Astrocytes are one of the most abundant types of glial cells in the central nervous system (CNS) and play pivotal roles in metabolic support, synaptic regulation, and neurotransmitter homeostasis. Astrocytic dysfunction is closely associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), and lipid metabolism constitutes a central axis for maintaining astrocyte function and CNS homeostasis. Here, we provide a systematic review of recent advances in astrocyte lipid metabolism, summarizing the fundamental roles of astrocytes in the CNS and focusing on the biosynthesis, degradation, and trafficking mechanisms of fatty acids, cholesterol, and the tightly linked organelles known as lipid droplets. We further analyze the relationships and potential pathogenic mechanisms linking lipid metabolic disturbances, such as impaired fatty acid β-oxidation, cholesterol accumulation, and dysregulated lipid droplet dynamics, to neurodegeneration. The review also presents current frameworks for classifying reactive astrocytes, including the classical A1/A2 paradigm and more recently identified subtypes, and examines how lipid metabolic processes influence phenotype transitions. Finally, we propose a regulatory axis: lipid metabolism dysregulation leads to cellular phenotype conversion, which in turn drives disease progression, to emphasize the central role of lipid metabolism in astrocyte reactivity and neuropathology. This synthesis fills a gap in the literature at the interface of lipid metabolism and astrocyte functional regulation, and it offers a conceptual framework and candidate targets to guide future investigation into metabolic mechanisms of neurodegeneration and the development of precision therapeutic strategies.
The medial prefrontal cortex (mPFC), which abundantly expresses corticotropin-releasing hormone (CRH) and its receptors, is a key region for integrating somatosensory, cognitive, and emotional information. Although CRH has been implicated in itch modulation, the cellular and local-circuit roles of CRH-positive neurons in the mPFC remain poorly defined. Here, we combined behavioral assays, in vivo fiber photometry, chemogenetics, optogenetics, immunofluorescence, and ex vivo whole-cell patch-clamp recordings to determine how mPFC CRH neurons regulate itch-related scratching in mice. mPFC CRH neurons were predominantly vasoactive intestinal polypeptide (VIP)-expressing inhibitory interneurons and responded rapidly to both histaminergic and non-histaminergic pruritic stimuli. Chemogenetic activation increased spontaneous and pruritogen-evoked scratching, whereas chemogenetic inhibition reduced pruritogen-evoked scratching. Consistent with this observation, histamine stimulation elevated c-Fos expression in layer 5 pyramidal (PYR) neurons. Optogenetic activation of mPFC CRH neurons elevated spontaneous excitatory postsynaptic current (sEPSC) frequency, reduced rheobase, and depolarized the resting membrane potential in PYR neurons. Bath-applied CRH similarly increased sEPSC frequency and reduced rheobase. Pharmacological experiments further showed that both CRHR1- and GABAA receptor-dependent signaling contribute to the regulation of PYR-neuron excitability. Collectively, mPFC CRH neurons promote itch-related scratching through the coordinated actions of CRH and GABA, which together enhance the activity of downstream layer 5 PYR neurons. These findings identify a local prefrontal microcircuit involved in itch regulation and suggest potential targets for treating intractable pruritus.
BACKGROUND:Repeated exposure to general anesthetics during early brain development may cause persistent neurobehavioral abnormalities, but the contribution of oligodendroglial dysfunction remains unclear. We examined whether neonatal sevoflurane exposure alters oligodendroglial development, myelin basic protein (MBP), and transforming growth factor-β (TGF-β)-associated signaling in the medial prefrontal cortex (mPFC) and hypothalamus. METHODS:C57BL/6 mouse pups received 3% sevoflurane in 40% O2 for 2 h daily on postnatal days 6-8. Motor and social behaviors were assessed at P30-P32. RNA sequencing, qPCR, immunofluorescence, and Western blotting assessed oligodendroglial markers, MBP, and TGF-β1. Recombinant mouse TGF-β1 was administered intranasally, and RepSox was used to interfere with TGF-β receptor I/ALK5-related signaling. RESULTS:Sevoflurane impaired rotarod and balance-beam performance, social interaction, and social recognition memory without changing habituation distance. Transcriptomic analysis indicated relative suppression of the TGF-β signaling pathway gene set. At P8 and P56, sevoflurane reduced SOX10-and OLIG2-positive cell densities and the proportion of APC+SOX10+ cells among total SOX10+ cells in the mPFC and arcuate nucleus. MBP immunoreactivity and mPFC MBP protein abundance were reduced at P56. Regional TGF-β1 immunoreactivity and mPFC TGF-β1-immunoreactive protein abundance were also reduced. Intranasal TGF-β1 increased detectable TGF-β1 abundance and partially improved behavioral outcomes. CONCLUSION:Neonatal sevoflurane exposure is associated with persistent oligodendroglial and MBP abnormalities. Convergent transcriptomic, protein, and pharmacological findings support altered TGF-β-associated signaling as a contributor to the long-term phenotype.
