOR). This necessitates escalating doses, thereby increasing the risk of adverse effects. Traditional opioids activate both G protein-dependent and β-arrestin signaling pathways, accelerating tolerance development and causing severe side reactions. In contrast, biased MOR agonists stabilize a receptor conformation that promotes sustained G protein coupling and signaling, potentially maximizing Gi/o protein pathway activation for analgesic effects while reducing β-arrestin pathway recruitment, which contributes to tolerance and complications. Additionally, biased MOR agonists may delay opioid tolerance by modulating the Toll-like receptor signaling pathway, the release of pro-inflammatory cytokines, and synaptic plasticity. This review discusses the profiles of specific biased agonists (e.g., TRV130, PZM21, BMS-986122, and SR-17018), along with current challenges and future research directions. Our aim is to clarify the molecular mechanisms and signaling pathways by which biased MOR agonists may delay opioid tolerance, providing a foundation for more effective therapeutic strategies in chronic pain management.
C3 and C5 complement cascade activation in brain injury and disease: Molecular mechanisms, pathological roles, and therapeutic implications.
Woodard GE
Neurochem Int · 2026 Jun · PMID 42025804 · Publisher ↗
The complement system represents a crucial component of innate immunity with increasingly recognized roles in central nervous system pathology and homeostasis. Complement components C3 and C5 serve as central molecular h...
The complement system represents a crucial component of innate immunity with increasingly recognized roles in central nervous system pathology and homeostasis. Complement components C3 and C5 serve as central molecular hubs in the complement cascade, orchestrating inflammatory responses, synaptic pruning, and neuronal injury across diverse neurological conditions. This comprehensive review examines the molecular mechanisms underlying C3 and C5 activation in the brain, their pathological contributions to acute brain injuries including traumatic brain injury and ischemic stroke, and their complex involvement in chronic neurodegenerative diseases such as Alzheimer disease, multiple sclerosis, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. Emerging evidence demonstrates that complement activation in the central nervous system extends beyond traditional immune functions to encompass critical roles in neurodevelopment, synaptic plasticity, and neural circuit refinement. The dual nature of complement function in the brain, exhibiting both neuroprotective and neurodegenerative properties depending on context and activation levels, presents unique therapeutic challenges and opportunities. This review synthesizes current understanding of complement-mediated neuroinflammation, discusses validated and emerging therapeutic strategies targeting C3 and C5, evaluates complement biomarkers for disease diagnosis and monitoring, and identifies critical knowledge gaps requiring future investigation. Understanding the nuanced roles of C3 and C5 in neurological disease provides essential foundations for developing targeted immunomodulatory therapies that preserve beneficial complement functions while mitigating pathological activation.
Inhibition of S100A9 mitigates aging-related mitochondrial dysfunction and neurodegeneration in Parkinson's disease.
Tan LL, Ma XY, Xia YM … +9 more , Li T, Li MA, Wu J, Nie X, Huang SB, Cui C, Zhao WJ, Qiao CM, Shen YQ
Neurochem Int · 2026 Jun · PMID 41985718 · Publisher ↗
Aging is the most important risk factor for Parkinson's disease (PD). S100A9, a calcium-binding protein, is closely related to a variety of aging-related diseases, but its role in the pathogenesis of PD is still unclear....
Aging is the most important risk factor for Parkinson's disease (PD). S100A9, a calcium-binding protein, is closely related to a variety of aging-related diseases, but its role in the pathogenesis of PD is still unclear. This study aims to investigate the role of S100A9 in aging-related mechanisms in PD. C57BL/6J mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP; 15 mg/kg four times daily), followed by Paquinimod (a S100A9 inhibitor; 7 mg/kg, once a day for 7 days after model establishment, totaling 8 doses). We found that MPTP induced significant motor deficits and dopaminergic nerve damage, accompanied by up-regulation of p21 expression, down-regulation of Lamin B1 expression, and significant increases in SASP factors such as MMP9, IL-1α, IL-1β, and IL-6. Treatment with recombinant S100A9 protein induced senescence-like molecular alterations and reduced expression of mitochondrial biogenesis-associated genes in astrocytes in vitro. Inhibition of S100A9 effectively improved movement disorders, restore TH-positive fiber density, reduce the expression of cell senescence markers and SASP factors, and up-regulate mitochondrial function-related genes. Studies have shown that S100A9 plays a key bridge between aging and neurodegeneration in PD. Inhibition of S100A9 may be a potential therapeutic strategy to alleviate cell senescence and mitochondrial damage in PD.
Disrupting PQBP1-eEF2 protein-protein interaction: From synaptic translation to immunity and cancer.
Kamel EM, Khadrawy SM, Ali MAM … +5 more , Ahmed NA, Yassin NYS, Alkhedhairi S, Alkhayl FFA, Lamsabhi AM
Neurochem Int · 2026 Jun · PMID 41960772 · Publisher ↗
Polyglutamine-binding protein 1 (PQBP1) has emerged as a multifaceted regulator of gene expression, acting not only in the nucleus to influence transcription and splicing but also in the cytoplasm to control protein synt...
