Brain Research[JOURNAL]
Sun
200 papers
Elevated FKBP5 expression associates with epilepsy-related molecular changes and promotes neuronal hyperexcitability.
Cai M, Wang S, Liu M … +4 more , Lai B, Chen C, Ding J, Wang X
Brain Res · 2026 Mar · PMID 41519279 · Publisher ↗
OBJECTIVE: Epilepsy is one of the neurological disorders, characterized by recurrent, spontaneous seizures arising from neuronal hyperexcitability and hypersynchrony in the brain. The mechanisms of epilepsy are intricate...
OBJECTIVE: Epilepsy is one of the neurological disorders, characterized by recurrent, spontaneous seizures arising from neuronal hyperexcitability and hypersynchrony in the brain. The mechanisms of epilepsy are intricate and remain elusive. FKBP5 has emerged as a significant protein implicated in neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to investigate the role of FKBP5 in a kainic acid (KA)-induced intrahippocampal epilepsy model and assessed how FKBP5 gain-of-function and FKBP51 inhibition influence neurotransmitter dynamics and neuronal excitability. METHODS: We examined the expression of FKBP5 in the hippocampus of the kainic acid (KA)-induced epilepsy model. To explore the impact of FKBP5 on neuronal activity, we overexpressed FKBP5 in primary cortical neurons and astrocytes, assessing extracellular glutamate levels in neuron-astrocytes co-cultures with or without the FKBP51-selective inhibitor SAFit2 (250 nM). Intrinsic excitability, voltage-gated Na currents, and network activity were evaluated using whole-cell patch-clamp recordings and high-density microelectrode arrays (HD-MEAs). RESULTS: We observed an elevated level of FKBP5 in the hippocampus of a kainic acid (KA)-induced chronic epilepsy mouse model, whereas cortical FKBP5 did not show clear changes across the examined post-insult time points.. Moreover, FKBP5 overexpression induced a remarkable increase in the extracellular glutamate level in co-cultured primary cortical neurons and astrocytes. Intriguingly, FKBP5 overexpression modifies the electrophysiological properties of primary neurons, resulting in increased intrinsic excitability and enhanced Na currents. Additionally, the network activity exhibits hyperexcitability with FKBP5 overexpression. Notably, SAFit2 treatment was also associated with elevated extracellular glutamate in the co-culture system, while intracellular FKBP5 and EAAT2 protein levels showed no significant group differences in the current dataset. CONCLUSION: These findings suggested that FKBP5 played a significant role in regulating neuronal excitability and extracellular glutamate homeostasis. However, due to discrete sampling and the lack of continuous seizure monitoring, the present in vivo data do not establish a definitive causal contribution of FKBP5 to epileptogenesis, warranting future studies integrating longitudinal EEG and cell-type-specific manipulations.
Role of the dentate gyrus of hippocampus on acute pain modulation: Investigating of dopaminergic-opioidergic interactions in pain-related behaviors in the tail-flick test.
Sotoudeh SS, Abtin S, Mozafari R … +1 more , Haghparast A
Brain Res · 2026 Mar · PMID 41513080 · Publisher ↗
Previous studies have shown that injections of opioid and dopamine agonists alone into the dentate gyrus (DG) increase the threshold for acute pain responses. Therefore, this study aimed to investigate whether the opioid...
Previous studies have shown that injections of opioid and dopamine agonists alone into the dentate gyrus (DG) increase the threshold for acute pain responses. Therefore, this study aimed to investigate whether the opioid and D1-like dopamine receptor (D1R) interact to modulate acute pain in DG. One hundred and forty-seven adult male Wistar rats were cannulated unilaterally in the DG. Separate groups of animals received different doses of SCH23390 (6, 12, and 24 mmol/0.5 μL), a D1R antagonist, before injection of an effective dose of morphine (25 mmol/0.5 μL). In another experiment, animals received different naloxone (5, 15, and 45 mmol/0.5 μL) dose, an opioid receptor antagonist, before administering the effective dose of SKF38393 (6 mmol/0.5 μL). Acute pain threshold was assessed using the tail-flick test. Behavioral data analysis indicated that blockade of D1R in the DG significantly attenuated morphine-induced antinociception (P < 0.001). Furthermore, the antinociceptive effects of SKF38393 were significantly reduced by blocking opioid receptors in the DG (P < 0.01). Interestingly, the effect of SCH23390 in reducing the antinociceptive effects of morphine (η2 = 0.65) was numerically higher than the effect of naloxone in reducing the antinociceptive effects of SKF38393 (η2 = 0.46). The results suggest a strong interaction between opioidergic and dopaminergic systems in the DG in modulating acute pain. These findings can be used to reveal the precise mechanisms of pain modulation in brain circuits and to develop new strategies in pain management with greater efficacy and fewer side effects.