The pathophysiology of non-suicidal self-injury (NSSI) remains largely unknown; however, a few studies suggest that oxidative stress contributes to self-injurious behaviors associated with NSSI and other mental disorders. Bay k-8644, an activator of L-type voltage-gated calcium channels, has been reported to induce self-injurious behaviors, particularly in early adolescent mice, yet the role of oxidative stress remains elusive. Ginsenoside Re (GRe) exerts neuroprotective effects through various mechanisms, including antioxidant activity. In the present study, we investigated changes in the endogenous antioxidant system in this model and evaluated the effects of GRe. Bay k-8644 (50 μg, i.c.v.)-induced self-injurious behaviors were accompanied by decreased glutathione peroxidase (GPx) activity and GPx-1 expression in the striatum of mice, along with increased phosphorylation of protein kinase Cδ (PKCδ), one of the redox-sensitive kinases. These changes were associated with decreased Nrf2 activity and reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, suggesting that disruption of the GSH-related endogenous antioxidant system is involved in Bay k-8644-induced self-injurious behaviors. Pretreatment with GRe (20 mg/kg/day, p,o.) attenuated Bay k-8644-induced PKCδ phosphorylation, restored Nrf2 activity and the GSH/GSSG ratio, and prevented decreases in GPx activity and GPx-1 expression, thereby alleviating self-injurious behaviors in wild-type (WT) mice. Similarly, PKCδ gene knockout (KO) significantly inhibited these Bay k-8644-induced alterations. In contrast, GRe did not provide additional protective effects in PKCδ KO mice. These findings suggest that GRe attenuates Bay k-8644-induced self-injurious behaviors by restoring Nrf2 activity and GSH-related endogenous antioxidant system, in association with modulation of PKCδ signaling.
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ)-associated synaptic failure, intracellular Ca2+ dysregulation, and progressive impairment of lysosome-dependent clearance pathways. Aβ induces sustained Ca2+ overload, resulting in pathological hyperactivation of CaMKII, which normally participates in the regulation of autophagy. However, whether CaMKII hyperactivation contributes to Aβ-induced late-stage autophagy-lysosomal dysfunction and mitophagy failure remains unclear. This study aimed to examine the effects of the CaMKII inhibitor KN93 in Aβ25-35-exposed rat organotypic hippocampal slice cultures (OHSCs, ex vivo model) and the mouse brain in vivo. The results showed that Aβ25-35 induced intracellular Ca2+ elevation, CaMKII hyperactivation, and marked accumulation of LC3-II and p62. Ultrastructural and biochemical analyses revealed impaired lysosomal maturation, defective autophagosome-lysosome coupling, and accumulation of autophagic vacuoles, consistent with a blockade of late-stage autophagic flux. Increased levels of immature cathepsin D and reduced colocalization of LC3 with lysosomal markers further supported compromised lysosomal competence. Damaged mitochondria were recruited to lysosomal compartments but failed to undergo effective degradation, indicating abortive mitophagy under Aβ25-35 exposure. KN93 attenuated Aβ25-35-induced defects in lysosomal protease maturation, autophagosome-lysosome fusion, and mitochondrial clearance in both the ex vivo OHSCs model and the in vivo mouse brain. KN93 also ameliorated cognitive impairment in Aβ25-35-exposed mice. Taken together, these findings indicate that CaMKII hyperactivation contributes to Aβ25-35-induced autophagy-lysosomal dysfunction and neuronal damage, and that pharmacological inhibition of CaMKII with KN93 restores intracellular degradative capacity and ameliorates cognitive impairment under Aβ stress.
