Exp. Neurol. [JOURNAL]
Sun
200 papers
Plant-derived extracellular vesicles restore cellular energetics for peripheral nerve regeneration through glycolysis reprogramming.
Zhou H, Xu G, Chen Q … +7 more , Liu Y, Li S, Huo N, Liu J, Wang W, Yang N, Zhou N
Exp Neurol · 2026 Jul · PMID 41794111 · Publisher ↗
Peripheral nerve injury (PNI) causes a severe energy crisis at the injury site, restricting peripheral nerve regeneration. However, effective intervention strategies are lacking to maintain energy homeostasis. Emerging r...
Peripheral nerve injury (PNI) causes a severe energy crisis at the injury site, restricting peripheral nerve regeneration. However, effective intervention strategies are lacking to maintain energy homeostasis. Emerging research has underscored the potential of plant-derived extracellular vesicles for PNI treatment. In this study, we demonstrated that Gastrodia elata derived extracellular vesicles (GEDEVs) exhibited neuroregenerative effects. GEDEVs selectively boosted pro-regenerative phenotypes in PC12 cells. In addition, GEDEVs reprogrammed cellular metabolism in dorsal root ganglion (DRG) neurons by upregulating aerobic glycolysis and downregulating oxidative phosphorylation. This reprogramming preserved adenosine triphosphate (ATP) availability for DRG neurons while suppressing reactive oxygen species (ROS) production. The results of RNA sequencing indicated that key glycolytic enzymes, such as PKM2 and LDHA, were significantly upregulated and may contribute to this metabolic shift. In vivo, GEDEVs promoted nerve regeneration and functional recovery. GEDEVs demonstrated a favorable safety profile, with no significant toxicity observed in vitro or in vivo assessments. In conclusion, this study demonstrates that GEDEVs represent a promising nanotherapeutic approach for enhancing nerve regeneration in PNI.
Decoy oligodeoxynucleotides and peptides as a promising approach for managing myocardial infarction and stroke.
Mahjoubin-Tehran M, Rezaei S, Almahmeed W … +3 more , Aromolaran AS, Kesharwani P, Sahebkar A
Exp Neurol · 2026 Jul · PMID 41786072 · Publisher ↗
Myocardial infarction (MI) is one of the main causes of mortality worldwide. Stroke ranks as another frequent cause of death and the foremost cause of disability. Acute MI is one of the most profound expressions of coron...
Myocardial infarction (MI) is one of the main causes of mortality worldwide. Stroke ranks as another frequent cause of death and the foremost cause of disability. Acute MI is one of the most profound expressions of coronary artery illness and continues to be a predominant source of morbidity and death globally, although significant advancements in prognosis have occurred over the last decade. Importantly, MI elevates the risk of stroke in comparison to those without MI. Coronary heart disorder and certain subtypes of ischemic stroke have analogous pathogeneses, including inflammation and atherosclerosis progression. Moreover, MI may serve as a risk factor for stroke due to factors such as emboli following revascularization, atrial fibrillation associated with acute MI, or blood stasis in a partially functioning left ventricle. Moreover, stroke and MI share certain risk factors, including advancing age, diabetes, hypercholesterolemia, hypertension, and smoking. Oligonucleotides and decoy peptides are used to disrupt biological processes by imitating natural binding sites. Decoy peptides function as structural analogs of receptor proteins, attaching to ligands and obstructing their interaction with the real receptors. Conversely, oligonucleotide decoys are small DNA sequences that attach to transcription factors and prevent them from attaching to the sequences of their target genes. This review summarizes decoy-based research on MI and stroke.
Shift in motor-state equilibrium explains gait therapy effects of apomorphine in experimental Parkinsonism.
Kabaoglu B, Garulli EL, De Sa R … +11 more , Vogt A, Behrsing R, Skrobot M, Paulat R, Pollak P, Guldin LS, Gerster M, Neumann WJ, Endres M, Harms C, Wenger N
Exp Neurol · 2026 Jul · PMID 41765318 · Publisher ↗
Gait impairments remain a major therapeutic challenge in Parkinson's disease (PD). Apomorphine is gaining renewed clinical attention with the expanding use of pump infusion systems. Yet the specific role of apomorphine o...
Gait impairments remain a major therapeutic challenge in Parkinson's disease (PD). Apomorphine is gaining renewed clinical attention with the expanding use of pump infusion systems. Yet the specific role of apomorphine on the neural regulation of gait has remained poorly characterized, limiting its targeted use for symptom-specific therapy in PD. Here, we examined the neurobehavioral effects of apomorphine on runway locomotion in the unilateral 6-hydroxydopamine (6-OHDA) rat model. Therapeutic drug doses significantly increased total walking distance, related to reduced akinesia and prolonged gait episodes. Conversely, 3D kinematic analysis revealed reduced limb velocities under medication. At the neural level, therapy doses selectively enhanced cortical high-gamma rhythms without substantially altering beta or low-gamma activity. Instead, beta and low-gamma oscillations were consistently suppressed during motor activity in both medication ON and OFF conditions. Neurobehavioral correlations showed that transitions into gait were facilitated by reductions in beta and low-gamma activity, whereas transitions to akinesia were primarily suppressed when high-gamma activity was elevated. Our findings highlight that cortical oscillations can serve as state specific biomarkers for gait impairments in PD. We further propose that the complex therapy effects of apomorphine are best explained by a shift in motor-state equilibrium that is defined by the transitions of akinesia, stationary movements and gait. Together, these insights establish a mechanistic framework to guide the development of targeted gait therapies in PD.