Polyglutamine-binding protein 1 (PQBP1) has emerged as a multifaceted regulator of gene expression, acting not only in the nucleus to influence transcription and splicing but also in the cytoplasm to control protein synthesis. A recent discovery identified a direct interaction between PQBP1 and the translation elongation factor eEF2, unveiling a new checkpoint in the elongation phase of protein synthesis. PQBP1 binds preferentially to the non-phosphorylated form of eEF2 and protects it from phosphorylation at Thr56 by its kinase eEF2K. Through this mechanism, PQBP1 promotes continuous elongation under conditions where unchecked eEF2K activity would otherwise stall ribosomes. The PQBP1-eEF2 complex plays critical roles in maintaining global proteome homeostasis and enabling activity-dependent protein synthesis in neurons. Disruption of this protein-protein interaction (PPI), whether by genetic mutations in PQBP1 or by sequestration of PQBP1 in cellular aggregates, has been linked to pathological states ranging from intellectual disability and impaired synaptic plasticity to altered innate immune responses and possibly tumorigenesis. In this review, we summarize the current understanding of the PQBP1-eEF2 interaction, its structural basis and regulation, the physiological processes it governs, and the consequences of its disruption in disease. We also discuss therapeutic considerations - when stabilizing this interaction might be beneficial (e.g. to restore synaptic function in neurodegeneration) versus when inhibiting it could be advantageous (e.g. to dampen excessive translation in cancer). Finally, we highlight experimental strategies and open questions for future research on this newly recognized nexus of translation control.
Inhibition of ESCRT-III activates alternative pathways for protein degradation and secretion.
Fujiwara M, Sakai R, Takahashi M … +3 more , Matsumoto G, Hashimoto T, Kabuta T
Neurochem Int · 2026 Jun · PMID 41933658 · Publisher ↗
Mutations in components of the endosomal sorting complex required for transport (ESCRT)-III, such as CHMP2B and VPS4A/B, are known to cause neurological disorders, including frontotemporal lobar degeneration (FTLD) and d...
Mutations in components of the endosomal sorting complex required for transport (ESCRT)-III, such as CHMP2B and VPS4A/B, are known to cause neurological disorders, including frontotemporal lobar degeneration (FTLD) and developmental encephalopathies. Although ESCRT complexes are required for macroautophagy and for certain forms of microautophagy, the effects of ESCRT-III dysfunction on intracellular protein degradation remain unclear. In this study, we investigated how ESCRT-III dysfunction affects intracellular protein clearance using multiple genetic manipulations, including a dominant-negative form of VPS4 and an FTLD-associated CHMP2B mutant. We found that despite marked suppression of macroautophagic flux, inhibition of ESCRT-III promoted protein clearance in multiple cell types, including Neuro2a cells. Such clearance was also observed in ATG13-or ATG5-knockout cells, confirming that this process occurs independently of macroautophagy. Imaging revealed increased punctate accumulation of substrate proteins in lysosomes, suggesting the activation of a microautophagy-like pathway independent of ESCRT-III. In addition, ESCRT-III inhibition enhances extracellular vesicle-independent protein secretion. Cell-to-cell transmission of aggregated tau, assessed using conditioned medium, was also promoted by ESCRT-III inhibition. These findings suggested that ESCRT-III dysfunction, while impairing canonical autophagy, paradoxically activates alternative degradation and secretion pathways that may contribute to the pathogenesis of neurological disorders.
AICAR improves depression-like behaviors and is associated with hippocampal AMPK activation and modulation of neurogenesis and neuroinflammation in a microbiota disruption model.
Takahashi K, Kurokawa K, Kawaguchi R … +2 more , Takeda H, Tsuji M
Neurochem Int · 2026 Jun · PMID 41932583 · Publisher ↗
Gut microbiota alterations are associated with the onset of depression; however, the underlying mechanisms remain unclear. Activation of hippocampal AMP-activated protein kinase (AMPK) in ulcerative colitis mice with dis...