Neuropathic pain (NP) is a debilitating chronic condition whose molecular mechanisms remain incompletely understood, limiting the development of effective disease-modifying therapies. Lactylation, a lactate-derived post-translational modification of histone and non-histone lysine residues, has recently emerged as a critical epigenetic mechanism that directly couples glycolytic activity to transcriptional reprogramming. Following peripheral nerve injury, four pain-relevant cell populations undergo cell-type-specific glycolytic reprogramming through distinct upstream cascades: the AREG-EGFR-PKM2 axis in dorsal root ganglion sensory neurons, RUNX1-CMPK2 in spinal microglia, Sox9-HK1 in spinal astrocytes, and LDHA in peripheral Th17 cells. The resulting intracellular lactate accumulation drives lactylation through three mechanistic modes: transcriptional activation of pro-nociceptive genes, silencing of analgesic mediators, and direct inactivation of pain-suppressive signaling proteins. A self-reinforcing feedback loop between glycolysis and lactylation further perpetuates the chronic pain state. This review synthesizes current mechanistic evidence, evaluates emerging pharmacological strategies targeting this metabolic epigenetic axis, and discusses outstanding translational challenges including reader protein identification, sex-based variability, and human tissue validation.
Ischemic stroke is a leading cause of permanent neurological disability worldwide, primarily driven by neuronal injury mechanisms such as excitotoxicity and oxidative stress. Consequently, understanding the molecular basis of post-ischemic neural repair has emerged as a critical focus in translational neuroscience. Accumulating evidence now points to a central orchestrator in this repair process: dynamic epigenetic regulation. This regulation, which encompasses mechanisms like DNA methylation/demethylation, histone modifications, non-coding RNA networks, and chromatin remodeling, modulates key repair pathways including neuroinflammation, axonal regeneration, and synaptic plasticity. In this context, the present review synthesizes current evidence on two fronts: first, how these epigenetic mechanisms regulate neuroinflammation and oxidative stress; and second, their specific roles in promoting neurogenesis and neuroplasticity after stroke. By integrating these insights, this review aims to provide a coherent theoretical foundation for the rational development of epigenetic-targeted therapeutic strategies to enhance functional recovery following stroke.
Early-life exposure to methamphetamine (MA) induces long-lasting neuroadaptive changes, particularly within glutamatergic pathways, which may contribute to behavioral and cognitive impairments. The present study investigated the interaction between early postnatal MA exposure and environmental conditions on behavioral outcomes and glutamate levels in adolescent rats. Rat pups were administered MA (5 mg/kg) or saline during postnatal days (PD) 1-12, either directly or indirectly via lactating dams. Animals were subsequently reared under different pre-weaning (standard vs. enriched environment) and post-weaning (single vs. group housing) conditions. Behavioral performance was assessed using habituation, object recognition/location, and Morris water maze tasks, while glutamate levels in the striatum and hippocampus were quantified using ELISA. Direct MA exposure induced moderate alterations in locomotor activity and spatial learning, whereas indirect exposure produced only minimal effects. In contrast, environmental conditions exerted pronounced influences on both behavior and glutamate levels. Environmental enrichment and post-weaning housing affected exploratory behavior and performance in cognitive tasks, although the direction and magnitude of these effects varied across behavioral paradigms and experimental conditions. Environmental conditions were also associated with region-specific alterations in glutamate levels, including increased striatal and decreased hippocampal glutamate under enriched pre-weaning conditions. As only male offspring were included, these findings cannot be generalized to females, and comparable effects in females cannot be assumed without direct experimental evidence. Overall, environmental factors exerted a stronger influence on behavioral and glutamatergic outcomes than early MA exposure, but their behavioral effects were task- and context-dependent rather than uniformly beneficial. These findings highlight the importance of environmental conditions in shaping neurobehavioral and glutamatergic outcomes following early-life psychostimulant exposure.
