Neurochemical Research最新文献

Drug-induced sleep disruption exacerbates addiction, causes long-term cognitive and emotional deficits, and becomes a key relapse trigger. However, despite the potent stimulant and hallucinogenic effects of synthetic cathinones, their impact on sleep–wake behaviors remains unstudied, and the role of striatal dopamine D2 receptors in mediating psychostimulant-induced arousal has yet to be identified. This study aimed to elucidate the mechanisms underlying N-ethylpentylone (NEP, a second-generation synthetic cathinone) induced alterations in sleep-wake behavior, specifically investigating the relative contributions of dopamine receptors (DARs) and serotonin receptors. Using the in vitro PRESTO-Tango assay, we characterized the interactions between NEP and various DARs, revealing that NEP produced the strongest β-arrestin recruitment response at dopamine D2 receptor (D2R) among the dopamine receptor subtypes tested. In vivo electroencephalogram/electromyogram (EEG/EMG) recordings in wild-type (WT) mice demonstrated that NEP dose-dependently promoted wakefulness and reduced non-rapid eye movement (NREM) sleep. This was accompanied by decreased θ-band and increased α-band power spectral density during wakefulness. Pharmacological blockade of D2R with haloperidol significantly attenuated NEP-induced wake promotion and partially reversed the aberrant EEG oscillations. Crucially, conditional knockout of D2R specifically in striatum markedly diminished the wake-promoting effects of NEP. In contrast, pharmacological blockade of the serotonin 2 A receptor (5-HT2AR) with 1 mg/kg MDL100907 did not significantly alter NEP-induced sleep–wake changes. Furthermore, immunofluorescence staining analysis confirmed that D2R blockade effectively reversed NEP-induced c-Fos expression in the striatum. Together, these findings demonstrated striatal D2R played a critical role in NEP-induced arousal.

Nicotine, a psychoactive compound primarily known for its role in tobacco addiction, has attracted increasing interest for its neuromodulatory and neuroprotective properties. Acting predominantly through nicotinic acetylcholine receptors, nicotine influences multiple neurotransmitter systems, modulates neuroinflammation, and supports synaptic plasticity. These mechanisms may be therapeutically relevant in disorders characterized by neurodegeneration or disrupted neurocircuitry, including Parkinson’s disease, Alzheimer’s disease, schizophrenia, attention-deficit/hyperactivity disorder, depression, and post-traumatic stress disorder. This review critically examines the current state of preclinical and clinical evidence, with particular attention to receptor subtype activity, cognitive and emotional modulation, and human trial data. Although nicotine’s addictive potential and receptor desensitization remain concerns, advances in selective ligands offer new therapeutic avenues. By consolidating mechanistic insights and disease-specific data, this review highlights both the promise and challenges of developing nicotinic-based therapeutics for brain disorders.

Despite hyposmia being a dominant non-motor manifestation of Parkinson’s disease (PD), its underlying driving mechanisms are poorly defined. The redox protein Thioredoxin-1 (Trx-1) offers neuroprotection against various insults; however, its potential involvement in the neural proliferation in the subventricular zone (SVZ) and neural differentiation in the olfactory bulb (OB) related to MPTP-induced olfactory dysfunction have not been previously established. Our research demonstrates that when Trx-1 is downregulated in the substantia nigra pars compacta (SNpc), MPTP-triggered olfactory deficits are significantly intensified. A key anatomical discovery in our study is the existence of projections from the SNpc to the SVZ. We established that the MPTP-driven death of SNpc dopaminergic (DAergic) neurons correlates with decreased dopamine D1 receptor (D1R) levels in the SVZ, an effect that is magnified by the loss of Trx-1. Alongside D1R reductions, MPTP suppressed a cascade of SVZ signaling molecules (phosphorylated PKA, Wnt3a, β-catenin, Pax6, cyclin D1, and CDK4), with Trx-1 deficiency causing even steeper declines. Furthermore, Trx-1 knockdown hindered the generation of immature neurons and disrupted DAergic neuronal differentiation within the OB. Collectively, our findings suggest that reduced Trx-1 expression in the SNpc may contribute to PD-related olfactory deficits, potentially via inhibiting SVZ neural proliferation, decreasing immature and mature neuron populations, and disrupted differentiation of OB immature neurons. By accelerating MPTP-triggered degeneration of DAergic neurons in the SNpc, Trx-1 downregulation reduces the SVZ of DAergic input. This disruption impairs D1R-mediated the neural proliferation in the SVZ, as well as the maturation and differentiation of immature neurons in OB, ultimately driving the progression of olfactory dysfunction in a PD mouse model.