Gut microbiota alterations are associated with the onset of depression; however, the underlying mechanisms remain unclear. Activation of hippocampal AMP-activated protein kinase (AMPK) in ulcerative colitis mice with disrupted gut microbiota balance produces antidepressant effects. However, the relationship between hippocampal AMPK and antibiotic treatment (ABX)-induced depression-like behavior remains unclear. Therefore, we aimed to investigate whether 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), an AMPK activator, is associated with the prevention of ABX-induced depression-like behaviors. ABX mice exhibited depression-like behaviors, as evidenced by prolonged immobility and reduced sucrose preference. In the hippocampus of the ABX mice, Iba1 and pro-inflammatory microglial markers were upregulated, whereas brain-derived neurotrophic factor (BDNF), CD206, arginase-1, and interleukin-10 were downregulated. Additionally, levels of AMPK phosphorylation, cAMP response element binding protein (CREB), and tropomyosin-related kinase B (TrkB) were decreased. AICAR administration attenuated these behavioral and molecular alterations. Phosphorylated AMPK was colocalized with the neuronal marker-NeuN-and microglial marker-Iba1. AICAR ameliorated the reduction in hippocampal neuron proliferation and survival and reduced microglial activation-associated morphological changes in the hippocampus. These findings suggest that AICAR administration is associated with antidepressant-like effects, potentially involving enhanced neurogenesis and attenuation of neuroinflammation in the hippocampus of ABX mice. Together, this study highlights the significance of hippocampal AMPK phosphorylation in depression associated with gut microbiota alterations, and suggests a potential target for therapeutic interventions.
GABAergic neuronal ontogeny in the central nervous system of the viviparous teleost Poecilia sphenops.
Hotha A, Ganesh CB
Neurochem Int · 2026 Jun · PMID 41932582 · Publisher ↗
The neurotransmitter gamma-aminobutyric acid (GABA) plays essential roles in vertebrate neurodevelopment and neuroendocrine regulation. However, the post-embryonic ontogeny of the GABAergic system remains relatively poor...
The neurotransmitter gamma-aminobutyric acid (GABA) plays essential roles in vertebrate neurodevelopment and neuroendocrine regulation. However, the post-embryonic ontogeny of the GABAergic system remains relatively poorly characterized, particularly in viviparous teleosts. In this study, we describe postnatal GABAergic development across the central nervous system of Poecilia sphenops from birth to 120 days post-birth (DPB). Immunofluorescence labeling revealed that GABAergic neurons were present at birth predominantly in the spinal cord and hindbrain, indicating early maturation of circuits supporting sensorimotor, visceral, and autonomic functions. During juvenile development, GABA-immunoreactive (GABA-ir) neurons progressively extended into mesencephalic and diencephalic regions, with neuronal differentiation generally preceding the incorporation of GABA-ir fibre systems in midbrain integration centres and neuroendocrine forebrain nuclei. The telencephalon exhibited delayed maturation, with GABAergic neurons initially restricted to limited subdivisions at birth and broader neuronal and fibre differentiation occurring during later juvenile stages, whereas the olfactory bulb showed a complete absence of GABAergic immunoreactivity at birth, with GABAergic elements emerging only during juvenile development. Inferior lobe and gustatory hindbrain nuclei retained early and persistent GABA-ir populations, whereas hypophysiotropic and pituitary-projecting elements differentiated only during advanced juvenile phases. Quantitative morphometric analysis revealed prolonged, nucleus-specific enlargement of GABAergic neuronal somata, indicating extended postnatal maturation of GABAergic circuits. Together, these findings demonstrate a rostrocaudal and functional gradient in the emergence and maturation of GABAergic systems in P. sphenops, with GABAergic circuits maturing earliest in caudal sensorimotor regions and latest in forebrain and neuroendocrine areas.
Altered microbiota drive prelimbic cortex suppression and lower pain thresholds after sleep deprivation.
Wu Y, Li N, Bai Y … +5 more , Wang L, Zhang Y, Wang J, Liu X, Ni X
Neurochem Int · 2026 Jun · PMID 41912086 · Publisher ↗
Sleep disturbances are increasingly recognized as a lifestyle factor for abnormal pain perception. Recent studies highlight the critical role of gut microbiota in maintaining physiological balance and reveal a bidirectio...
Sleep disturbances are increasingly recognized as a lifestyle factor for abnormal pain perception. Recent studies highlight the critical role of gut microbiota in maintaining physiological balance and reveal a bidirectional relationship between microbiota alterations, sleep disorders, and pathological pain. This study investigates the potential role of microbiota in linking sleep deprivation to abnormal pain. Using a chronic sleep deprivation (CSD) model in mice, we observed significantly lower pain thresholds compared to controls. Brain-wide functional ultrasound imaging revealed reduced cerebral blood volume responses to pinprick stimulation in the prelimbic cortex (PrL) of CSD mice, indicating decreased neuronal activity during pain processing. This finding was confirmed by fiber photometry of calcium influx and c-Fos staining in the PrL. Importantly, chemogenetic activation of PrL neurons effectively reversed CSD-induced pain hypersensitivity. CSD also caused significant microbiota alterations, including increased diversity and changes in specific genera associated with brain function-related metabolic pathways. Fecal microbiota transplantation (FMT) demonstrated a causal relationship, as control mice that received microbiota from CSD mice developed pain hypersensitivity, whereas CSD mice that received control microbiota exhibited restored pain thresholds Notably, FMT-induced pain behavior changes correlated with PrL activity alterations. Our study indicates that CSD suppresses PrL activity and causes pain hypersensitivity through alterations in gut microbiota. This study emphasizes the gut-brain axis as a critical pathway in the interplay between sleep deprivation and pain regulation.