Mitochondrial dysfunction and disrupted neuronal lipid homeostasis in Parkinson's disease: Potential mechanisms and therapeutic implications.
Quan Z, Ku CY, Xie T … +3 more , Fok HT, Schweitzer D, Akefe IO
Exp Neurol · 2026 Jun · PMID 41759571 · Publisher ↗
BACKGROUND: Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by dopaminergic neuron loss and pathological accumulation of alpha-synuclein. Emerging evidence highlights a crucial inter...
BACKGROUND: Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by dopaminergic neuron loss and pathological accumulation of alpha-synuclein. Emerging evidence highlights a crucial interplay between mitochondrial dysfunction and disrupted lipid homeostasis as central mechanisms driving PD pathogenesis. OBJECTIVE: This scoping review synthesises current evidence on the relationship between mitochondrial dysfunction and neuronal lipid dysregulation in PD and identifies potential therapeutic targets within these intersecting pathways. METHODS: Following the PRISMA-ScR guidelines, a comprehensive literature search was conducted across PubMed, Embase, and Web of Science for studies published between 2015 and 2025. Two independent reviewers screened and selected eligible studies based on predefined inclusion criteria. RESULTS: Analysis revealed four central interconnected pathological mechanisms: ferroptosis, alpha-synuclein-lipid interactions, mitochondrial dysfunction, and impaired autophagy/mitophagy. These mechanisms collectively contribute to oxidative stress, membrane destabilisation, and bioenergetic collapse, driving dopaminergic neuronal vulnerability. CONCLUSIONS: The findings underscore a complex, bidirectional relationship between mitochondrial dysfunction and lipid dysregulation in PD. Therapeutic strategies targeting iron accumulation, lipid peroxidation, and alpha-synuclein aggregation are promising. However, further mechanistic studies are required to clarify these interactions and advance the development of effective disease-modifying interventions.
Vascular integrity and immune infiltration in SCI pain: Can exercise tip the balance?
Giddings GA, Detloff MR
Exp Neurol · 2026 Jun · PMID 41734862 · Publisher ↗
Chronic neuropathic pain is a debilitating consequence of spinal cord injury (SCI), yet effective treatments remain limited. Exercise reduces pain incidence after SCI, but the underlying mechanisms linking vascular and i...
Chronic neuropathic pain is a debilitating consequence of spinal cord injury (SCI), yet effective treatments remain limited. Exercise reduces pain incidence after SCI, but the underlying mechanisms linking vascular and immune regulation to pain resilience are unclear. Here, we investigated how aerobic exercise influences blood brain/spinal cord barrier (BBB/BSCB) integrity, vascular protein expression, and neuroimmune activation along the sensory neuroaxis. Female rats received unilateral cervical SCI or served as uninjured controls and were assigned to sedentary or forced wheel exercise groups. Behavioral testing revealed that exercise prevented SCI induced tactile allodynia and normalized avoidance of noxious stimuli. Using Evans Blue dye to assess BSCB permeability, we found that the blood spinal cord barrier was transiently disrupted after SCI but recovered by six weeks. Exercise restored expression of the tight junction protein occludin at the lesion epicenter, while the vascular marker CD13 remained stable. Cortical barrier proteins were unchanged, yet glial activation was regionally distinct: the anterior cingulate cortex (ACC) exhibited robust microglial and astrocytic reactivity not observed in the primary somatosensory cortex. Exercise reduced astrocytic reactivity in the ACC and normalized microglial activation below the lesion, indicating that its immune effects are spatially selective rather than global. Together, these findings demonstrate that post SCI exercise stabilizes tight junctions, limits maladaptive glial activation, and preserves vascular immune homeostasis across pain processing circuits. This work identifies the ACC as a uniquely reactive cortical site in SCI pain and highlights vascular resilience as a potential therapeutic target for preventing chronic pain.
Microbiome- metabolome signatures and Behavioral alterations in a progressive MPTP-induced mouse model of Parkinson's disease.