Identification of the disulfidptosis-related gene IQGAP1 as a potential diagnostic biomarker in Parkinson's disease.
Li J, You J, Li Z … +3 more , Zang J, Wu L, Zhao T
Brain Res · 2026 Mar · PMID 41506340 · Publisher ↗
BACKGROUND: Parkinson's disease is the second most common and fastest-growing neurodegenerative disorder worldwide. However, its complex pathogenic mechanisms remain incompletely understood, and effective therapeutic str...
BACKGROUND: Parkinson's disease is the second most common and fastest-growing neurodegenerative disorder worldwide. However, its complex pathogenic mechanisms remain incompletely understood, and effective therapeutic strategies are still lacking. Disulfidptosis is a newly identified form of regulated cell death that has been shown to be closely associated with multiple diseases; nevertheless, its role in Parkinson's disease has not yet been elucidated. In this study, we systematically investigated the expression patterns and potential functions of disulfidptosis-related differentially expressed genes that are significantly associated with Parkinson's disease risk, using bulk transcriptomic data and single-cell RNA sequencing analyses. METHODS: We integrated single-cell RNA sequencing data with large-scale transcriptomic datasets to construct a disulfidptosis-related diagnostic model for Parkinson's disease. First, twenty-five known disulfidptosis-related genes were collected from published literature and public databases. Differential expression analysis of GEO datasets was then performed to identify significantly differentially expressed genes between Parkinson's disease and healthy control samples, which were subsequently used to build an initial diagnostic model. The expression profiles of key genes were further validated in external cohorts to enhance the robustness and reliability of the model. Next, single-cell RNA sequencing data from patients with Parkinson's disease were incorporated to refine the identification of DRGs that were significantly associated with disease risk. Finally, quantitative real-time reverse transcription PCR was employed to experimentally validate the expression of the critical genes. RESULTS: We identified four DRGs in total. Using least absolute shrinkage and selection operator regression and random forest algorithms, three hub genes with diagnostic potential were further screened. After validation in external datasets and at the single-cell level, IQGAP1 was ultimately confirmed as the key gene by quantitative real-time reverse transcription PCR, showing significantly upregulated expression in Parkinson's disease samples. CONCLUSION: This study provides the first evidence suggesting that disulfidptosis-related genes may be involved in the pathogenesis of Parkinson's disease and highlights IQGAP1 as a key molecule with potential value in Parkinson's disease risk assessment and diagnosis. These findings not only offer a new perspective for elucidating the molecular mechanisms underlying Parkinson's disease, but also provide a theoretical basis for identifying potential biomarkers and optimizing individualized therapeutic strategies, thereby further promoting the application of precision medicine in the field of Parkinson's disease.
Diffusion spectrum imaging-based machine learning for temporal lobe epilepsy lateralization.
Wang ZM, Hou Y, Wu C … +2 more , Zhang M, Lu J
Brain Res · 2026 Mar · PMID 41506339 · Publisher ↗
OBJECTIVE: Accurate preoperative lateralization of temporal lobe epilepsy (TLE) remains challenging, particularly in cases with subtle or MRI-negative lesions. This study aimed to overcome limitations of conventional MRI...