Copper depletion ameliorates neuronal damage after intracerebral hemorrhage.
Zhang W, Wu G, Wang L … +1 more , Ren S
Neurochem Int · 2026 Jun · PMID 41912085 · Publisher ↗
BACKGROUND: Intracerebral hemorrhage (ICH) is a severe subtype of stroke. There are currently no specific treatment strategies for secondary brain injury and neurological deficits following ICH. Copper (Cu) is an essenti...
BACKGROUND: Intracerebral hemorrhage (ICH) is a severe subtype of stroke. There are currently no specific treatment strategies for secondary brain injury and neurological deficits following ICH. Copper (Cu) is an essential cofactor for all living organisms. Cytotoxicity can occur when copper ion concentration exceeds the homeostatic threshold, leading to cell death. However, the relationship between copper and ICH is unclear. METHODS: In vivo, an ICH model was established in male Sprague-Dawley rats by stereotactically injecting autologous blood into the right basal ganglia. In vitro, we employed hemin and CuCl to simulate ICH conditions and induce cuproptosis in BV2 microglial cells. To investigate the role of copper in brain injury and neuronal damage, we administered the copper chelator tetrathiomolybdate (TTM) and knocked down the essential cuproptosis gene ferredoxin 1 (FDX1). RESULTS: Our findings demonstrate that following ICH, elevated copper levels and FDX1 expression, low expression of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and lipoic acid synthetase (LIAS), loss of mitochondrial membrane potential and neuronal impairment (increased growth associated protein 43 (GAP43) and decreased microtubule associated protein 2 (MAP2) expression), ultimately lead to neuronal death. Both TTM and si-FDX1 treatment attenuated the copper overload and inhibited cuproptosis, thereby ameliorating the ICH-induced phenotype. CONCLUSION: Copper depletion attenuates ICH-induced neuronal damage by inhibiting cuproptosis, highlighting a potential therapeutic strategy for mitigating secondary brain injury and neuronal damage following ICH.
Genome editing in Parkinson's disease: Unlocking therapeutic avenues through CRISPR-Cas systems.
Singh RP, Maity P, Jaiswal C
Neurochem Int · 2026 Jun · PMID 41905621 · Publisher ↗
Parkinson's disease (PD) is an illness that causes both motor and non-motor symptoms in the patient which occurs as a result of a progressive loss of dopamine-producing neurons in the substantia nigra. Even though the su...
Parkinson's disease (PD) is an illness that causes both motor and non-motor symptoms in the patient which occurs as a result of a progressive loss of dopamine-producing neurons in the substantia nigra. Even though the success of symptomatic treatments is promising, at the same time there is currently no effective therapy that can halt or reverse disease progression. Key genes such as SNCA, LRRK2, and PINK1 are considered as the main hopefuls aspect for the treatment of Parkinson's because mutations of these genes are the reason for the appearance of the familial and sporadic kinds of the disease, respectively. The CRISPR-Cas system, a breakthrough genome-editing technology which enables precise and targeted genetic modifications, renders the possibilities of both PD research and therapy. Examining the mechanics of prime editing, base editing, and CRISPR-Cas9 highlights how effective and precise these methods are for modifying genes. An overview of recent developments in the use of CRISPR to create PD models is also included in the current review, with a focus on the roles these models play in clarifying disease pathways and locating new treatment targets. These models include isogenic cell lines, transgenic animals, and induced pluripotent stem cells (iPSCs). This review highlights the potential of CRISPR-based strategies to correct PD-associated mutations, modulate pathogenic gene expression, and develop neuroprotective interventions targeting key processes such as mitochondrial dysfunction. Furthermore, it critically evaluates the role of CRISPR-based technologies as transformative tools in PD research and therapy while highlighting key challenges for their clinical translation.
Multiplexed neurochemical monitoring reveals glutamate modulates dopamine neurotransmission in the nucleus accumbens.
Donarski ED, Connors SS, Venton BJ
Neurochem Int · 2026 May · PMID 41831486 · Full text
Dopamine (DA) and glutamate (Glu) play vital roles in cognitive function, motor control, reward systems, and addiction. However, neurotransmitters are typically measured one at a time instead of simultaneously, which wou...