Das A, Das R, Das A … +1 more , Aich P
Exp Neurol · 2026 Jun · PMID 41724229 · Publisher ↗
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, motor deficits, and systemic metabolic dysfunction. Using a chronic MPTP-induced C57BL/6 mouse model, we i...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, motor deficits, and systemic metabolic dysfunction. Using a chronic MPTP-induced C57BL/6 mouse model, we integrated behavioral, transcriptional, metabolomic, and microbiome analyses to investigate gut-metabolite-brain interactions in PD. MPTP-treated mice exhibited significant motor and non-motor impairments alongside increased α-synuclein and inflammatory markers in the midbrain. Untargeted LC-MS metabolomics revealed differential enrichment of host- and microbiome-derived metabolites, including altered arginine/proline, sphingolipid, tryptophan, and riboflavin metabolism. 16S rRNA sequencing demonstrated decreased Firmicutes/Bacteroidetes ratio and enrichment of lipopolysaccharide-producing taxa, functionally linked to amino-acid metabolism via correlation network analysis. These data define a coordinated gut-metabolite-brain axis underpinning PD pathology, highlighting microbiome-derived circulating metabolites as potential early biomarkers and therapeutic targets. While these findings are derived from a toxin-based, male-only PD model, they delineate robust gut-metabolite-brain signatures that provide a strong framework for future validation in α-synucleinopathy models and mixed-sex cohorts.
The role of IGF1 signaling in remote ischemic conditioning-mediated amelioration of Alzheimer's disease pathology and cerebral insulin resistance.
Li J, Sun W, Guo S … +8 more , Bai J, Yuan T, Gao F, Zhang X, Ma H, Ma Y, An J, Wang R
Exp Neurol · 2026 Jun · PMID 41720208 · Publisher ↗
BACKGROUND: Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) share common pathological features, notably insulin resistance. Remote ischemic conditioning (RIC) is a clinically validated intervention with broa...
BACKGROUND: Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) share common pathological features, notably insulin resistance. Remote ischemic conditioning (RIC) is a clinically validated intervention with broad distant organ protection. Nevertheless, RIC's effects on cerebral insulin resistance (CIR) in AD animal models remain poorly understood. This study aims to investigate RIC's effects in reducing CIR and AD pathology across models. METHODS: The study used ICV streptozotocin (STZ) to induce sporadic AD (sAD) and APP/PS1 transgenic rats as familial AD (fAD) models. RIC was established by three cycles of five minutes of ischemia followd by five minutes of reperfusion in rats' hindlimbs, conducted five times a week over four weeks. Additional experiments generated AD cell models with OAβ1-42, STZ, or mature TauP301L in primary hippocampal neurons and SH-SY5Y cells. CIR and AD pathology-related behavioral and biomarker assessments were performed. RESULTS: RIC intervention reduces CIR, β-amyloid (Aβ) and Tau pathology. Additionally, RIC improves anxiety-like, depression-like behaviors and cognitive impairments in sAD rats. Mechanistically, it increases peripheral/central IGF1 levels, activates the IGF1R/IRS1-AKT-GSK3β pathway in sAD/fAD models, and enhances GLUT1-AMPK pathway for glucose metabolism. Additionally, RIC boosts antioxidative and anti-apoptotic responses by modulating FOXO3a phosphorylation and nuclear translocation. In vitro, IGF1 administration mirrored RIC's protective effects against OAβ1-42, TauP301L, or STZ administration. CONCLUSIONS: Findings show that RIC effectively inhibits CIR by enhancing the IGF1R/IRS1-AKT-GSK3β pathway and glucose-mitochondrial energy metabolism. This study identifies a novel RIC neuroprotective mechanism, offering a multi-target AD prevention/treatment strategy.
Glucose transporter 3 gene deficiency modifies Huntington's disease progression in zQ175 model mice.
Daida T, Shin BC, Barry J … +6 more , Da Silva T, Argueta D, Cheng L, Ozay Y, Cepeda C, Devaskar SU
Exp Neurol · 2026 Jun · PMID 41720207 · Full text
In Huntington's disease (HD), reduced neuronal glucose transport plays an important role. We investigated the effects of GLUT3 knock-down (KD) on the trajectory of the HD phenotype in zQ175 model mice. GLUT3 (G3) express...
