Neurochemical Research最新文献

Although it has been shown that electroacupuncture (EA) can regulate the activation of astrocytes, forming a stable microenvironment for nerve cell survival, and participating in the repair of spinal cord injury (SCI), the underlying mechanisms are not fully understood. The study aimed to investigate the effects of EA stimulation on motor function recovery in mice after SCI by regulating astrocyte activation, and explore the involvement and regulatory role of Hippo-YAP signaling pathway. In this study, we established T10 thoracic SCI model by clip compression technique, and applied EA at Jiaji points on both sides of the spine at T12 and L2 levels at 6 h after model establishment. The results showed that compared with the SCI group, the EA group showed significantly higher BMS scores at 7, 14 and 28 days post-injury, and better hindlimb motor function recovery at 28 days after SCI (P < 0.05). An improvement in the degree of inflammatory reaction, the extent of glial scar formation, and the atrophy of neurons, an increase in the number of Nissl bodies, a decrease in karyorrhexis were observed in the EA group at different time points post-injury. The EA group showed significantly decreased expression of inflammatory factors (IL-1β, TNF-a and IL-6), GFAP and CSPGs, increased expression of p-MST1 and p-YAP, decreased expression of MST1 and YAP, increased p-MST1/MST1 ratio and p-YAP/YAP ratio than the SCI group at each time point post-injury (all P < 0.05). The EA group also showed significantly up-regulated expression of ZO-1, CLN-5, 5-HT and NFH, significantly increased density of NeuN-positive neurons and significantly decreased expression of CS56, CD68 compared to the SCI group at 14 days post-injury (all P < 0.05). Our findings suggest that EA stimulation may down-regulate the activation level of the astrocytes by activating the Hippo-YAP signaling pathway and decreasing the transcriptional activity of its downstream effector YAP, thus inhibiting the formation of glial scar and the release of inflammatory factors, enhancing the repair of the blood-spinal cord barrier, facilitating neuron survival and axon regeneration, leading to improvement in the recovery of hindlimb motor function in mice after SCI.

Major depressive disorder (MDD) is a prevalent and complex condition with limited treatment success in many patients. Photobiomodulation (PBM), particularly transcranial PBM (tPBM) using red to near-infrared light, has emerged as a promising non-invasive intervention. However, optimal parameters and precise mechanisms remain unclear. This research aimed to analyze the effects of transcranial photobiomodulation (red and infrared) on behavioral and biological parameters related to MDD in a chronic mild stress (CMS) model. Male Wistar rats were exposed to CMS for five weeks and subsequently categorized into two groups—resilient (CMS-R) and susceptible (CMS-S)—based on their performance in the sucrose consumption test (SCT). The CMS-S group was further divided into three subgroups: (1) sham treatment, (2) tPBM red (600 nm), and (3) tPBM infrared (840 nm). A control group of non-stressed animals was included for baseline comparisons. Biological measures included lipid damage (TBARS), antioxidant defense (TEAC), mitochondrial complex IV activity (CCO), and nitric oxide (NO) concentration in the prefrontal cortex and blood were measured. As expected, post-tPBM treatment (both red and infrared groups) exhibited increased sucrose consumption compared to the sham (p < 0.001). The red and infrared presented higher serum TEAC levels than the sham and control groups, but these effects did not reach statistical significance (p = 0.306). In contrast, the red group showed lower peripheral TBARS levels than the sham group (p = 0.0048); such effect was similar to the control non-stress group. The infrared group showed higher NO levels within the hippocampus than the sham group p = 0.0134) and higher prefrontal CCO activity levels than the red group (p = 0.012), which was similar to the control non-stress group. Our study demonstrated that animals treated with tPBM using red (600 nm) or infrared (840 nm) wavelengths exhibited significant improvements in both behavioral and biological parameters in the CMS model. In particular, tPBM may offer therapeutic benefits by ameliorating oxidative stress and enhancing mitochondrial function, thereby presenting a promising alternative for the management of MDD.