This study aimed to investigate how α-synuclein (α-syn) is associated with microglial activation and inflammatory amplification in Parkinson’s disease (PD), particularly under pro-inflammatory conditions. In vitro, BV2 microglial cells were stimulated with α-syn preformed fibrils (PFFs) and lipopolysaccharide (LPS). In vivo, a composite PD mouse model was established using 6-OHDA, LPS, and SNCA-overexpressing adeno-associated virus (AAV). Inflammatory changes were assessed by quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Midbrain transcriptomic profiles from model mice were analyzed using Affymetrix microarrays. Bioinformatic analyses included differential expression analysis with the limma package, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA). Transcriptomic analysis showed coordinated upregulation and strong positive correlations (R > 0.73) among Snca, Tnfa, and Il1b in PD model mice. Enrichment analyses indicated prominent involvement of inflammation- and immune-related processes, including the JAK–STAT signaling pathway. In vitro, α-syn PFFs induced inflammatory responses in BV2 cells, and these responses were further enhanced by LPS co-stimulation. In vivo, the composite model showed increased α-syn aggregation, enhanced microglial activation, and elevated pro-inflammatory cytokine release under combined pathological conditions. Together, these findings indicate an amplified inflammatory response under combined pathological insults. Our findings suggest that α-syn aggregation is associated with enhanced microglial activation and inflammatory cytokine responses, and may exacerbate neuroinflammatory processes under inflammatory conditions in PD models.

Graphical Abstract

α-Syn exacerbates microglial pro-inflammatory skewing and promotes neuroinflammation in PD.

Hypoxic-ischemic encephalopathy (HIE) is a severe perinatal brain injury that often leads to neurological impairments in survivors. Currently, effective therapeutic strategies for HIE remain limited and require further exploration. Emerging evidence indicates that microglia-mediated neuroinflammation plays a pivotal role in the pathophysiology of HIE. Nevertheless, clinically effective anti-inflammatory agents specifically targeting HIE are still lacking. Glycerol-3-phosphate (G3P) is a biologically significant metabolite involved in various cellular metabolic pathways. In this study, we investigated the neuroprotective effects of G3P against hypoxic-ischemic (HI)-induced brain injury by modulating microglial activation. In LPS-treated microglia, G3P suppressed the release of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential (MMP), and promoted a shift toward an anti-inflammatory microglial phenotype. In addition, G3P treatment in zebrafish showed no toxicity and significantly mitigated HI-induced oxidative stress, while suppressing both the recruitment and pro-inflammatory activation of mpeg1⁺ macrophages and lyzc⁺ neutrophils. Moreover, administration of G3P dramatically reduced infarct volume and alleviated neuronal loss in rats with hypoxic-ischemic brain damage (HIBD). Y-maze and Morris water maze tests demonstrated that G3P treatment significantly enhanced spatial learning and memory in HIBD rats. Furthermore, G3P markedly reduced the hyperactivation of microglia and astrocytes in both cortical and hippocampal regions. Mechanistically, Immunofluorescence and Western blot analyses revealed that G3P exerted anti-inflammatory effects by inhibiting cyclic GMP-AMP synthase -stimulator of interferon genes (cGAS-STING) signalling pathway and its downstream TBK1/the nuclear factor kappa B (NF-κB) signaling pathway. These findings highlight G3P as a promising therapeutic candidate for HIE.