In Huntington's disease (HD), reduced neuronal glucose transport plays an important role. We investigated the effects of GLUT3 knock-down (KD) on the trajectory of the HD phenotype in zQ175 model mice. GLUT3 (G3) expression was reduced in heterozygous (HT) and homozygous mice. zQ175 mice when crossed with Emx1-G3KD HT mice, created conditional GLUT3-KD in cortical pyramidal neurons (CPNs), allowing examination of Q175WT/G3WT, Q175WT/G3KD, Q175HT/G3WT, and Q175HT/G3KD genotypes. Immunohistochemically, higher GLUT3 expression and number of GLUT3 positive CPNs were observed in Q175WT/G3WT compared to Q175WT/G3KD, Q175HT/G3WT, and Q175HT/G3KD, with no difference among these three groups, supporting a protective floor effect. Behaviorally, Q175HT/G3KD mice faced difficulty learning tasks and thereby performed worse than the other three groups. Electrophysiologically, the basic membrane properties of cortical pyramidal neurons (CPNs) were not affected. In contrast, in striatal medium-sized spiny neurons (MSNs) significant increases in cell membrane input resistance occurred in Q175HT/G3WT and Q175HT/G3KD compared to Q175WT/G3WT and Q175WT/G3KD, with no difference between Q175HT/G3WT and Q175HT/G3KD. Upon examination of spontaneous glutamatergic and GABAergic synaptic currents, the cumulative interevent intervals (IEI) revealed increased glutamatergic activity in GLUT3 KD, suggesting increased cortical excitability, with a concomitant compensatory increase in GABA synaptic activity. In striatal MSNs, a subtle but significant decrease in sEPSCs frequency occurred between Q175HT/G3WT and Q175HT/G3KD. The key change was an increase in frequency of sIPSCs in Q175HT/G3WT and Q175HT/G3KD compared to Q175WT/G3WT. These results underscore complex modifications of the HD phenotype among groups related to the interplay between GLUT3 KD, compensatory mechanisms, and floor effects.
UCP2 protects against intracerebral hemorrhage-induced ferroptosis via suppression of TRIM21-dependent GPX4.
Zhang RC, Lu HB, Zhu J … +6 more , Liu YW, Wang XY, Shi Y, Dai LL, Zhu SG, Cheng YB
Exp Neurol · 2026 Jun · PMID 41720206 · Publisher ↗
Intracerebral hemorrhage (ICH) is characterised by acute onset, rapid progression, and high mortality and disability rates. Ferroptosis is closely related to ICH injury. However, the exact aetiology of ICH-induced brain...
Intracerebral hemorrhage (ICH) is characterised by acute onset, rapid progression, and high mortality and disability rates. Ferroptosis is closely related to ICH injury. However, the exact aetiology of ICH-induced brain injury remains unclear. Uncoupling protein 2 (UCP2), an inner mitochondrial membrane protein, exhibits neuroprotective effects against ICH-induced brain injury as well as reduces oxidative stress and ROS in multiple tissues. Therefore, we aimed to elucidate the mechanisms by which UCP2 is involved in ICH-induced ferroptosis using a hemin-induced in vitro rat astrocyte (AST) model. We investigated the morphological and biochemical characteristics of hemin-exposed cultured ASTs, as well as quantified UCP2 expression. UCP2 knockdown-induced alteration in cell death and ferroptosis indices were monitored. Critically, we identified that UCP2 mitigates ferroptosis by suppressing TRIM21-mediated ubiquitination of glutathione peroxidase 4 (GPX4). We observed significantly decreased cell viability, typical ferroptosis-related morphological changes, significantly increased lipid peroxidation products malondialdehyde (MDA) and lipid ROS, and significantly decreased glutathione (GSH) expression in our in vitro hemin-induced intracerebral hemorrhage model. UCP2 expression was significantly upregulated. Mechanistically, UCP2 inhibited TRIM21 E3 ligase activity, thereby blocking GPX4 ubiquitination and degradation, which preserved cellular antioxidant capacity. Collectively, we observed the occurrence of ferroptosis and enhanced UCP2 expression in our in vitro ICH model. UCP2 knockdown aggravated the hemin-induced cell death and increased the ferroptosis sensitivity concomitant with enhanced TRIM21-dependent GPX4 ubiquitination.
Exosomes for brain drug delivery: The cutting edge in nanomedicine.
Ghaedi A, Saem A, Bazrgar A … +8 more , Dowran R, Mallahi A, Zarimeidani F, Rahmati R, Shahvandi E, Goodarzian M, Vakili S, Savardashtaki A
Exp Neurol · 2026 Jun · PMID 41702499 · Publisher ↗
The challenges of delivering therapeutic agents to the central nervous system (CNS) have spurred interest in exosomes as versatile drug delivery vehicles. These small vesicles, derived from various cells, possess unique...
The challenges of delivering therapeutic agents to the central nervous system (CNS) have spurred interest in exosomes as versatile drug delivery vehicles. These small vesicles, derived from various cells, possess unique attributes such as low immunogenicity and the ability to traverse the blood-brain barrier, making them promising tools for CNS-targeted therapies. This review provides an overview of recent progress in using exosomes for drug delivery in the treatment of neurological disorders. It will also assess administration routes, methods of drug loading, and modifications designed to enhance specificity for the CNS. Our study also addresses existing challenges and future directions for clinical implementation, underscoring the dual role of exosomes as therapeutic carriers and diagnostic biomarkers for neurological diseases.
Depleting non-resolving neuroinflammation in chronic spinal cord injury attenuates thermal hypersensitivity.