OBJECTIVE: Accurate preoperative lateralization of temporal lobe epilepsy (TLE) remains challenging, particularly in cases with subtle or MRI-negative lesions. This study aimed to overcome limitations of conventional MRI by developing a diffusion spectrum imaging (DSI)-based machine learning approach for noninvasive TLE lateralization. METHODS: We retrospectively analyzed DSI scans from 49 unilateral TLE patients (29 left, 20 right) and 25 healthy controls (HC). Local connectome fingerprints and quantitative anisotropy (QA) features were extracted. A support vector machine (SVM) was trained to classify patients from controls and to identify the epileptogenic hemisphere. Model performance was evaluated using 10-fold stratified cross-validation, with feature selection and dimensionality reduction performed within each training fold. RESULTS: The DSI-based SVM achieved high accuracy in distinguishing TLE from HC. With fingerprint features, accuracy was 97.3% (sensitivity 0.959, specificity 1.000); QA features yielded the same accuracy 97.3% (sensitivity 0.980, specificity 0.960). For lateralization among patients, the fingerprint model reached 100% accuracy versus 91.8% for QA. In the three-class classification task (left TLE, right TLE and HC), the models achieved accuracies of 78.4% (fingerprint) and 73.0% (QA). The fingerprint-based classifier yielded F1-scores of 0.943 for HC, 0.727 for LTLE, and 0.650 for RTLE; QA achieved F1-scores of 0.875, 0.677, and 0.632, respectively. DeLong's test found no significant AUC differences. CONCLUSION: DSI-derived metrics combined with machine learning enable accurate, noninvasive lateralization of TLE. This approach addresses clinical necessities by reliably detecting epileptogenic zones, including cases with subtle structural abnormalities, offering significant potential to enhance presurgical decision-making and patient outcomes.
Measurement of respiration in ex vivo mitochondria isolated from fresh human brain.
McCarty PJ, Werner BA, Scheck AC … +5 more , Wang E, Singh IN, Gaitanis J, David Adelson P, Frye RE
Brain Res · 2026 Mar · PMID 41506338 · Publisher ↗
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A mouse model of a patient derived P544L mutation in the Slc6a8 gene shows hypoactivity and cognitive deficits.
Perna MK, Gechijian LN, Blanchette HS … +4 more , Liou R, Williams MT, Vorhees CV, Skelton MR
Brain Res · 2026 Mar · PMID 41500337 · Publisher ↗
Creatine (CR) is essential for normal brain function. A lack of brain CR results in intellectual disability, epilepsy, and language delay in humans. The most common cause of CR deficiency in humans results from mutations...
Creatine (CR) is essential for normal brain function. A lack of brain CR results in intellectual disability, epilepsy, and language delay in humans. The most common cause of CR deficiency in humans results from mutations in the CR transporter (SLC6A8). Several large deletion models of Slc6a8 have been characterized and are excellent models for global creatine loss. However, other SLC6A8 variants are reported in humans with creatine transporter deficiency (CTD), including missense mutations, deletions, and point mutations resulting in phenotypes ranging from mild to severe in humans. The purpose of these experiments was to determine if mice carrying a point mutation of the Slc6a8 gene showed cognitive deficits, further validating a new model of CTD. These Slc6a8 knock-in (Slc6a8) mice carry the P544L proline to leucine substitution seen in some humans with CTD. The Slc6a8 mice have lower overall body weight and lower brain creatine content. Behavioral assessment revealed deficits in spatial memory but not associative or object recognition memory in Slc6a8 mice. These findings are in line with clinical findings and other CTD models. In addition, we show that Slc6a8 mice are hypoactive in a home-cage environment. These experiments support the use of Slc6a8 mice as a valid representative of behavioral changes in human patients and to develop targeted therapies to rescue specific behavioral deficits in CTD.
Lysergic acid diethylamide modulates hippocampal and cortical local field potential oscillatory rhythms in male mice.
Rabinovitch BS, Silverman N, Ji D … +3 more , Shizgal D, Lewis EC, Carlen PL
Brain Res · 2026 Mar · PMID 41485616 · Publisher ↗
BACKGROUND AND RATIONALE: Lysergic acid diethylamide (LSD) is a promising therapeutic for psychiatric disorders, but its physiological profile on the nervous system remains elusive. Rodent electrophysiological data has u...