Dopamine (DA) and glutamate (Glu) play vital roles in cognitive function, motor control, reward systems, and addiction. However, neurotransmitters are typically measured one at a time instead of simultaneously, which would allow a better picture of neurotransmitter interactions. In this study, we multiplexed dopamine detection using fast-scan cyclic voltammetry (FSCV) and glutamate detection using genetically encoded iGluSnFR fluorescent probes to simultaneously investigate dopamine and glutamate signaling in mouse nucleus accumbens slices. We perturbed glutamate transmission to identify how faster synaptic glutamate regulated slower dopamine volume transmission. After bathing brain slices in a buffer containing 100 μM glutamate, dopamine release decreased by nearly half. We then used drugs to inhibit different glutamatergic proteins to test their effects on dopamine release. Blocking the excitatory amino acid transporter (EAAT2) using DL-TBOA (20 μM) increased glutamate concentrations and decreased dopamine release. Blocking metabotropic glutamate receptors (mGluR2/3) with LY 341495 (40 μM) did not affect dopamine release and the mGluR2 agonist LY 379268 (10 μM) also did not affect dopamine release, so the effect was not mediated by metabotropic group 2/3 receptors. Blocking NMDAR with D-AP5 (50 μM) decreased glutamate but did not change dopamine release. Blocking AMPA/kaintate receptor function with NBQX (5 μM) did not change glutamate release but did increase dopamine release. This work demonstrates the importance of simultaneous detection of related neurotransmitters while showing that glutamate and dopamine release have an inverse relationship that is partially mediated by binding to AMPA and Kainate receptors.
Biphasic response of silent synapses: Differential remodeling of hippocampal synaptic plasticity by status epilepticus in juvenile versus adult mice.
Dai J, Zeng Q, Cheng L … +3 more , Chen H, Jiang L, Hu Y
Neurochem Int · 2026 May · PMID 41825802 · Publisher ↗
OBJECTIVE: To investigate age-dependent mechanisms of silent-synapse transformation and their contribution to hippocampal circuit reorganization following convulsive brain injury induced by status epilepticus (SE). METHO...
OBJECTIVE: To investigate age-dependent mechanisms of silent-synapse transformation and their contribution to hippocampal circuit reorganization following convulsive brain injury induced by status epilepticus (SE). METHODS: Three-week-old (juvenile) and eight-week-old (adult) C57BL/6J mice were used. SE was induced by intraperitoneal kainic acid (KA). Hippocampal assessments were performed at 3 days (acute phase) and 28 days (chronic phase) post-SE. Dendritic spines in the dentate gyrus (DG) were visualized by Dil staining and confocal imaging to quantify total density and subtype distributions. Western blot was used to measure hippocampal expression of AMPA receptor subunits (GluA1-GluA4), NMDA receptor subunits (GluN1, GluN2A, GluN2B), and PSD95. Surface synaptic localization of GluA1 in CA1 was further evaluated by immunofluorescence staining and multi-threshold colocalization quantification with Synapsin. Whole-cell patch-clamp recordings were performed to determine the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in CA1. Correlation analyses were conducted to examine the association between DG filopodia density and CA1 sEPSC frequency during the acute phase. RESULTS: (1) After SE, juvenile mice exhibited increased densities of mushroom and stubby spines at both time points (P < 0.01) accompanied by a reduction in filopodia density (P < 0.01). In contrast, adult mice showed decreased mushroom spine density (P < 0.01) with increased filopodia formation during the acute phase (P < 0.01). (2) In the juvenile group, the expression levels of GluA1, GluA4, GluN2A, GluN2B, and PSD95 in the hippocampus were significantly elevated during the acute phase after SE. By the chronic phase, GluA3 expression remained upregulated while GluA4 was downregulated, and GluN2A/GluN2B remained persistently increased. In adults, GluA1 was decreased and GluA4 increased during the acute phase. GluN1 remained elevated across both phases, and GluN2A increased selectively in the chronic phase. PSD95 upregulation in adults was observed only in the chronic phase. Immunofluorescence analysis further corroborated the biochemical findings by showing increased surface synaptic GluA1 colocalization with Synapsin in CA1 at 3 days post-SE in juveniles, but decreased colocalization in adults. (3) Electrophysiological assessment revealed that the juvenile group showed increased sEPSC frequency (P < 0.05) and decreased amplitude (P < 0.01), whereas adults exhibited reduced sEPSC frequency (P < 0.05) without a significant change in amplitude. (4) Correlation analyses revealed a strong negative association between DG filopodia density and CA1 sEPSC frequency at 3 days post-SE in both age groups (juveniles: r = -0.908, p = 0.033; adults: r = -0.964, p = 0.036), indicating an age-dependent but coordinated structure-function coupling across hippocampal subregions during the acute post-SE period. CONCLUSIONS: SE bidirectionally modulates silent synapse transformation in an age-dependent manner. The juvenile brain adapts to pathological stimuli induced by SE through rapid conversion of silent synapses into functional mature synapses. In contrast, the adult brain exhibits reduced synaptic maturity and suppressed synaptic function, which may exacerbate post-epileptic neural network dysfunction.
Human Neuraminidase 3 reduces the severity of Tay-Sachs disease symptoms in a mouse model.
Basırlı H, Seyrantepe V
Neurochem Int · 2026 May · PMID 41819452 · Publisher ↗
Tay-Sachs disease (TSD) is a neurodegenerative disorder caused by mutations in the HEXA gene, encoding the α-subunit of β-hexosaminidase A. HexA deficiency leads to impaired degradation and accumulation of GM2 gangliosid...