Capes DE, Slone VK, Winchester DK … +7 more , Salazar J, Opoku PAD, Li Y, Hash MT, Kumari R, Hawk GS, Stewart AN
Exp Neurol · 2026 Jun · PMID 41698640 · Publisher ↗
Macrophage and microglial densities around spinal cord injury (SCI) lesions remain chronically elevated. The influence of non-resolving neuroinflammation on ongoing functions, repair, or regeneration after SCI is not wel...
Macrophage and microglial densities around spinal cord injury (SCI) lesions remain chronically elevated. The influence of non-resolving neuroinflammation on ongoing functions, repair, or regeneration after SCI is not well understood. We administered a 2-week treatment of the CSF1-R antagonist, PLX-5622 (PLX), to deplete inflammatory microglia/macrophages (Iba-1-cells) within and around chronic contusion SCI lesions starting after 9-weeks post-injury and evaluated changes in locomotor functions and thermal hypersensitivity. Spinal cord sections were assessed for axon growth within the lesion and spared tissue compartments around the injury as well as in the grey matter caudal to the injury. Flow cytometry was performed to evaluate the influence of PLX on both microglia and macrophage populations within the spinal cord. While PLX significantly depleted Iba-1 cells both around and within the lesion, flow cytometry revealed no measurable depletion of macrophage populations but validated a depletion effect on microglia. Iba-1-cell depletion with PLX reduced locomotor abilities by the end of the 2-week treatment period without exacerbating the lesion pathology. Motor abilities remained decreased relative to pre-treatment levels after allowing for Iba-1-cell repopulation by removal of PLX. Inflammatory depletion resolved thermal hypersensitivity which remained resolved after inflammatory repopulation. CGRP axons were significantly elevated in chronic contusive lesions after Iba-1-cell repopulation, but no CGRP axon sprouting was observed below the lesion. Collectively our work supports a role of chronic neuroinflammation as an ongoing regulator of motor and sensory behaviors after SCI. SIGNIFICANCE STATEMENT: Elevated macrophage and microglial densities persist around chronic spinal cord injury (SCI) lesions for life and very little is understood about their ongoing contributions to repair or function. Our work identifies that non-resolving neuroinflammation plays an active role in producing neuropathic pain and impeding endogenous repair that can be ameliorated by depleting macrophages and microglia from the spinal cord at chronic timepoints. Our work provides a novel perspective on the nature of chronic neuroinflammation after SCI as it relates to ongoing motor and sensory functions as well as axon growth.
Corrigendum to 'PGAM5 promotes RIPK1-PANoptosome activity by phosphorylating and activating RIPK1 to mediate PANoptosis after subarachnoid hemorrhage in rats' [Experimental Neurology 384 (2025) 115072].
Jiajia D, Wen Y, Enyan J … +8 more , Xiaojian Z, Zhen F, Jia Z, Jikai W, Xiaoxin Y, Aihua L, Fangen K, Fei L
Exp Neurol · 2026 May · PMID 41690891 · Publisher ↗
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Integrated application of Raman spectroscopy in traumatic brain injury: A systematic review and clinical perspective.
David L, Borșa RM, Onaciu A … +7 more , Voicescu GT, Moldovan CS, Toma V, Știufiuc GF, Lupan-Mureșan EM, Știufiuc RI, Golea A
Exp Neurol · 2026 Jun · PMID 41690497 · Publisher ↗
BACKGROUND: This systematic review explores the application of Raman spectroscopy (RS) in traumatic brain injury (TBI) research, emphasizing the need for innovative and efficient diagnostic tools. The development of such...
BACKGROUND: This systematic review explores the application of Raman spectroscopy (RS) in traumatic brain injury (TBI) research, emphasizing the need for innovative and efficient diagnostic tools. The development of such techniques aims to alleviate healthcare costs while providing timely assessment of injury severity. METHODS: A systematic literature search for the use of RS in TBI was conducted in PubMed, Scopus, and Web of Science from inception to July 28, 2025, following PRISMA guidelines. We included only original English-language studies (animals and humans) in free full-text format. Risk of bias was assessed using specific tools for both animal and human models. Findings were classified according to the cohorts, and spectroscopic technique alongside their particularities. RESULTS: The initial search found 261 articles, with 26 studies meeting the inclusion criteria. Among them: 15 were animal studies and 11 translational/human-relevant studies. Among animal studies, 3 focused on in-situ monitoring and TBI classification, 2 on blast-induced models, 5 on blood biomarker analysis, 2 on retinal-based point-of-care diagnostics, and 3 on Raman microscopy. The translational research studies aimed to identify and validate TBI biomarkers for developing future diagnostic strategies in human patients. DISCUSSION: RS distinguished injured from control tissue through spectral changes reflecting protein and lipid alterations and differentiated lesion areas by revealing astrogliosis-related reorganization. Instantaneous in-situ RS devices achieved >92% accuracy in severity classification and detected biomarker-related molecular changes. Point-of-care RS platforms using lateral flow strips enabled rapid detection of specific TBI biomarkers (GFAP, NAA, NSE, S100B, UCH-L1), showing performance comparable to ELISA while offering faster, simpler, and cost-efficient testing.
