Neurochemical Research最新文献

Ischemic stroke (IS) is a leading cause of death and permanent disability worldwide. Diabetes is a major risk factor for IS and independently increases mortality. This study investigated the neuroprotective effects of Myrtenal (Myrt) in a rat model of IS under both diabetic and non-diabetic conditions. Sprague Dawley rats received Myrt (40 mg/kg, intraperitoneally) for 28 days before undergoing 60-minute middle cerebral artery occlusion followed by 24 h of reperfusion. Neurological outcomes were assessed using behavioral tests, infarct volume was measured by TTC staining, and biochemical analyses evaluated oxidative stress (MDA, SOD, CAT, GSH-Px) and inflammatory markers (NLRP3, TNF-α, IL-6, IL-1β). Western blotting was performed to examine BDNF/TrkB, p-PI3K/p-Akt signaling, and apoptosis-related proteins (Caspase-3, Bcl-2, Bax). IS impaired neurological function and increased infarct size, apoptosis, inflammation, and lipid peroxidation, while reducing antioxidant enzymes and BDNF/TrkB and p-PI3K/p-Akt levels (p < 0.05). These pathological changes were more severe in diabetic rats. Pretreatment with Myrt significantly ameliorated these effects in both diabetic and non-diabetic groups (p < 0.05). These findings suggest that Myrt exerts neuroprotective effects against IS by suppressing inflammation, oxidative stress, and apoptosis, possibly through modulation of BDNF/TrkB and p-PI3K/p-Akt pathways. These findings indicate that Myrt may possess neuroprotective potential in IS under both hyperglycemic and normoglycemic conditions.

Post-stroke cognitive impairment (PSCI) is a prevalent cerebrovascular condition resulting from ischemic stroke. This study aimed to determine the expression levels of NEXN-AS1 in PSCI, evaluate its clinical significance, and further uncover the molecular mechanisms through which it contributes to the initiation and progression of PSCI. The quantification of NEXN-AS1, miR-92a-3p, and NRF1 expression was performed using qRT-PCR. The diagnostic utility of serum NEXN-AS1 was assessed through ROC analysis. Risk factors associated with cognitive impairment following stroke were identified using both univariate and multivariate logistic regression. A cellular model of cognitive dysfunction was established via oxygen-glucose deprivation/reperfusion (OGD/R). The PSCI animal model was established through the Middle cerebral artery occlusion (MCAO) surgery. Inflammatory status was determined by measuring cytokine levels, including IL-6, IL-1β, and IL-10, while oxidative stress was evaluated by quantifying ROS, MDA, and CAT. In stroke patients, NEXN-AS1 expression was notably downregulated and further decreased in cases with PSCI. It served as a reliable biomarker for distinguishing stroke patients from healthy individuals and PSCI from post-stroke cognitive normality (PSCN) groups. Upregulation of NEXN-AS1 in BV2 cells following OGD/R stimulation led to increased proliferation, decreased inflammatory response, and reduced oxidative stress. Moreover, miR-92a-3p expression reversed the protective effects of NEXN-AS1 under OGD/R conditions. Overexpression of NEXN-AS1 alleviated cognitive dysfunction, inflammatory response and oxidative stress in PSCI rats, while overexpression of miR-92a-3p counteracted the protective effect of NEXN-AS1 on PSCI rats. Further analysis identified NRF1 as a downstream target of miR-92a-3p. NEXN-AS1 exerts protective effect against ischemic brain injury in both in vitro and in vivo models by regulating miR-92a-3p. Therefore, NEXN-AS1 may predict the occurrence of PSCI, and NEXN-AS1 may contribute to PSCI pathogenesis via regulation of the miR-92a-3p/NRF1 axis.