BACKGROUND AND RATIONALE: Lysergic acid diethylamide (LSD) is a promising therapeutic for psychiatric disorders, but its physiological profile on the nervous system remains elusive. Rodent electrophysiological data has utilized in vivo single-unit electrophysiology recordings, while clinical neurophysiology studies have focused on spectral signatures using electroencephalography (EEG) and magnetoencephalography (MEG). No study to date has examined these spectral signatures in freely-behaving mice. Studying neural activity when an animal is physically restricted (i.e. head-fixed recordings) is stressful to animals, which informed our decision to avoid this confound of additional physical stress on observed effects. Moreover, how LSD acutely modulates intracranial oscillatory rhythms is not known. EXPERIMENTAL APPROACH: Here we present the first in vivo electrophysiological investigation of LSD's cortico-hippocampal effects in freely-behaving male C57BL/6J mice using intracranial EEG (iEEG) recordings. We did not posit a hypothesis concerning the specific effects of LSD on power spectral density (PSD) due to the lack of preclinical literature as well as LSD's promiscuous pharmacological profile. This study was purely exploratory. KEY RESULTS: Following intraperitoneal (IP) administration of 30 µg/kg LSD, there was a global decrease in PSD signal power in both broadband and discrete narrow band oscillatory rhythms of the ventral hippocampus CA1 and CA3 regions. Similar but less robust effects were observed in the somatosensory and medial prefrontal cortices. These data confer with the existing clinical neurophysiology data. Lastly, LSD increased between-subject PSD signal power variance, suggesting individual-specific effects. CONCLUSION AND IMPLICATIONS: Our data lends further credibility to the entropic brain theory of psychedelic drug actions. We conclude that the preclinical intracranial acute spectral signatures of LSD coincide with their clinical counterparts. Further work is needed to study cross-regional connectivity, such as frequency coupling.
Evaluation of neurobiochemical and behavioral responses to carvone nanoemulsion: A neuroprotective approach for Alzheimer's disease-associated dementia in a rat model.
Kabiri S, Gholizadeh Dangheralou P, Khazaeifard F … +4 more , Rostami Mehr S, Mansouri SM, Rahimi Rad N, Abbasi-Maleki S
Brain Res · 2026 Mar · PMID 41485615 · Publisher ↗
BACKGROUND: Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO...
BACKGROUND: Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO) using a rat model of AD-associated dementia. METHOD: Our experimental groups comprised non-AD control rats (CON), untreated AD rats (AD), and AD rats treated with CANO at two different dosages: 40 mg/kg (CANO40) and 80 mg/kg (CANO80). We assessed various behavioral parameters, malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) levels,ferric-reducing ability of plasma (FRAP). RESULTS: AD induction caused a significant reduction in step-through latency (P < 0.001), center time (P < 0.001), the number of visits (P < 0.001), and total distance traveled (P < 0.001), time spent in open arms (P < 0.001), and both FRAP (P < 0.001) and BDNF levels (P < 0.001) in comparison to the CON group, while elevating escape latency, time in target zone and platform location latency, and MDA levels (P < 0.001). Treatment with CANO, particularly at the CANO80 dosage, significantly improved these parameters compared to the AD group, resulting in decreased time in the target zone (P < 0.001), escape latency (P < 0.001), and platform location latency (P < 0.001) and higher FRAP (P < 0.05) and BDNF levels (P < 0.05), along with decreased MDA levels (P < 0.05). CONCLUSION: CANO, especially at the 80 mg/kg dosage, shows promise in alleviating symptoms associated with AD-associated dementia. However, further research is warranted to validate and expand upon these findings.
Cortical parvalbumin-positive neurons: Functional and ontogenetic characteristics and their relationship to brain pathologies.
Becerra-Hernández LV, Ortiz-Muñoz D, Sánchez-Escobar A … +3 more , González-Acosta CA, Buriticá-Ramírez E, Martínez-Cerdeño V
Brain Res · 2026 Mar · PMID 41485614 · Publisher ↗
Cortical GABAergic interneurons can be classified based on electrophysiological, biochemical, and morphological criteria. Among them, parvalbumin-positive interneurons primarily exhibit chandelier and basket cell morphol...
Cortical GABAergic interneurons can be classified based on electrophysiological, biochemical, and morphological criteria. Among them, parvalbumin-positive interneurons primarily exhibit chandelier and basket cell morphologies and are characterized by a fast-spiking firing pattern. These cells originate from the medial ganglionic eminence during human brain development and are widely distributed across neocortical layers I-VI, with a predominance in layers II and III. Their distinct morphology, extensive axonal arborization, and specific synaptic contacts position them as key regulators of pyramidal neuron activity through axo-axonal and perisomatic inhibition. Parvalbumin-positive interneurons have been extensively studied in the context of neurological and psychiatric disorders associated with excitation/inhibition imbalances, including traumatic brain injury, epilepsy, autism spectrum disorder, and schizophrenia. Given the growing body of evidence, this review provides an in-depth examination of the pathophysiological roles of parvalbumin-positive interneurons, highlighting their selective vulnerability to various types of neural insults.