An integrative genomic framework to identify remote ischemic preconditioning-responsive genes associated with stroke risk.
Liu S, Wu Q, Wang T … +8 more , Luo Z, Xu C, Li W, Zhang R, Zhu Y, Huang S, Liu C, Zhao H
Exp Neurol · 2026 Jul · PMID 41690496 · Publisher ↗
BACKGROUND: Remote ischemic preconditioning (RIPC) is a promising, non-invasive strategy for reduction in ischemic injury after stroke, yet its molecular mechanisms and translatability from animal models to humans remain...
BACKGROUND: Remote ischemic preconditioning (RIPC) is a promising, non-invasive strategy for reduction in ischemic injury after stroke, yet its molecular mechanisms and translatability from animal models to humans remain insufficiently defined. In particular, whether RIPC-induced gene programs causally contribute to reduced stroke risk in humans is unclear. Here, we aimed to establish a translational framework linking RIPC-induced gene regulation in mice to causal genetic and epigenetic determinants of stroke risk in humans. METHODS: Using a mouse transient middle cerebral artery occlusion (tMCAO) model, we performed multi-tissue transcriptomic profiling across central (cerebral cortex, hippocampus, striatum, hypothalamus, and insular cortex) and peripheral (spleen and peripheral blood mononuclear cells; n = 5/group) tissues under five experimental conditions. Mouse differentially expressed genes were mapped to human orthologs and integrated with human expression quantitative trait loci data and large-scale, multi-ancestry stroke genome-wide association studies using Mendelian randomization to identify RIPC-regulated beneficial genes (RBGs). DNA methylation sites within RBGs were further evaluated, and machine-learning models were constructed to assess their predictive potential. Key genes were experimentally validated in the MCAO model. RESULTS: We identified 23 core RBGs showing significant causal associations with reduced stroke risk. Functional enrichment analyses linked these genes to pathways involved in neuroprotection, immune modulation, and tissue repair. Mendelian randomization analyses supported causal effects of specific RBG-associated DNA methylation sites on stroke risk. Predictive modeling based on combined RBG signatures demonstrated strong translational performance (AUC = 0.97). Experimental validation confirmed that RIPC upregulated key RBGs, including Abcc5, Fam83h, Pom121, Mst1r, and Metap1d (n = 12/group, p < 0.05), accompanied by reduced infarct volume (15.2 % ∼ 18.4 %, n = 12/group, p < 0.001) and improved neurological outcomes. CONCLUSIONS: This study presents an integrative framework centered on RIPC-regulated beneficial genes, linking experimental transcriptomic responses with human genetic associations. The findings provide a basis for prioritizing candidate pathways involved in ischemic injury modulation and for guiding future translational studies.
Mitochondrial calcium uniporter knockdown in hippocampal neurons effectively attenuates synaptic plasticity impairment and pathology in APP/PS1/tau model of Alzheimer's disease.
Wu L, Hou F, Wang Z … +5 more , Wu M, Wang X, Cao J, Wang Y, Cai H
Exp Neurol · 2026 Jun · PMID 41687804 · Publisher ↗
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regula...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, in which mitochondrial dysfunction plays a critical role. The mitochondrial calcium uniporter (MCU) is a key regulator of mitochondrial calcium (mCa) uptake, and its dysregulation contributes to calcium imbalance and mitochondrial impairment. In this study, we investigated the effects of MCU knockdown in hippocampal neurons on synaptic plasticity and neuropathology in APP/PS1/tau mice. It was found that MCU knockdown reduced mCa overload, restored mitochondrial membrane potential (MMP), and attenuated excessive reactive oxygen species (ROS) production in the hippocampus. These mitochondrial improvements were associated with a rescue of impaired synaptic plasticity, including enhanced long-term potentiation (LTP) and reduced long-term depression (LTD) through activating the CaMKII/CREB/BDNF/TrkB signaling pathway. Furthermore, MCU knockdown alleviated hippocampal amyloid β (Aβ) pathology by decreasing APP/BACE1/RAGE levels while increasing NEP/LRP1 levels, and mitigated tau pathology through downregulation of GSK3β/CDK5 expression. In addition, hippocampal neuronal number and activity were improved, as reflected by increased N-acetylaspartic acid (NAA)/creatine (Cr) and glutamic acid (Glu)/Cr. Collectively, these findings indicated that MCU knockdown in hippocampal neurons ameliorated mitochondrial dysfunction, synaptic deficits, and AD-related pathology, highlighting MCU as a potential therapeutic target for AD.
The serotonin receptor 7 as an emerging target to restore altered neuroplasticity in Angelman syndrome.