Tay-Sachs disease (TSD) is a neurodegenerative disorder caused by mutations in the HEXA gene, encoding the α-subunit of β-hexosaminidase A. HexA deficiency leads to impaired degradation and accumulation of GM2 ganglioside, causing progressive neurodegeneration in patients. Interestingly, Hexa-/- mice show a relatively mild phenotype, suggesting degradation of stored GM2 ganglioside through a 'bypass' involving a sialidase. To investigate whether sialidase Neu3 contributes to GM2 degradation, mice deficient in both HEXA and NEU3, Hexa-/-Neu3-/-, were generated. Abnormal GM2 accumulation was revealed in the brains of Hexa-/-Neu3-/- mice using thin-layer chromatography and mass spectrometric analyses. Immunohistological and histological analyses indicated astrogliosis, Purkinje cell loss, and progressive neurodegeneration. Furthermore, the mice exhibited marked neurological abnormalities, including slowed movement, ataxia, and tremors, as well as a shortened lifespan of approximately 20 weeks. Hence, Hexa-/-Neu3-/- mice, which mimic the neuropathological and clinical abnormalities observed in patients, were considered the early-onset TSD model. The role of endogenous human Neu3 in GM2 degradation remains unknown. To evaluate its therapeutic potential, we administered AAVrh10-hNeu3 intrathecally to 8-week-old Hexa-/-Neu3-/- mice, either alone or with an anti-inflammatory agent, Istradefylline. Treatment with human Neu3 and Istradefylline extended lifespan to 28 weeks, improved body weight, and reduced GM2 accumulation. Additionally, fewer lysosomal LAMP1- and TUNEL-positive cells, and higher CNPase levels were revealed. Rotarod and footprint analyses showed improvements at 20 weeks. Our results provide the first in vivo evidence that AAV-mediated human Neu3 expression and Istradefylline may slow disease progression, reduce neuropathology, and lessen motor deficits in the Hexa-/-Neu3-/- mouse model of TSD.
Kynureninase deficiency ameliorated monocytic recruitment and severity in a mouse model of multiple sclerosis.
Yoshidomi K, Kunisawa K, Hasegawa M … +15 more , Kon Y, Kosuge A, Tanabe M, Ojika H, Yamamoto Y, Fujigaki H, Fujigaki S, Tezuka H, Saitoh S, Kumamoto K, Kugita M, Nagao S, Saito K, Nabeshima T, Mouri A
Neurochem Int · 2026 May · PMID 41794052 · Publisher ↗
Multiple sclerosis (MS) is a common autoimmune demyelinating disease of the central nervous system (CNS). Although activation of the kynurenine (KYN) pathway has been observed in patients with MS, its pathological signif...
Multiple sclerosis (MS) is a common autoimmune demyelinating disease of the central nervous system (CNS). Although activation of the kynurenine (KYN) pathway has been observed in patients with MS, its pathological significance remains unclear. In this study, we investigated the role of the KYN pathway in MS using an experimental autoimmune encephalomyelitis (EAE) mouse model, a widely recognized animal model of MS. We found an increase in the expression of kynureninase (KYNU), a key enzyme in the KYN pathway that is specifically localized within monocytes in the spinal cord of EAE mice. This was accompanied by a significant accumulation of quinolinic acid (QUIN) in the spinal cord. Importantly, similar increases in KYNU expression and QUIN levels were observed in the spinal cord of proteolipid protein overexpressing mice (PLP-tg mice), another model of demyelination. Notably, KYNU knockout (KO) reduced EAE severity and monocyte recruitment to the spinal cord of EAE model mice. These findings suggest that the increase in KYNU expression and the subsequent accumulation of QUIN may contribute to the exacerbation of MS. Taken together, our results indicate that KYNU could be a novel therapeutic target for MS.
Neuroinflammatory and functional outcomes after TBI are sex-dependent: Lessons from estrous-phase stratified female mice.
Royal T, Ahluwalia P, Gulhane M … +15 more , Salles EL, Gaur P, Ahluwalia M, Randhawa T, Sunil S, Budim S, Akter K, Khan MB, Ghosh S, Baban B, Hess DC, Vale FL, Dhandapani KM, Kolhe R, Vaibhav K
Neurochem Int · 2026 May · PMID 41791496 · Publisher ↗
Traumatic brain injury (TBI) initiates complex neuroinflammatory cascades that significantly influence recovery outcomes. Although sex differences in neuroinflammation have been reported previously, findings remain incon...