Iron accumulation in the substantia nigra is a hallmark of Parkinson’s disease (PD), but its cellular drivers remain unclear. Oligodendrocytes, the most iron-rich cells in the brain, have been implicated in PD pathology. Our previous studies showed that 6-hydroxydopamine (6-OHDA) promotes iron accumulation in neurons and astrocytes by increasing iron influx and decreasing efflux. However, its effects on oligodendrocyte iron metabolism remain unknown. In this study, we examined how 6-OHDA affects iron homeostasis and inflammatory gene expression in MO3.13 oligodendrocytes. Using MTT, calcein-AM fluorescence assays, RT-PCR, and Western blotting, we compared undifferentiated and differentiated cells. In undifferentiated oligodendrocytes, 6-OHDA increased transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) while reducing ferroportin 1 (FPN1), resulting in enhanced iron uptake and reduced export. In contrast, differentiated cells showed decreased TfR1 and IRP1 and increased FPN1, promoting iron efflux. 6-OHDA also induced stage-specific inflammatory responses. In undifferentiated cells, IL-1β and TNF-α mRNA levels rose in a dose-dependent manner, whereas differentiated cells selectively upregulated IL-1β. These results suggest that undifferentiated oligodendrocytes undergo iron-related inflammation that may promote differentiation, while differentiated cells respond with a more restricted cytokine profile. This study is the first to demonstrate that 6-OHDA promotes iron accumulation in undifferentiated oligodendrocytes by disrupting the IRP1-mediated balance between TfR1 and FPN1. Moreover, 6-OHDA induces distinct inflammatory responses depending on the stage of oligodendrocyte differentiation. These findings highlight the dual role of oligodendrocytes as both iron reservoirs and modulators of the neuroinflammatory microenvironment, providing new insights into the cellular mechanisms underlying nigral iron accumulation in PD, and suggesting that oligodendrocytes play a critical regulatory role in PD pathogenesis.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease for which no effective clinical therapies currently exist. The neuroprotective potential of Chaetoglobosin F (CF), a fungal secondary metabolite, was investigated in this study using a Caenorhabditis elegans (C. elegans) model of AD that are transgenic nematodes expressing amyloid-beta (Aβ). Key parameters evaluated included paralysis rate, lifespan, motor and cognitive functions, Aβ plaque aggregation, intracellular reactive oxygen species (ROS), and autophagosome formation. The transcriptional levels of genes were examined by real time PCR. Results showed that treatment with CF significantly delayed paralysis, extended lifespan, and ameliorated Aβ-induced deficits in locomotion and chemotaxis. CF markedly reduced Aβ plaque accumulation, suppressed intracellular ROS levels, and promoted autophagosome formation. Furthermore, CF had potent inhibitory effects on acetylcholinesterase (AChE) activity. These beneficial effects were correlated with the upregulation of crucial genes, including daf-16, skn-1, pmk-1, mtl-1, unc-51, bec-1, lgg-1, sod-1 and sod-3, which confirmed the improving antioxidant defenses and autophagy. Our findings demonstrate that CF confers strong neuroprotection against Aβ-induced toxicity in C. elegans by co-regulating oxidative stress and autophagy through the Insulin/IGF-1 (IIS) and p38 MAPK signaling pathways. These results suggest that CF is a promising natural compound for further investigation as a potential therapeutic agent for AD.

Graphical Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by memory loss, neurodegeneration, amyloid plaque accumulation and tau hyperphosphorylation. Dysregulation of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2 A (PP2A) plays a pivotal role in tau pathology, contributing to synaptic dysfunction and memory impairment. Current AD medications offer limited palliative care, underscoring the need for multifaceted therapeutic strategies. Ficus deltoidea (FD), a medicinal plant renowned for its antioxidant and anti-inflammatory properties, has demonstrated neuroprotective effects, however, its specific role in modulating tau-associated proteins in AD remains underexplored. Thus, this study investigated the neuroprotective properties of FD on the spatial learning and memory, hippocampal histology and the levels of GSK-3β and PP2A in an AD-like rat model. Male rats were administered D-galactose (60 mg/kg) and aluminum chloride (200 mg/kg) for 11 weeks to induce AD-like characteristics. Rats were divided into six groups: control, AD model, donepezil-treated (1 mg/kg), and FD-treated groups receiving 50, 100 and 200 mg/kg of FD extract. Behavioural performances were assessed using the open field test (OFT) and modified elevated plus maze (mEPM). FD administration significantly improved spatial learning and memory in AD-like rats. Nissl staining revealed an increase in viable hippocampal granule neurons in FD-treated rats. Immunoblot analysis reported a reduction in GSK-3β and an increase in PP2A levels, suggesting reduced hippocampal tau phosphorylation. These findings indicate that FD confers neuroprotection by restoring the kinase-phosphatase balance, which in turn enhances hippocampal neuronal survival and memory, thereby supporting its potential as a phytotherapeutic agent for AD intervention.