Penna E, Pizzella A, Abate N … +7 more , Conte N, Cimmino F, Mollica MP, Di Giaimo R, Baudry M, Bi X, Crispino M
Exp Neurol · 2026 Jun · PMID 41687803 · Publisher ↗
The serotonin receptor 7 (5-HT7R) has been indicated as a key modulator of neuronal structure and function, playing critical roles in synaptic plasticity, dendritic spine formation, and cytoskeletal remodeling. 5-HT7R ac...
The serotonin receptor 7 (5-HT7R) has been indicated as a key modulator of neuronal structure and function, playing critical roles in synaptic plasticity, dendritic spine formation, and cytoskeletal remodeling. 5-HT7R activation promotes neurite outgrowth, enhances long-term potentiation (LTP), stimulates local protein synthesis at synapses, and regulates mitochondrial functions, and the mTOR pathway. These properties make the 5-HT7R a compelling candidate for therapeutic intervention in neurodevelopmental disorders characterized by synaptic dysfunctions. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene, resulting in impairments of synaptic plasticity, dendritic spine density, protein synthesis, mitochondrial activity and mTOR signaling. Intriguingly, many of the processes altered in AS are the ones that are positively regulated by 5-HT7R activation. For instance, AS animal models exhibit reduced LTP and altered dendritic morphology and 5-HT7R stimulation enhances synaptic strength and spine formation in the brain of wild type rodents. Moreover, BDNF/TrkB function signaling is impaired and mitochondrial integrity is disrupted in AS and 5-HT7R agonists enhance the altered BDNF/TrkB signalling and restore mitochondrial dysfunctions in Rett syndrome (RTT) mice model. Interestingly, recent evidence demonstrates that pharmacological activation of 5-HT7Rs increases synaptic protein synthesis, restores LTP, enhances dendritic spine density, and improves cognitive function in an AS mouse model. These encouraging results open the way to future studies using neurons and brain organoids generated from iPSCs obtained from AS patients, which represent novel tools in preclinical research. Overall, 5-HT7R stimulation, by counteracting the molecular alterations associated with the loss of UBE3A, may represent a novel approach to restore neural function in the mature brain, leading to translational applications in AS patients, and possibly also in other synaptopathies. Clinical trial number: not applicable.
Neutrophil extracellular traps (NETs) in cerebrovascular disease mechanisms, detection, and therapeutic targeting.
Li Z, Wu SH, Zhang X … +3 more , Li T, Xin M, Liu F
Exp Neurol · 2026 Jun · PMID 41687802 · Publisher ↗
Neutrophil extracellular traps (NETs) play a vital role in the pathophysiology of cerebrovascular diseases. During cerebral ischemia-reperfusion injury, NETs enhance the stability of immunothrombi by forming DNA-histone...
Neutrophil extracellular traps (NETs) play a vital role in the pathophysiology of cerebrovascular diseases. During cerebral ischemia-reperfusion injury, NETs enhance the stability of immunothrombi by forming DNA-histone scaffolds, thereby conferring resistance to thrombolysis. They also exacerbate damage to the blood-brain barrier (BBB) by degrading tight junction proteins via activation of inflammatory cascades. Additionally, the persistent formation of NETs impedes vascular remodeling and neural repair, thereby compromising long-term functional recovery. This review comprehensively examines the complex mechanisms of NETs in stroke and related CNS disorders, focusing on key molecular pathways that regulate their formation. It summarizes current detection methodologies and targeted intervention strategies based on preclinical models, while critically evaluating the challenges associated with clinical translation. Emerging evidence indicates that targeting NETs during the acute phase may enhance reperfusion efficiency and ameliorate neural injury, whereas modulating NETs during the repair phase can promote tissue regeneration, thus offering a promising therapeutic avenue. However, clinical translation is hindered by significant obstacles, including narrow therapeutic windows, limited intervention specificity, the risk of infectious complications, and a lack of biomarkers for patient stratification. Future research should aim to elucidate NET heterogeneity, develop precise spatiotemporal modulation techniques, and advance translational applications through multidisciplinary collaboration.
Targeting cholinergic cells in a mouse model of Alzheimer's disease: Validating a quadruple transgenic model.
Farkas S, Jasper V, Nyers-Marosi K … +10 more , Petrovai B, Szabó A, Kvak EE, Sólyomvári C, Varga R, Kormos V, Makkai G, Ábrahám IM, Zelena D, Kovács T
Exp Neurol · 2026 Jun · PMID 41679590 · Publisher ↗
Alzheimer's disease (AD) is an increasing health and social problem worldwide with prevalent cholinergic cell involvement. To reveal the details of the exact mechanisms, further preclinical studies in animals are needed....