Alzheimer's disease (AD) represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol (OST), a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain unclear. This study elucidates the critical interplay between estrogen-cholinergic system imbalance and AD progression across distinct temporal windows in female AD models. By focusing on this sex-specific regulatory axis, we aimed to address a key gap in understanding AD pathogenesis and OST's targeted efficacy. We employed age-stratified 3×Tg-AD mice as an experimental model and utilized comprehensive behavioral paradigms to assess learning and memory functions. An age-dependent gradient of cognitive impairment, accompanied by varying degrees of neuropathological damage, was observed in 3×Tg AD mice across different age groups. OST significantly improved learning and memory performance in 3×Tg AD mice of all age groups. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment effectively alleviated damage to the estrogen-cholinergic-NGF axis through multiple synergistic mechanisms: upregulation of Acetylcholine (ACh), Choline acetyltransferase (ChAT), Tyrosine kinase-A (TrkA), and Nerve growth factor (NGF) expression; downregulation of Acetylcholinesterase (AChE) activity; and increased expression of Estradiol (E2), Estrogen receptor-α (ERα), and Estrogen receptor-β (ERβ). In addition, OST improved synaptic plasticity (Postsynaptic density protein-95 (PSD95), Synuclein (SYN), and Brain-derived neurotrophic factor (BDNF)), inhibited neuronal apoptosis (B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX)), and enhanced neurotransmitter signaling cascades (γ-aminobutyric acid (GABA), Glutamic acid (Glu), Epinephrine (E), and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.
Neonatal hypoxia-ischemia (HI) is a leading cause of long-term neurodevelopmental impairment and is increasingly associated with a heightened risk of attention-deficit/hyperactivity disorder (ADHD) and related behavioral abnormalities. Beyond its metabolic role, insulin functions as a neurotrophic and immunomodulatory factor in the developing brain. However, whether early enhancement of central insulin signaling can mitigate the neuroinflammatory and behavioral sequelae of HI remains unclear. Male and female Sprague-Dawley rats were subjected to HI (right common carotid artery ligation followed by 90 min of 8% oxygen) at P10 and randomized to Sham + Vehicle, Sham + Insulin, HI + Vehicle, or HI + Insulin groups (n = 12 males and 12 females/group). Recombinant human insulin (rhInsulin) (50 μg/day) was administered intranasally once daily from P10 to P12, and behavioral and histological outcomes were assessed at P21-P25. Neonatal HI produced persistent ADHD-like behavioral abnormalities and deficits in neurobiological outcomes. Notably, sex-specific responses were observed: males exhibited greater deficits in inattention, spatial working memory, impulsivity, adaptive social development, myelination and vascularization, whereas females showed more pronounced increases in repetitive and compulsive-like behaviors. Intranasal rhInsulin treatment significantly attenuated HI-induced behavioral deficits by 100% and increased myelination (MBP+) by 64% in cingulate white matter, restored dendritic expression (MAP2+) by 56%, and reduced astrocytes (GFAP+) by 70% in hippocampal regions, indicating suppression of chronic astrogliosis neuroinflammation. Furthermore, intranasal rhInsulin increased cerebral vascular volume by 49% and normalized vessel diameters as assessed by micro-computed tomography (microCT) imaging, suggesting enhanced neurovascular integrity. While our previous study demonstrated that intranasal rhInsulin attenuated acute brain injury, neuronal apoptosis, and short-term sensorimotor deficits following neonatal hypoxia-ischemia (HI), its effects on long-term neurodevelopmental outcomes remained unclear. The present study addresses this important knowledge gap by evaluating juvenile behavioral and neurobiological outcomes through P25, including ADHD-like behaviors, social deficits, repetitive behaviors, white matter integrity, astrogliosis, cerebrovascular development, and sex-specific treatment responses. Collectively, these findings identify central insulin signaling as a key regulator of post-HI neuroimmune and neurodevelopmental trajectories and support intranasal insulin as a promising, minimally invasive therapeutic approach to reduce the long-term neurobehavioral sequelae of neonatal brain injury.