Post-traumatic stress disorder (PTSD) is a long-lasting mental health condition characterized by persistent intrusive recollections, avoidance behaviors, mood and cognitive alterations, heightened arousal, and significant cognitive deficits, often accompanied by hypothalamic-pituitary-adrenal (HPA) axis dysregulation and neuroinflammation. This study evaluated the therapeutic potential of octreotide (OCT), a synthetic somatostatin analog, in a rat model of PTSD induced by foot-shock contextual fear conditioning. Male Wistar rats (n = 40) were randomly assigned to four groups (n = 10/group): Saline/No Stress (control), OCT/No Stress (drug alone), Saline/PTSD (model + saline), and OCT/PTSD (model + OCT). OCT was administered intraperitoneally at 50 µg/kg daily for 21 days post-induction. Behavioral outcomes were assessed using the Open Field Test (anxiety-like exploration and locomotor activity), Elevated Zero Maze (anxiety-like avoidance), and Morris Water Maze (spatial learning and memory). Plasma corticosterone concentrations were recorded on Days 0, 1, 7, 14, and 21. Hippocampal TNF-α, superoxide dismutase (SOD) activity, and malondialdehyde levels were quantified post-behavioral testing via ELISA. The Saline/PTSD group displayed significantly elevated plasma corticosterone (P < 0.0001 from Day 1 onward), increased hippocampal TNF-α (P < 0.0001), decreased SOD activity (P < 0.0001), elevated MDA (P < 0.0001), reduced locomotor activity and central exploration in the Open Field Test (P < 0.0001 to P < 0.01), and impaired spatial memory retention in the Morris Water Maze probe trial (P < 0.0001). The Elevated Zero Maze did not reveal any significant differences. OCT treatment in the OCT/PTSD group significantly attenuated these alterations compared to the Saline/PTSD group, normalizing corticosterone from Day 7 onward, reducing TNF-α and MDA (P < 0.0001), restoring SOD activity (P < 0.01), and improving Open Field exploration and Morris Water Maze probe performance (P < 0.01). These findings demonstrate that OCT is associated with neuroprotective, anti-inflammatory, and antioxidant effects in a PTSD model, attenuating HPA hyperactivity, neuroinflammation, oxidative stress, and behavioral/cognitive deficits (though direct SSTR-mediated mechanisms remain to be experimentally confirmed). Given its established safety profile and clinical approval for other indications, OCT represents a promising candidate for repurposing in PTSD treatment.

Transferrin is the principal iron-carrier protein and is primarily synthesized in the liver, oligodendrocytes (OLG), and choroid plexus. We previously demonstrated that apotransferrin (aTf) treatment induces OLG maturation in vitro and in vivo. Given that approximately 80% of myelin consists of lipids, predominantly cholesterol, tight regulation of lipid metabolism is essential during myelin formation. Lipid droplets (LDs) are dynamic intracellular organelles that store fatty acids as neutral lipids, including triglycerides and cholesterol esters. Recent studies have demonstrated the presence and regulated turnover of LDs in glial cells, suggesting roles in both physiological and pathological processes. During OLG maturation, the demand for lipid synthesis increases markedly to sustain membrane expansion and myelin production. Because this high lipid demand, we hypothesized that aTf-induced OLG maturation is associated with metabolic reprogramming involving lipid droplet dynamics, which may serve as a source of fatty acids for membrane biogenesis and energy production. In this context, LDs may represent a critical metabolic hub through which OLGs regulate lipid homeostasis and adapt to increased bioenergetic demands. However, the mechanisms governing LD biogenesis and turnover in oligodendroglial cells during development and under different metabolic conditions remain poorly understood. Importantly, LDs are now recognized as active participants in cellular metabolism, stress responses, and membrane biogenesis rather than passive lipid storage compartments. The aim of this study is to characterize LD dynamics, as well as specific lipid and protein profiles, in the Oli-Neu cell line and in oligodendroglial cells during the maturation process in the presence of aTf. We specifically investigate whether the aTf-induced increase in LD abundance reflects enhanced membrane biosynthetic requirements, with augmented energy production supported by β-oxidation of fatty acids released from triglycerides stored within LDs.