Alzheimer's disease (AD) is an increasing health and social problem worldwide with prevalent cholinergic cell involvement. To reveal the details of the exact mechanisms, further preclinical studies in animals are needed. Our aim was to create a mouse model that represents the progression of AD with easy cholinergic manipulation. The 3xTg-AD and ChAT-Cre strains were crossbred. After serial genotyping, a colony, homozygote for all four genes (PSEN1, APPSwe, tauP301L and Cre; 3xAD-ChAT-Cre) was established. The presence of amyloid-β (Aβ) plaques and phosphor-Tau (pTau) aggregates was confirmed by immunohistochemistry. To test the functionality of the Cre enzyme, a stimulating DREADD virus (AAV8-hSyn-DIO-hM3Dq-mCherry) was injected unilaterally into the nucleus basalis magnocellularis, and clozapine-N-oxide-induced c-Fos activation was compared between the two hemispheres. Behavioral characterization was performed using the Y-maze, social discrimination (SDT), single pellet reaching (SPR), fox odor (FOT), and splash tests (ST). Food, water consumption and body weight change were investigated. Immunostaining and RNAscope confirmed the expression of Cre in ChAT-positive cells and the progressive appearance of pathological hallmarks (Aβ and pTau). The c-Fos activity was significantly increased in the virus-injected hemisphere. Compared with control mice, 3xAD-ChAT-Cre mice showed decreased locomotion (Y-maze, SDT, FOT), increased anxiety (FOT, ST) and weaker fine motor skills (SPR). In conclusion, newly created animals have a functional Cre recombinase enzyme in cholinergic cells. Additionally, the animals presented the pathophysiological hallmarks of AD in specific brain areas and maintained the typical behavioral alterations previously reported in 3xTg-AD mice. Thus, this strain seems to be appropriate for further studies.
The interaction effects of hypertension and aging on brain network in spontaneously hypertensive rats: A resting-state functional magnetic resonance imaging study.
Yang Y, Zhu Q, Wang L … +7 more , Gao D, Zhao Y, Li T, Du J, Liu D, Niu H, Geng Z
Exp Neurol · 2026 Jun · PMID 41679589 · Publisher ↗
Although both hypertension and aging are considered primary risk factors for cognitive impairment, the combined effects of hypertension and aging on the functional network of the brain remain poorly understood. We aimed...
Although both hypertension and aging are considered primary risk factors for cognitive impairment, the combined effects of hypertension and aging on the functional network of the brain remain poorly understood. We aimed to investigate the interactions between hypertension and aging on the brain functional network in spontaneously hypertensive rats (SHRs). Using resting-state functional magnetic resonance imaging, we investigated the interactive effects of hypertension and aging on the brain network in terms of topological metrics and connectivity patterns. We detected changes in the functional connectivity density, topological metrics and functional network connectivity in 20-week-old and 80-week-old SHRs compared with those in age-matched Wistar-Kyoto rats. The functional hub in the brain shifted from the retrosplenial granule to the caudate putamen in SHRs from the young adult stage to the aged stage, while the small-world topology was preserved. We investigated the effects of interactions between hypertension and aging on functional connectivity involving a large-scale increased network in aged SHRs. We identified alterations in the functional hub and network associated with hypertension and aging. Our study supports the viewpoints of compensatory functional reorganization and neural plasticity. Network analysis is a promising technique for exploring brain function in rats and could provide potential neuroimaging biomarkers. It is essential to identify a neuroimaging biomarker that not only allows the prediction of brain abnormalities but also helps in understanding the neurobiological mechanisms underlying hypertension and aging.
Disease models of anti-N-methyl-d-aspartate receptor encephalitis: Investigating pathogenesis and targeted therapy.
Zhou T, Zhang C, Lu Y … +2 more , Qiao S, Zhang S
Exp Neurol · 2026 Jun · PMID 41679588 · Publisher ↗
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder characterized by antibodies that specifically target the GluN1 subunit of NMDAR in neuronal cells. It is the most extensively studied...
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder characterized by antibodies that specifically target the GluN1 subunit of NMDAR in neuronal cells. It is the most extensively studied form of autoimmune encephalitis (AE). Although it primarily affects young women, the condition can occur in individuals of all ages and genders. Our understanding of NMDAR encephalitis has advanced considerably since the identification of antibodies associated with this unique neuropsychiatric syndrome. Various cytokines, chemokines, and other molecules found in cerebrospinal fluid (CSF) have been investigated as potential triggers for the onset of NMDAR encephalitis. However, definitive biomarkers for disease development or prognosis remain elusive. The disorder generally responds well to immunotherapy, with many patients achieving favorable clinical outcomes. Nevertheless, diagnosing and managing NMDAR encephalitis remains challenging. Exploring the underlying pathophysiological mechanisms is crucial for improving diagnostic accuracy and treatment effectiveness. To this end, cellular and animal models of the disease are widely used to study its mechanisms, helping to control for confounding factors such as variable incidence rates and patient heterogeneity. Developing research models for anti-NMDAR encephalitis enables a deeper understanding of its pathogenic processes, providing valuable insights for precise clinical diagnosis and therapy. This review aims to clarify the pathogenic mechanisms and potential treatment strategies identified to date within the context of research models for anti-NMDAR encephalitis.
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