Traumatic brain injury (TBI) initiates complex neuroinflammatory cascades that significantly influence recovery outcomes. Although sex differences in neuroinflammation have been reported previously, findings remain inconclusive as the role of the female estrous cycle in post-injury responses is not well understood. In this study, we aimed to characterize sex-based differences in neuroinflammatory, vascular, and behavioral outcomes following TBI, with particular emphasis on the different phases of the estrous cycle in female mice. Male and female mice were subjected to controlled cortical impact (CCI) and subsequently assessed for behavioral deficits, cerebral blood flow (CBF), immune cell infiltration, and inflammatory genes expression. Although TBI induced robust neuroinflammation and reduction in CBF in both sexes, female mice showed significantly increased myeloid, microglial and T-cell presence, as well as elevated expression of key inflammatory transcripts (Btk, Inpp5d, and Tmem173), while downregulation in Grm2 expressions. Stratified cohort of female mice as per phases in estrous cycle (proestrus, estrus, metestrus, and diestrus) before injury showed alterations in Inpp5d, Csf3r, Csf1r, CD84, Tmem173, Homer1, Grm2 and Supt7l. Notably, female injured mice showed differential improvements in select parameters, although estrous cycle phase at the time of impact had limited but phase-dependent impact on CBF. Female mice did not show significant changes in the behavioral tests as compared to male or different estrous phenotypes. However, female mice showed higher frequency to visit center in an open arena. These findings highlight sex-specific neuroinflammatory and transcriptional responses to TBI, with moderate modulation by estrous cycle. Our study further suggests that one estrous phase could be more vulnerable to neuroinflammation or neurovascular injury than others on cellular and molecular level. However, this interphase difference might be masked in the studies including randomly cycled female population. Thus, our results underscore the importance of incorporating sex, estrous and hormonal status into sex-dependent studies on TBI and other brain diseases research to inform the development of targeted therapeutic strategies.
Acute "in vivo" LPS causes an early presynaptic C1q and C3 accumulation and increases the "prunability" of cortical synaptosomes.
Taddeucci A, Torre V, Rosenwasser N … +7 more , Saccani P, Olivero G, Bruno S, Giunti D, Uccelli A, Usai C, Pittaluga A
Neurochem Int · 2026 May · PMID 41791495 · Publisher ↗
LPS acutely injected in 3-month-old male C57BL/6 mice (1.25 mg/kg, i.p.) were sacrificed 12 h after the injection. LPS treatment activates complement in the central nervous system and promotes local inflammation, as conf...
LPS acutely injected in 3-month-old male C57BL/6 mice (1.25 mg/kg, i.p.) were sacrificed 12 h after the injection. LPS treatment activates complement in the central nervous system and promotes local inflammation, as confirmed by cortical TNF-α/IL-1b mRNA overexpression and increased GFAP and CD11b immunopositivity. We extended the study to presynaptic adaptations in isolated cortical synaptosomes from control (vehicle-injected, CTR) and LPS-injected mice. Synaptosomal engulfment was measured as MAP2 immunopositivity in LPS-activated BV2 or N9 microglia previously incubated with CTR or LPS-injected mouse synaptosomes. MAP2, absent in microglia, is present in synaptosomes, where its density is conserved despites LPS-injection. Microglia incubated with LPS-injected mice synaptosomes were immune-positive for MAP2, and the immunostaining was higher than that in microglia exposed to CTR particles, suggesting an increased "prunability" of LPS-injected mouse synaptosomes. Cortical synaptosomes were also labelled with pHrodo and then incubated with BV2 microglia. The red fluorescence was higher in microglia exposed to pHrodo-labelled LPS-injected synaptosomes, again suggesting their increased engulfment when compared to CTR. Lastly, LPS-injected cortical synaptosomes showed a significant presynaptic accumulation of C1q and C3, but not of C5. Our data confirm that acute systemic LPS challenge causes presynaptic adaptation which increases the "prunability" of nerve terminals, promoting their removal by activated microglia. The conclusion relies on the data obtained with two experimental techniques that permit to monitor synaptosomal engulfment representing useful tools i) to study changes in the "prunability" of nerve endings and ii) to test the efficiency of therapeutics for the management of central synaptopathy.
Representation and control of remifentanil-induced hyperalgesia and pain-like hypersensitivity by distinct neural ensembles in the anterior cingulate cortex.
Wang X, Zhao S, Li G … +5 more , Zhang H, Liu J, Sun X, Gao T, Zhang L
Neurochem Int · 2026 May · PMID 41780803 · Publisher ↗
Remifentanil-induced hyperalgesia (RIH) is a common but severe clinical problem that occurs following intraoperative analgesia with remifentanil. However, it still remains unknown how RIH signals are encoded in the brain...