The aim of this study was to investigate the effects of intraperitoneal ozone therapy in a post-traumatic epilepsy (PTE) model. An in vivo PTE model was established in male Sprague–Dawley rats, which were randomised to control (n = 8), PTE (n = 10), and PTE + Ozone (n = 10) groups. 0.7 mg/kg ozone was administered intraperitoneally for 3 consecutive days. Seizure activity was video recorded for 120 min and evaluated for latency, frequency, duration, and severity. Behavioral assessments of locomotor activity, anxiety, and spatial memory were conducted using open field, elevated plus, and radial arm maze tests on days 4–6 after the first ozone application. Blood and brain tissues were collected for biochemical assays (SUR1, TRPM4, IL-1β, IL-6, TNF-α, TAS, TOS, OSI, thiol–disulfide homeostasis), histological analyses (H&E, Cresyl Violet, and 8-OHdG immunostaining), and qRT-PCR of epilepsy-related miRNAs. Significant differences were observed among the groups for all serum and brain biomarkers (p < 0.001). The PTE group showed marked increases in SUR1, TRPM4, IL-1β, IL-6, TNF-α, TOS, OSI, TT, NT, and DIS levels, accompanied by a decrease in TAS. Ozone treatment partially reversed these changes by reducing cytokine and oxidative stress markers, improving thiol–disulfide balance, and restoring TAS levels. Behavioural testing revealed beneficial effects of ozone, including reduced immobility, fewer errors in the radial arm maze, and increased open-arm exploration. Although seizure severity, latency, and duration were not significantly altered, seizure frequency showed a decreasing trend (p = 0.067). Immunofluorescence for 8-OHdG revealed increased hippocampal oxidative DNA damage in the PTE group, which was attenuated following ozone treatment. Analysis of miRNA expression revealed downregulation in the PTE group, whereas ozone treatment resulted in overall upregulation. There was no statistically significant difference between miRNA expression results and the PTE + Ozone group (p = 0.056–0.076). Ozone therapy mitigated oxidative stress and inflammation, improved redox homeostasis, enhanced cognitive and locomotor performance, and reduced hippocampal DNA damage in the PTE model. Furthermore, the observed upregulation of specific miRNAs following ozone treatment highlights a potential molecular mechanism contributing to its neuroprotective effects.

REM sleep deprivation (REMSD) contributes to neurodegenerative diseases like Alzheimer’s Disease (AD). This study examined REMSD’s effects on cognition, ER stress, and AD-like pathology in rats, alongside melatonin’s therapeutic potential. REMSD was induced for six days using the modified multiple platform method (MMPM). Cognitive function was tested via the Morris Water Maze (MWM). Rats received melatonin (20 mg/kg), 4-PBA (as a positive control, 100 mg/kg), or vehicle during deprivation/recovery periods. Western blotting and ELISA assessed ER stress markers (BiP, pIRE1, pPERK, peIF2-α, CHOP and GRP94, GADD34), Alzheimer related molecules (Aβ40/42, Tau, APP, GSK3β) and apoptosis-related proteins (Caspase 2, Caspase 12, BAX/Bcl-2). In addition, the mRNA expression levels of ATF4 and ATF6 were determined by PCR. Recovery sleep restored cognition, but melatonin/4-PBA enhanced it further. REMSD was associated with increased ER stress and AD-like pathology, whereas melatonin and 4-PBA appeared to attenuate these alterations, possibly by influencing the unfolded protein response (UPR) and reducing protein misfolding. Melatonin shows promise in countering SD-associated neurodegeneration, highlighting sleep’s role in proteostasis and its potential clinical use in AD and protein-misfolding disorders.