WAC is a chromatin-associated regulatory protein involved in transcriptional control and has been identified as an autism-associated gene in human genetic studies. However, its functional role in regulating behavior and synaptic processes remains incompletely understood. Using Caenorhabditis elegans, we investigated the consequences of wac deficiency on food-associated social behavior, growth-associated phenotypes, and cholinergic pathway function. wac-deficient worms showed a marked reduction in food-leaving behavior, supporting impaired behavioral responsiveness to food-associated environmental cues, while aggregation behavior was not significantly altered. PHX2587 wac deletion mutant worms also exhibited reduced body length, decreased pharyngeal pumping, and shortened lifespan, indicating broader growth and physiological impairment. Stage-resolved analysis of cholinergic pathway genes revealed stage-associated transcriptional changes, with coordinated upregulation of multiple presynaptic and postsynaptic cholinergic components (ace-1, cha-1, cho-1, lev-1, lev-10, unc-17, unc-29, unc-38, and unc-50) emerging most prominently at the young adult stage. Functional RNAi analysis further identified cho-1, which encodes the high-affinity presynaptic choline transporter, as a genotype-specific modifier of cholinergic sensitivity in PHX2587 worms. Importantly, cho-1 RNAi not only reduced aldicarb hypersensitivity but also partially suppressed the reduced body length phenotype and improved food-leaving behavior in PHX2587 worms, while having limited effects in wild-type N2. Together, these findings support a functional relationship between wac deficiency and cho-1-associated cholinergic modulation, suggesting that presynaptic choline transport contributes to selected behavioral and physiological consequences of wac loss.
BACKGROUND:The amyloid-β protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Chemically synthesized Aβ(1-42) is the most widely employed resource for AD mechanistic research and drug screening. However, solid-phase synthesis introduces truncated and modified byproducts, causing batch-to-batch heterogeneity and compromised experimental reproducibility. METHODS:Herein, we established an optimized recombinant expression system utilizing a thermal green protein (TGP) fusion tag combined with TEV protease site-specific cleavage to produce tag-free, authentic human Aβ(1-42) in Escherichia coli. We systematically performed side-by-side biophysical characterization, including secondary structural transition and amyloid aggregation kinetics, to compare purified recombinant Aβ(1-42) (RecAβ) and conventional synthetic Aβ(1-42) (SynAβ). Human iPSC-derived neurons (iNs) and primary murine microglia were further applied to evaluate and compare their neurotoxicity and microglial regulatory functions. RESULTS:The optimized TGP-TEV platform enabled robust production of high-purity RecAβ(1-42), yielding 6-7 mg intact peptide per liter of bacterial culture. Biophysical assays demonstrated that RecAβ shares highly conserved secondary structural features with SynAβ but exhibits significantly enhanced aggregation propensity. Functional assays revealed that RecAβ- and SynAβ-derived Aβ-derived diffusible ligands (ADDLs) exert equivalent neurotoxicity in human iNs. While both fibril preparations display comparable microglial binding recognition and lysosomal clearance kinetics with subtle temporal differences, RecAβ fibrils induce more severe microglial phagolysosomal dysfunction than SynAβ fibrils. CONCLUSION:This work establishes a robust, reproducible recombinant strategy for generating authentic human Aβ(1-42). RecAβ recapitulates core AD-relevant bioactivities of commercial SynAβ while possessing stronger aggregation potency and enhanced capacity to disrupt microglial homeostatic function. This standardized recombinant Aβ preparation provides a useful tool for the investigation of Aβ biology and screening of AD therapeutic candidates.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, leading to debilitating motor and non-motor symptoms. Current therapeutic strategies, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, and surgical interventions primarily offer symptomatic relief without halting disease progression. Long-term use of these treatments is often associated with complications such as motor fluctuations, dyskinesia, and systemic side effects, underscoring the urgent need for safer and disease-modifying approaches. In recent years, increasing attention has been directed toward natural products as potential therapeutic agents for PD due to their multi-targeted mechanisms and favorable safety profiles. Among these, plant-derived saponins have emerged as promising candidates owing to their diverse pharmacological properties. Saponins exhibit potent antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation activities, enabling them to modulate key pathological pathways involved in PD, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and α-synuclein aggregation. Experimental studies have demonstrated the neuroprotective effects of various saponins such as astragaloside IV, ginsenosides, bacosides, dioscin, and notoginsenosides in animal models of PD. These compounds have been shown to preserve dopaminergic neuronal integrity, enhance mitochondrial function, regulate apoptotic signalling, and promote autophagy. Despite these promising findings, challenges such as poor bioavailability in natural products and limited access to brain remain significant barriers to clinical translation. This review provides a comprehensive overview of current PD therapies and their limitations, while highlighting the therapeutic potential of plant-derived saponins as multi-target agents. It also discusses recent advances in drug delivery strategies that may enhance their clinical applicability. Overall, saponins represent a promising avenue for the development of novel neuroprotective and disease-modifying therapies for PD.
Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is closely associated with microglia-driven neuroinflammation, yet effective therapeutic strategies remain limited. Histone deacetylase 6 (HDAC6) has been implicated in neuroinflammatory regulation, but its role in microglial inflammatory activation after SAH remains unclear. In the present study, we investigated whether HDAC6 targeting attenuates SAH-induced EBI through modulation of microglia-associated neuroinflammation. A mouse prechiasmatic cistern blood-injection model of SAH and an Hb-stimulated primary microglia model were used to evaluate the effects of compound 13-7, an HDAC6-targeting inhibitor. We found that HDAC6 expression was significantly upregulated after SAH and was predominantly localized in microglia and neurons. Treatment with compound 13-7 increased α-tubulin acetylation in microglia, reduced brain edema, improved neurological deficits, and decreased neuronal apoptosis. In addition, compound 13-7 attenuated microglial inflammatory activation, reduced pro-inflammatory gene expression, decreased brain tissue levels of TNF-α, IFN-γ, and IL-6, and increased IL-4, IL-5, and IL-10 levels. In vitro, compound 13-7 protected neurons primarily through modulation of microglia-mediated inflammatory responses rather than by directly acting on neurons. Mechanistically, compound 13-7 reduced the p-P65/P65 ratio and suppressed NF-κB-related inflammatory gene expression in Hb-stimulated microglia. Collectively, these findings demonstrate that HDAC6 targeting attenuates SAH-induced EBI and improves neurological outcomes, at least partly by suppressing microglia-associated neuroinflammation and restoring inflammatory cytokine balance. Inhibition of NF-κB signaling may contribute to the anti-inflammatory effects of compound 13-7, highlighting HDAC6 as a potential therapeutic target for SAH-induced EBI.
Parkinson's disease (PD) is frequently associated with cognitive impairments, especially deficits in working memory and hippocampus-dependent memory. However, the contribution of dorsal hippocampus (dHipp) Ca2+/calmodulin-dependent protein kinase Ⅱ α (CaMKⅡα)-positive neurons to these deficits remains unclear. In this study, we investigated the impacts of chemogenetic modulation of dHipp CaMKⅡα-positive neurons on cognitive function, hippocampal theta rhythm, and monoamine levels in both sham-operated and unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. 6-OHDA lesions of the medial forebrain bundle impaired spatial working memory and hippocampus-dependent memory, reduced the peak theta frequency in the dHipp, and decreased dopamine levels in the striatum, medial prefrontal cortex (mPFC), dHipp and ventral hippocampus (vHipp). In sham-operated rats, chemogenetic manipulation of dHipp CaMKⅡα-positive neurons did not alter memory performance or theta rhythm. Aside from an increase in dopamine levels in the mPFC following activation, chemogenetic manipulation had no effect on monoamines. In contrast, in the 6-OHDA-lesioned rats, activation of dHipp CaMKⅡα-positive neurons improved spatial working memory and hippocampus-dependent memory, increased the peak theta frequency in the dHipp, and elevated dopamine levels in the mPFC, dHipp and vHipp, whereas inhibition exacerbated cognitive deficits, reduced the peak theta frequency in the dHipp, and decreased the level of noradrenaline in the above brain regions. These findings suggest that activation or inhibition of dHipp CaMKⅡα-positive neurons exerts opposing effects on cognitive function specifically in parkinsonian rats, which may be associated with alterations in hippocampal theta oscillations and monoaminergic transmission. Targeting dHipp CaMKⅡα-positive neurons may offer a promising therapeutic strategy for cognitive symptoms in PD.