Remifentanil-induced hyperalgesia (RIH) is a common but severe clinical problem that occurs following intraoperative analgesia with remifentanil. However, it still remains unknown how RIH signals are encoded in the brain. Here, we uncover the critical role of the anterior cingulate cortex (ACC) in mediating RIH using chemogenetic approach. Chemogenetic manipulation of the excitatory neurons in the ACC was found to affect RIH bidirectionally. Furthermore, we reported that RIH and formalin-induced pain-like hypersensitivity (PLH) were represented and processed by separate neural ensembles in the ACC. Using a virus-mediated target-recombination-in-active population (TRAP) system, RIH- and PLH-activated neural ensembles in the ACC were labeled and manipulated respectively. Chemogenetic manipulation of RIH-activated neural ensembles in the ACC selectively affected RIH but not PLH. Conversely, chemogenetic manipulation of PLH-activated neurons in the ACC significantly affected PLH, whereas the intervention did not alter RIH. Moreover, RIH- and PLH-activated neural ensembles in the ACC were found to differ dramatically in histological locations and electrophysiological properties. These findings reveal the contribution of the ACC to the development of RIH and separate encoding of RIH and PLH by distinct neural ensembles in the ACC. Our study provides a novel perspective for the understanding of RIH information processing in the brain.
Lentiviral-mediated CD81 modulation in the nucleus accumbens: effects on cocaine-induced conditioned reward and relapse in male rats.
Bahi A, Dreyer JL
Neurochem Int · 2026 May · PMID 41780802 · Publisher ↗
Cocaine use disorder is a major public health issue with no approved pharmacological treatments. Drug-associated contextual memories can trigger intense craving and relapse. Although CD81 has been linked to cocaine-induc...
Cocaine use disorder is a major public health issue with no approved pharmacological treatments. Drug-associated contextual memories can trigger intense craving and relapse. Although CD81 has been linked to cocaine-induced locomotion, its role in conditioned reward and relapse remains unclear. This study investigated the role of CD81 expression in the nucleus accumbens (NAc) during the acquisition and drug-primed reinstatement of cocaine-conditioned place preference (CPP) in rats. Adult male Wistar rats underwent viral manipulation of CD81 in the NAc via lentiviral vectors to induce either knockdown (shRNA) or overexpression. These manipulations were performed either before cocaine conditioning (10 mg/kg) to assess acquisition or after extinction and prior to a cocaine priming injection (5 mg/kg) to assess reinstatement. CD81 mRNA levels were measured postmortem, and Pearson correlation analyses were conducted between gene expression and behavioural outcomes. CD81 knockdown significantly reduced CPP acquisition and reinstatement, whereas CD81 overexpression increased conditioned preference in both phases. Doxycycline treatment suppressed transgene expression and abolished the behavioural effects of CD81 overexpression. Correlation analyses revealed a significant positive association between CD81 mRNA levels and CPP magnitude. These findings indicate that CD81 contributes to modulation of cocaine-conditioned reward and relapse-like behaviour within the NAc. Further investigation in additional preclinical models will be necessary to clarify the broader relevance of CD81 in addiction-related neuroplasticity.
The caspase 11/gasdermin D pathway is a key driver of stress-induced neuroinflammation and behavioral dysfunction in rats.
Tiwari S, Mohammed Z, Tiwari A … +6 more , Yadav E, Atta SR, Kaushik S, Chopra A, Singh I, Ghosh S
Neurochem Int · 2026 May · PMID 41765184 · Publisher ↗
Chronic low-grade inflammation is an established hallmark of stress-related psychiatric disorders. While the canonical NLRP3 inflammasome, which activates caspase 1 and IL1β, has been implicated in stress, the contributi...
Chronic low-grade inflammation is an established hallmark of stress-related psychiatric disorders. While the canonical NLRP3 inflammasome, which activates caspase 1 and IL1β, has been implicated in stress, the contribution of the non-canonical inflammasome pathway remains unknown. Using a rat model of repeated social defeat, we report the first evidence that psychosocial stress triggers a sex-specific activation of the non-canonical inflammasome pathway in the brain and peripheral immune cells, as evidenced by the cleavage of caspase 11 and its downstream effector, gasdermin D. To establish a causal role, we demonstrated that both genetic knockdown of caspase 11 and pharmacological inhibition of either caspase 11 or gasdermin D significantly reduced stress-induced IL1β release. This reduction in inflammation was accompanied by a broad amelioration of behavioral deficits, including attenuated anxiety and fear acquisition, enhanced fear extinction, reduced synaptic loss, and improved working memory. Crucially, when compared to single-pathway inhibition, the combined targeting of both canonical and non-canonical pathways demonstrated significantly higher efficacy in mitigating neuroinflammation, preventing hippocampal dendritic spine loss, and mitigating behavior deficits. Additionally, this combination therapy also reduced peripheral inflammation. Corroborating these in vivo findings, ex vivo studies using peripheral blood mononuclear cells isolated from stressed rats confirmed that the non-canonical caspase 11/gasdermin D pathway works in concert with the NLRP3 canonical pathway to drive IL1β induction. Our findings reveal a novel dual-inflammasome mechanism underlying psychosocial stress-induced pathophysiology and establish a foundational rationale for co-targeting the NLRP3 and caspase 11/gasdermin D pathways as a promising transdiagnostic therapeutic strategy.
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