Cerebral ischemia/reperfusion injury is a leading cause of neurological deficits, with limited treatment options available. Ginsenoside Rb1 (GRb1), a major bioactive compound of Panax ginseng, has shown neuroprotective potential. This study investigates whether GRb1 exerts its protective effects against cerebral ischemia/reperfusion injury, focusing on its effects in promoting mitophagy as the underlying mechanism. Male C57BL/6J mice underwent middle cerebral artery occlusion for 30 min followed by reperfusion. Mice were divided into four groups: Sham, Vehicle, GRb1-treated, and GRb1 combined with Mdivi-1, a mitophagy inhibitor. GRb1 (20 mg/kg) and Mdivi-1 (40 mg/kg) were administered intraperitoneally at 1 h, 12 h, and 24 h post-ischemia, followed by daily injections. Cognitive function and anxiety-like behavior were assessed using the Morris Water Maze and Open Field Test. Neuroinflammation, mitochondrial function, and connexin 43 phosphorylation were analyzed through immunofluorescence, Western blot, and ELISA. Mitophagy was evaluated by examining key markers, including PINK1, Parkin, Atg5, LC3 II, and p62. GRb1 significantly improved cognitive function and reduced anxiety-like behavior following ischemia/reperfusion injury. GRb1-treated mice exhibited decreased microglial activation and reduced levels of pro-inflammatory cytokines IL-1β and TNF-α while increasing the anti-inflammatory cytokine IL-10. Additionally, GRb1 preserved mitochondrial function by enhancing ATP production, increasing superoxide dismutase activity, and upregulating PGC1α while reducing Drp1 expression. Western blot analysis revealed that GRb1 decreased connexin 43 phosphorylation and enhanced mitophagy, as indicated by increased levels of PINK1, Parkin, Atg5, and LC3 II, with reduced p62 accumulation. Importantly, these protective effects were largely diminished when mitophagy was inhibited by Mdivi-1. GRb1 exerts its neuroprotective effects against cerebral ischemia/reperfusion injury through the activation of mitophagy. Targeting mitophagy may represent a promising therapeutic strategy for ischemic stroke and related neurological disorders.

Secondary injury after spinal cord injury (SCI) is driven by oxidative stress, microglial activation, and apoptosis. Fascin‑1, an actin‑bundling protein implicated in immune regulation, may influence these processes, but its role in SCI remains unclear. We analyzed a mouse spinal cord single‑nucleus RNA‑seq dataset across five time points after T9 SCI to define cell-type-specific Fascin‑1 dynamics. We modeled oxidative stress in human (HMC3) and mouse (BV2) microglia using H₂O₂ and assessed the effects of Fascin‑1 overexpression on viability, apoptosis, reactive oxygen species (ROS), redox biomarkers, and apoptosis/antioxidant proteins. In a rat contusion SCI model, we delivered AAV‑Fascin‑1 and evaluated locomotor recovery, histopathology, apoptosis, redox indices, and protein expression. Single‑nucleus analysis reveal that Fscn1 expression transiently decreased in microglia and astrocytes early after SCI, then recovered. In vitro, Fascin‑1 overexpression enhanced microglial viability under H₂O₂, reduced apoptosis and ROS, decreased MDA, restored SOD/GPx activity and the GSH/GSSG balance, downregulated Bax and cleaved Caspase‑3/9, and upregulated Bcl-2. In vivo, AAV‑Fascin‑1 improved BBB scores from day 7 to 14 post‑SCI, reduced lesion cavitation and fibrotic scarring, preserved Nissl‑positive neurons, and normalized redox indices and apoptosis/antioxidant protein levels. Fascin‑1 mitigates oxidative stress and apoptosis in microglia and attenuates secondary damage via activation of the NRF2/HO‑1 axis after SCI. These findings identify FSCN1 as a potential therapeutic target to enhance functional recovery following SCI.

The pathophysiological mechanism of epilepsy has not been fully elucidated. Abnormal synaptic plasticity in the hippocampus may be an important trigger. Decorin (DCN), an extracellular matrix protein, may affect synaptic remodeling by regulating the mTOR signalling pathway. However, its role and molecular mechanism in epilepsy remain unclear. In this study, a chronic epilepsy mouse model induced by kainic acid (KA) was established. The protein expression of DCN in the hippocampus was significantly increased during the occurrence of epilepsy. By using an adeno-associated virus (AAV) to knock down DCN expression in the hippocampus, the effect of DCN on the occurrence of epilepsy was explored. The experiments revealed that knocking down DCN could significantly shorten the duration of status epilepticus, reduce the frequency and severity of spontaneous seizures, etc. Moreover, DCN knockdown could improve synaptic remodelling by downregulating the expression of key proteins, such as AMPA/NMDA receptor subunits (GluN2A, GluN2B) and PSD95, on the postsynaptic membrane, and reducing the abnormal increase in dendritic spine density and the number of synaptic vesicles. Molecular mechanism studies revealed that DCN physically interacts with mTOR protein, and its knockdown coincided with reduced phosphorylation and activation of mTOR. These findings suggest a potential link between DCN and mTOR signalling. Therefore, the DCN-mTOR axis emerges as a potential target for modulating the excessive synaptic transmission associated with epilepsy. This study is the first to reveal that DCN participates in the pathological process of epilepsy by regulating mTOR-dependent synaptic plasticity, providing experimental evidence that the DCN-mTOR axis can be targeted to intervene in synaptic homeostasis imbalance.