OBJECTIVE:Paclitaxel-induced peripheral neuropathy is frequently accompanied by persistent neuropathic pain. Endoplasmic reticulum stress (ERS)-related responses and neuroinflammation in the dorsal root ganglion (DRG) may contribute to this toxicity. This exploratory study assessed associations between vitamin D status, nociceptive hypersensitivity, and DRG molecular markers in aged female mice. METHODS:Thirty-two 12-month-old female C57BL/6 mice were assigned to normal control, paclitaxel (PTX), vitamin D-sufficient plus PTX [VD(+) + PTX], or vitamin D-deficient plus PTX [VD(-) + PTX] groups (n = 8/group). Vitamin D sufficiency was established using calcitriol, whereas deficiency was induced using UV-free lighting and a vitamin D-deficient diet. PTX was administered on days 0, 2, 4, and 6. Paw withdrawal threshold (PWT) and latency (PWL) were assessed on days 0, 7, 14, and 21. DRG levels of total IRE1α, CHOP, GRP78, TNF-α, and IL-1β were measured by ELISA on day 21. RESULTS:PTX produced mechanical and thermal hypersensitivity. Compared with PTX, VD(+) + PTX mice had higher PWT on days 7, 14, and 21 and longer PWL on days 14 and 21. VD(-) + PTX mice showed more persistent hypersensitivity. ERS-related and inflammatory marker levels were lower in VD(+) + PTX mice than in PTX and VD(-) + PTX mice. CONCLUSION:Vitamin D sufficiency was associated with attenuated PTX-induced nociceptive hypersensitivity and lower DRG levels of ERS-related and inflammatory markers. Because UPR pathway activation and causal mediation were not directly tested, these findings represent exploratory associations rather than evidence of an ERS-mediated analgesic mechanism.
Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuronal death of unclear etiology. While levodopa remains the gold standard for managing PD motor symptoms, it lacks disease-modifying efficacy, necessitating new neuroprotective therapies. Mitochondrial dysfunction and impaired autophagy are key hallmarks of PD. This study utilized 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells to investigate the neuroprotective mechanisms of catalpol, an iridoid glycoside derived from Rehmannia glutinosa. We found that catalpol attenuated MPP+-induced neurotoxicity, mitochondrial membrane depolarization, and ATP depletion. This protection was critically dependent on autophagy; it was enhanced by the activator rapamycin but abolished by the inhibitor wortmannin and the autophagosome-lysosome fusion inhibitor bafilomycin A1. Catalpol activated autophagy by increasing autophagosome formation, elevating Beclin 1 and LC3-II levels, and promoting p62 degradation. Furthermore, catalpol reversed MPP+-induced mitophagy suppression and restored the regulatory protein PINK1 and DJ-1 expression. Given that Akt/BDNF/Bcl-2 and TrkB/BDNF pathways promote neuronal survival, we investigated their involvement. We found that the TrkB agonist 7,8-DHF mimicked catalpol's neuroprotection against MPP+-induced neurotoxicity, whereas the pan-Trk inhibitor GNF-5837 abolished it. Western blotting demonstrated that catalpol reversed MPP+-mediated suppression of TrkB and Akt phosphorylation, as well as BDNF and Bcl-2 expression. Molecular docking indicated that catalpol may interact with the TrkB ligand-binding domain as 7,8-DHF and shares key binding residues. Our findings suggest that catalpol exerts neuroprotection via a dual mechanism: preserving mitochondrial function through PINK1/DJ-1-mediated mitophagy and activating the TrkB/Akt/BDNF/Bcl-2 survival pathway, potentially by interacting with the TrkB receptor, highlighting its therapeutic potential for PD.