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and severely affects the physical and mental health of patients. The protein arginine methyltransferase 5 (PRMT5) has been shown to be associated with neuronal degeneration in PD, but its specific mechanism of mediating PD remains unclear. The purpose of this study was to investigate the role of PRMT5 in PD and its potential mechanism. PD models in rats and MN9D cells were induced by 6-hydroxydopamine (6-OHDA). Key genes and proteins were identified through real-time quantitative polymerase chain reaction (RT‒qPCR), Western blotting, and immunofluorescence staining; apoptosis levels were measured using flow cytometry; autophagosome formation was observed via monodansylcadaverine (MDC) staining; and neuronal damage in PD rats was evaluated using hematoxylin‒eosin (H&E) and Nissl staining. In this study, we found that PRMT5 levels were elevated in the peripheral blood of PD patients and in 6-OHDA-induced rat brain tissue and MN9D cells and that the expression of PRMT5 was positively correlated with the level of α-Syn. After PRMT5 was knocked down, α-Syn levels in PD rats decreased, neuronal damage was inhibited, and motor disorders improved. In addition, knockdown of PRMT5 promoted 6-OHDA-induced MN9D cell proliferation, inhibited apoptosis, and upregulated autophagy. Mechanistically, PRMT5 inhibits the activation of the Wnt/β-catenin signaling pathway through H3R8me2s modification to stabilize the expression of DKK1, thus inhibiting neuronal autophagy and promoting the development of PD. Our study suggests that PRMT5 may be a potential intervention target for improving PD progression.

Neuroimaging implicates the medial prefrontal cortex (mPFC) and insula in fibromyalgia (FM), but synaptic and network mechanisms are unclear. To verify mPFC hypersynapticity in a reserpine-induced FM model and test whether anterior insular deep brain stimulation (DBS) restores mPFC oscillations and pain behavior. Thirty-six male Sprague–Dawley rats received reserpine (1 mg·kg⁻¹ i.p., days 1–3) or vehicle. For Objective 1, mPFC tissue was analyzed by ELISA for glutamate, γ-aminobutyric acid (GABA), C-FOS, nerve growth factor (NGF), synaptophysin, and postsynaptic density protein-95 (PSD-95). For Objective 2, rats were assigned to control-sham, control-DBS, FM-sham, or FM-DBS. Monopolar DBS (130 Hz, 60 µs, 100 µA; 15 min·day⁻¹ for 3 days) targeted the anterior insula; local field potentials were recorded from mPFC, and thermal nociception was assessed by tail immersion and hot-plate tests. Reserpine increased glutamate, C-FOS, NGF, synaptophysin, and PSD-95 and reduced GABA (all p < 0.001), confirming hypersynapticity. Insular DBS increased delta-band normalized ratios (NR) in FM and controls (p < 0.0001), normalized FM-associated theta reductions, decreased alpha/beta NR in controls, and suppressed elevated gamma NR in FM (p < 0.0001). DBS increased withdrawal latencies in FM, indicating improved pain thresholds (p < 0.001). Reserpine induces biochemical hypersynapticity in mPFC, and brief anterior insular DBS rebalances mPFC oscillations and alleviates hyperalgesia. Insular DBS may correct cortical network dysfunction in FM.

Graphical Abstract

Injection of Reserpine into rats decrease the pain threshold by hot plate and tail immersion tests indicating development of fibromyalgia (FM). On the other hand, deep brain stimulation (DBS) for the anterior insular cortex (dorsal anterior insular cortex, AID) reset the fast rhythms of LFPs into slow LFPs in the cingulate cortex (Cg1) region of the medial prefrontal cortex (mPFC) as well as increase the pain threshold

Epilepsy is a common neurological disorder often accompanied by hippocampal myelin damage and impaired differentiation of oligodendrocyte precursor cells (OPCs). This study aimed to investigate the regulatory effects of Saracatinib on myelin regeneration and OPC maturation in a mouse model of epilepsy, as well as its underlying mechanisms, to provide new strategies for the treatment of epilepsy-related myelin damage. Changes in hippocampal myelin structure were observed using Fast Blue staining and transmission electron microscopy. Immunofluorescence was used to detect the number of oligodendrocyte precursor cell (OPCs, PDGFRα) and mature oligodendrocytes (ODCs, MBP+). Cell culture experiments verified the effects of Saracatinib on OPC differentiation, and SwissTargetPrediction and GSEA were used to predict its targets. Western blot and immunofluorescence further validated the role of the NOTCH1 signaling pathway in Saracatinib-mediated OPC differentiation. Saracatinib Reduced the Racine Score, Prolonged Seizure Latency, and Decreased Seizure Duration in an Epileptic Mouse Model. Epileptic model mice exhibited significant hippocampal myelin damage, characterized by thinning of myelin sheaths, reduced myelin quantity, and increased axonal exposure. Saracatinib treatment significantly improved myelin structure, restored myelin thickness and continuity, and alleviated axonal atrophy. Immunofluorescence showed that Saracatinib increased MBP expression and decreased PDGFRα expression, promoting the differentiation of OPCs into ODCs. Bioinformatics analysis and experimental validation demonstrated that Saracatinib promoted OPC maturation by inhibiting the NOTCH1 signaling pathway, and this effect could be reversed by the NOTCH1 agonist JAG1. Saracatinib significantly promotes hippocampal myelin regeneration and OPC maturation in epileptic mice by inhibiting the NOTCH1 signaling pathway, providing a potential molecular target and therapeutic strategy for the treatment of epilepsy-related myelin damage.