Elevated saturated fatty acids, such as palmitic acid (PA), induce lipotoxicity in peripheral nerve cells, a pathological feature of metabolic disorders such as type 2 diabetes and obesity that are frequently associated with neuropathic pain (NP). PA overload elicits a maladaptive stress response characterized by endoplasmic reticulum (ER) stress, disrupted intracellular calcium homeostasis, and impaired autophagic flux, ultimately promoting cell death. Although omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) protect against PA-induced lipotoxicity (PA-LTx), the mechanisms linking lipid handling, ER stress, and autophagy in Schwann cells remain poorly defined. Here, we investigated how PA and DHA regulate autophagic flux, ER stress signaling, and fatty acid–binding protein 5 (FABP5)–dependent lipid trafficking in immortalized Schwann cells (ISCs). PA exposure (300 µM PA:150 µM BSA, 24–48 h) significantly reduced cell viability, impaired autophagic flux as indicated by LC3-II and p62 accumulation, disrupted autophagosome–autolysosome balance, and increased susceptibility to autophagic inhibition by chloroquine. DHA co-treatment (50 µM) preserved cell viability, restored autophagic flux, and normalized autophagosome–autolysosome fusion. Mechanistically, PA induced ER stress marked by increased CHOP, ATF4, and Xbp1 expression, along with progressive ER calcium depletion, whereas DHA suppressed these responses and stabilized calcium homeostasis. Building on prior evidence that FABP5 protects neuron-like cells from PA-LTx, we identified a regulatory role for FABP5 in Schwann cells. PA robustly induced FABP5 expression, which was normalized by DHA and modulated by pharmacological manipulation of autophagy. FABP5 silencing exacerbated PA-induced ER stress, triggered a dysfunctional compensatory autophagy response, and impaired DHA-induced lipid droplet formation. Collectively, these findings demonstrate that functional autophagy and FABP5-dependent lipid buffering are critical adaptive responses to lipotoxic stress in Schwann cells, highlighting these pathways as potential therapeutic targets for NP-associated metabolic neuropathies.

Bipolar disorder (BD) is a severe psychiatric condition characterized by recurrent mood episodes and progressive neurobiological alterations associated with oxidative stress, mitochondrial dysfunction, and neuronal damage. Current pharmacological treatments remain limited by incomplete efficacy and significant adverse effects, highlighting the need for novel therapeutic strategies. The present study investigated the neuroprotective effects of beta-caryophyllene (BCP), a natural sesquiterpene and selective cannabinoid receptor type 2 (CB2R) agonist, in a rat model of mania induced by intracerebroventricular ouabain (OUA) administration. Wistar rats received acute BCP treatment (three doses administered at 8-h intervals) starting one hour after OUA. Behavioral, biochemical, histological, and molecular analyses were performed seven days later. OUA induced manic-like behavioral alterations characterized by hyperactivity, increased risk-taking, and increased reactivity. These behavioral alterations were accompanied by increased lipid peroxidation, alterations in antioxidant enzyme activity, and enhanced neuronal degeneration in hippocampal regions, as indicated by Fluoro-Jade C staining. BCP treatment attenuated behavioral abnormalities, reduced oxidative damage, and prevented OUA-induced neuronal degeneration in the CA1, CA3, and dentate gyrus. Molecular analyses revealed that BCP restored phosphorylation of protein kinase A (PKA) and glycogen synthase kinase-3β (GSK-3β), while reversing the reduction of nuclear factor erythroid-2-related factor 2 (NRF2) expression induced by OUA. Together, these findings support the hypothesis that modulation of redox homeostasis and changes in PKA/GSK-3β/NRF2 signaling may contribute to the neuroprotective and behavioral effects of BCP. These findings provide preclinical evidence supporting further investigation of BCP and the molecular mechanisms that may underlie its effects in experimental models relevant to BD.

Although dyslipidemia and lipid accumulation are established risk factors for numerous neurological diseases, including stroke and neurodegenerative disorders, whether dyslipidemia directly causes neuronal death or acts as a secondary factor remains debatable. To answer this question, ApoE-knockout is a more suitable model than ApoE4 mutants to study dyslipidemia because the E4 allele manifests an isoform-specific structural conformation that produces allele-specific effects. In this study, we examined neurological phenotype and mitochondrial and metabolic alterations in ApoE-knockout mice, which exhibited elevated serum cholesterol and triglyceride levels from an early age. These mutant mice exhibited mild cognitive phenotypes, suggesting that the functions of the cerebral cortex were affected by lipid dysregulation. Decreased electron transport chain complex IV activity indicated compromised mitochondrial function in 1-year-old mutant mice. Increased oxidative stress in cortical tissues, and downregulated expression of the key antioxidative genes indicated increased oxidative stress and mitochondrial damage in the mutant mice. Decreased mitochondrial mass was also observed, possibly due to the increase of mitophagy. However, no extensive cell death or significant reduction in cortical neuronal count was detected although the neurites degenerated in 1-year-old mutant mice. Upregulation of the Pgc1a gene, a master regulator of mitochondrial biogenesis, suggested the presence of protective mechanisms in the brain. Collectively, these findings, together with the phenotypes developed in Ldlr^−/− mutant mice, suggest that hyperlipidemia alone may be insufficient to induce significant neurodegeneration. There should be additional factors that play a crucial role in the pathogenesis of these diseases.