Microglia play a pivotal role in the pathophysiology of ischemic stroke, with substantial microglial demise occurring following cerebral ischemia. This study examined whether colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34), ligands of the colony-stimulating factor 1 receptor (CSF1R) critical for microglial survival, promote microglial proliferation and ameliorate outcomes after ischemic stroke. In a mouse model of middle cerebral artery occlusion (MCAO), endogenous CSF-1 levels showed dynamic changes within the first 24 h post-ischemia. Administration of CSF-1, but not IL-34, significantly improved neurological outcomes and reduced infarct volume. CSF-1 treatment was associated with a less reactive microglial morphology and an anti-inflammatory, homeostatic microglial phenotype. In vitro, CSF-1 enhanced Ki67 expression in oxygen-glucose deprivation (OGD)-exposed microglia, while decreasing pro-inflammatory cytokine production and excessive phagocytosis of neuronal debris. Conditioned medium from CSF-1-treated microglia and co-culture experiments further indicated that increased microglial numbers contribute to reduced OGD-induced neuronal apoptosis. Collectively, these findings suggest that CSF-1 fosters a neuroprotective microglial phenotype during acute ischemia, highlighting its potential as a therapeutic agent to mitigate ischemic brain injury through modulation of microglial proliferation and inflammatory responses.
Down syndrome (DS), caused by trisomy of chromosome 21, is characterized by early-onset oxidative stress, impaired neuronal development, and an increased risk of Alzheimer's disease (AD)-like neuropathology. Among chromosome 21 genes, the transcription factor BTB and CNC homology 1 (BACH1) has emerged as a critical regulator of redox homeostasis. Under physiological conditions, the balance between BACH1 and nuclear factor erythroid 2-related factor 2 (NRF2) warrants tight control of antioxidant defenses and heme metabolism. However, in DS, BACH1 overexpression disrupts this balance, impairing the induction of heme oxygenase-1 (HO-1) and of other cytoprotective pathways, thereby contributing to chronic oxidative stress, neuronal vulnerability, and pathological processes. The present review summarizes the molecular mechanisms that regulate the BACH1/HO-1 axis in the central nervous system. We recapitulate data from studies showing how dysregulation of this axis affects antioxidant defenses, iron homeostasis, ferroptosis, neuroinflammation, and mitochondrial function. We further provide evidence from the aging and AD literature, highlighting BACH1 as a convergent molecular node linking genetic and age-related neurodegeneration. Remarkably, we explore BACH1's contribution to the transition of DS to AD-like pathology. Finally, we evaluate emerging therapeutic strategies employing BACH1 inhibitors, NRF2 activators, and upstream signaling pathway modulators, and assess their applicability to the AD-like dementia context, concluding that targeting BACH1-dependent regulation of HO-1 represents a promising and unifying strategy to mitigate neurodegeneration in both DS and AD.
Both lateral hypothalamic area (LHA) and paraventricular thalamic nucleus (PVT) constitute pivotal nodes within the regulatory network of the central nervous system, where the γ-aminobutyric acidergic (GABAergic) neurons contribute significantly to the modulation of pain. In order to investigate the underlying mechanism of the GABAergic pathway from LHA to PVT in pain modulation, fiber photometry calcium signal recording, immunofluorescence histochemical staining, and neuroanatomical tract tracing were used in the present study. Fiber photometry recordings revealed that calcium signals of glutamate decarboxylase-positive (GAD+) neurons in the LHA were significantly increased in response to innocuous and noxious stimulation. Furthermore, in the spared nerve injury (SNI) mouse model of neuropathic pain, 37.26 ± 7.23% of GAD+ neurons in the LHA were activated, as indicated by c-FOS protein expression in the nuclei. Neuroanatomical tract tracing results showed that axons originating from GAD+ neurons in the LHA projected to the PVT, where these terminals established close appositions with calcium/calmodulin-dependent protein kinase IIα-positive (CaMKIIα+) neurons within the PVT. Furthermore, analysis of publicly available anatomical datasets confirmed the presence of fibers originating from the LHA and projecting to the PVT. Moreover, in the SNI model, GAD+ and c-FOS protein-positive (c-FOS+) double-labeled neurons comprised 19.45 ± 3.92% of the total projection neurons within the LHA-PVT pathway. These results collectively indicate that the GABAergic LHA-PVT pathway is activated in the SNI model of neuropathic pain, suggesting its involvement in the modulation of nociception.