Bipolar disorder (BD) is a chronic and prevalent psychiatric disease that has been considered a leading cause of disability among psychiatric conditions. Taking into account that there is yet no satisfactory disease-modifying treatment, we investigated the effect of genistein on ouabain-induced BD in male C57BL/6 mice. Animals were categorized into control, genistein control, ouabain model, lithium (Li)-treated, and genistein-treated groups. BD was induced by bilateral intracerebroventricular injection of 0.625 nmol ouabain. Genistein (10 mg/kg/day) was orally administered for 2 weeks following a single dose of ouabain. Open field test, sucrose preference test, and forced swim test were performed. Na⁺/K⁺-ATPase activity was evaluated through measuring the hippocampal levels of phosphorylated epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase, extracellular signal-regulated kinase, and cAMP response element-binding protein (p-CREB) by western blot analysis. The levels of brain-derived neurotrophic factor (BDNF), serotonin, oxidative stress, and inflammatory markers were quantified by ELISA. The BCL-2-associated X protein (BAX) to B-cell Lymphoma/Leukemia (BCL2) ratio was assessed by qRT-PCR. Genistein reduced manic and anxious behaviors during the manic phase and showed an antidepressant effect during the depression phase, all while maintaining an effective metabolic balance on body weight. Additionally, genistein increased serotonin, p-CREB, and BDNF levels while decreasing inflammation and apoptosis produced by ouabain. Furthermore, genistein restored the normal architecture in both hippocampal and cortical H&E-stained sections. Taken together, genistein was able to activate the Na⁺/K⁺-ATPase signalosome via a multifaceted mode of action, exerting a neuroprotective effect in an animal model of BD, promoting genistein as a therapeutic candidate for BD.

Graphical Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, marked by cognitive decline and memory loss. Its multifactorial etiology involves genetic, environmental, and cellular factors, with key pathological features including amyloid-beta (Aβ) plaques and tau tangles. Recent studies have highlighted the roles of liquid-liquid phase separation (LLPS) and autophagy in AD onset and progression. LLPS, an emerging biophysical phenomenon, facilitates protein aggregation and may contribute to early disease stages. Dysregulated autophagy results in the accumulation of toxic proteins, such as Aβ and tau, exacerbating neurodegeneration. This review explores the interplay between LLPS and autophagy in AD, a relationship often overlooked in the literature. It examines their biological mechanisms, synergistic effects on AD pathology, and potential therapeutic strategies. Additionally, we discuss the therapeutic potential of both natural and non-natural compounds in modulating LLPS and autophagy. While compounds like curcumin show promise, a comprehensive framework for their targeted use remains under development. This review provides theoretical support for the advancement of more precise AD therapies.

Chronic high-dose ketamine, widely recognized for its rapid antidepressant effects, poses significant risks to brain health, particularly in the hippocampus, a region critical for learning, memory, and emotional regulation. This narrative review aims to elucidate the molecular mechanisms underlying ketamine-induced apoptosis in hippocampal neurons, providing a comprehensive synthesis of current research findings. We examine how chronic exposure to high doses of ketamine disrupts glutamatergic signaling through NMDA receptor antagonism, leading to an imbalance in excitatory neurotransmission that triggers apoptotic pathways. Additionally, we explore the roles of neuroinflammation and oxidative stress in exacerbating neuronal vulnerability, highlighting the interplay between these mechanisms. The review discusses how chronic ketamine use activates glial cells, resulting in the release of pro-inflammatory cytokines and increased oxidative damage, further promoting neuronal cell death. Furthermore, we consider the implications of altered neurotrophic factor signaling and mitochondrial dysfunction in the context of ketamine’s neurotoxic effects. By integrating these molecular pathways, we provide insights into the critical factors contributing to ketamine-induced apoptosis. Finally, we highlight the need for further research to clarify the dose-response relationship, individual variability in treatment outcomes, and potential neuroprotective strategies. Ultimately, this review emphasizes the importance of balancing the therapeutic benefits of ketamine with its associated risks, advocating for a nuanced understanding of its long-term effects on brain health to inform clinical practices and optimize patient care.

Graphical Abstract

This graphical abstract summarizes the key molecular pathways underlying chronic high-dose ketamine-induced apoptosis in hippocampal neurons, as explored in this narrative review. The illustration depicts how ketamine's primary mechanism as an NMDA receptor antagonist initiates a cascade of detrimental events: (1) disruption of glutamatergic signaling homeostasis; (2) activation of microglia and astrocytes, leading to neuroinflammation through pro-inflammatory cytokine release; (3) induction of oxidative stress via reactive oxygen species (ROS) generation; (4) impairment of mitochondrial function, promoting cytochrome c release; and (5) dysregulation of neurotrophic factor signaling (e.g., BDNF). These interconnected pathways ultimately converge to activate caspase-dependent apoptotic cascades, resulting in hippocampal neuronal death. This integrative process highlights the critical balance required between ketamine's rapid antidepressant potential and its neurotoxic risks, emphasizing the need for further research into neuroprotective strategies.

This study aims to investigate the neuroprotective effect of 6-shogaol (6-SH) in rats after cardiopulmonary resuscitation (CPR), and to explore the molecular mechanism by which it regulates the miRNA-26a-5p/DAPK1 to inhibit excessive autophagy and calcium overload. A rat model of cerebral ischemia-reperfusion injury after cardiac arrest and CPR was established by asphyxia. Sham, CPR, and CPR + 6-SH groups were set up. DAPK1 overexpression and miRNA-26a-5p inhibition were also performed. Neurological function was evaluated using the Neurological Deficit Score (NDS). Hematoxylin-eosin staining was used to assess pathological damage in brain tissue. Immunofluorescence was used to observe the expression of autophagy markers. Quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot (WB) were used to detect the expression of autophagy- and calcium overload-related genes and proteins. A dual-luciferase reporter assay was conducted to verify the targeting relationship between miRNA-26a-5p and DAPK1. Molecular docking was used to analyze the binding interaction between 6-SH and miRNA-26a-5p. The results show that 6-SH significantly reduces brain injury and improves neurological function after CPR. It decreases the expression of autophagy-related proteins (VPS34, Beclin1, LC3) and the calcium overload marker (NMDAR2B). Further mechanistic studies show that 6-SH inhibits DAPK1 expression and attenuates excessive autophagy and calcium overload. In addition, 6-SH binds to miRNA-26a-5p and upregulates its expression, which in turn suppresses DAPK1. When miRNA-26a-5p is inhibited, the effects of 6-SH on DAPK1, autophagy, and calcium overload are partially reversed. In conclusion, 6-SH attenuates brain injury after CPR by regulating the miRNA-26a-5p/DAPK1 to suppress excessive autophagy and calcium overload.

Cerebral ischemia-reperfusion injury (CIRI) involves oxidative stress, inflammation, and regulated cell death, among which ferroptosis has emerged as a key contributor. However, therapeutic strategies targeting ferroptosis remain limited. This study investigated whether Ciwujianoside C (CC), a triterpenoid saponin from Acanthopanax senticosus, protects against CIRI by modulating ferroptosis via the NNAT/NF-κB pathway. In MCAO/R rats, CC reduced infarct size, improved neurological scores, and ameliorated oxidative stress and ferroptosis markers. In BV2 microglia and HT22 cells (a mouse hippocampal neuronal cell line) subjected to OGD/R, CC enhanced cell viability, decreased iron accumulation, and restored GPX4 and FTH1 expression while inhibiting NF-κB activation. Importantly, NNAT knockdown abolished these protective effects, demonstrating NNAT as a critical mediator. These findings reveal that CC protects against CIRI by suppressing ferroptosis through the NNAT/NF-κB axis, highlighting NNAT as a potential therapeutic target in CIRI.