Advances in plasma biomarkers for the diagnosis of Alzheimer's disease.
Wu H, Liu L, Zeng L
Brain Res · 2026 Mar · PMID 41483834 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment and deficits in other cognitive domains, ultimately leading to loss of independence in activities of daily living. A...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment and deficits in other cognitive domains, ultimately leading to loss of independence in activities of daily living. As AD becomes an increasingly prevalent global health burden, the demand for early diagnosis of AD in clinical practice is growing. Due to factors such as accessibility, invasiveness, and testing costs, blood-based biomarkers (BBMs) are generally more favored by patients and more feasible compared to lumbar puncture or neuroimaging. Blood-based biomarkers may represent a breakthrough area for AD diagnosis. This review summarizes the AD biomarkers that have been widely studied to date, aiming to provide a comprehensive understanding of these markers to advance early diagnosis and offer valuable insights for clinical practice. First, we summarize the currently discovered biomarkers that can be used for AD diagnosis. It is noted that only a few highly promising biomarkers have been practically applied in the clinical auxiliary diagnosis of AD (including APOE genotyping for assessing genetic risk; Aβ42/Aβ40, P-tau181/Aβ42, and p-tau217 for differentiating AD; NfL for monitoring AD progression). It should be noted that current AD biomarkers are only applicable for clinical auxiliary diagnosis and cannot completely replace classic assessment scales for independent diagnosis. Additionally, we summarize the clinical advantages and potential challenges of these biomarkers, as well as the differences in their applicability to different populations. We emphasize that extensive clinical cohort studies are still needed in the future to further clarify the specificity of blood biomarkers and develop more suitable laboratory testing methods for clinical use to meet the clinical demand for high-sensitivity and high-specificity AD biomarker detection.
From Tim4 to ischemic stroke: a mitochondrial pathway driving microglial M1 polarization.
Ye Z, Jin Y, Xu H … +5 more , Wang X, Lin A, Miao Q, Luo W, Jin Y
Brain Res · 2026 Mar · PMID 41483833 · Publisher ↗
Microglia dysfunction is a critical contributor in ischemic stroke, where T-cell immunoglobulin and mucin domain 4 (Tim4) may play a significant role. After ischemic stroke modeling with the middle cerebral artery occlus...
Microglia dysfunction is a critical contributor in ischemic stroke, where T-cell immunoglobulin and mucin domain 4 (Tim4) may play a significant role. After ischemic stroke modeling with the middle cerebral artery occlusion (MCAO) method, the changes in infarct volume, neurological deficits, cell apoptosis, microglial polarization, Tim4, mitochondrial fission proteins, mitochondrial membrane potential (MMP), and regulation of reactive oxygen species (ROS) were detected. In oxygen-glucose deprivation (OGD) model, the effects of Tim4 on microglial phenotypes, mitochondrial fission proteins, inflammatory factors, and MMP were evaluated. MCAO increased brain infarct volume, neurological deficits, apoptosis, and the proportion of M1-type microglia. In the OGD model, there was a drop in M2 microglia and a rise in M1 microglia, as well as upregulated tumor necrosis factor-alp (TNF-α) and Interleukin-1 beta (IL-1β). Upregulation of Tim4 was associated with increased levels of ROS in microglia, enhanced expressions of mitochondrial fission factor (MFF) and dynamin-related protein 1 (Drp1), and reduced MMP, which can be reversed by knocking down Tim4 expression. This implied that Tim4 could promote M1 microglial polarization and mitochondrial dynamics. However, Drp1 overexpression offset the effects of Tim4 knockdown on microglial polarization. In conclusion, Tim4 regulates the M1 microglial polarization via mitochondria, serving as a potential therapeutic target for ischemic stroke.
Plasma protein signatures associated with functional outcome heterogeneity in rtPA-treated acute ischemic stroke.
Wang L, Shen T, Huang S … +3 more , Hu Y, Luo Y, Li S
Brain Res · 2026 Mar · PMID 41482177 · Publisher ↗
OBJECTIVES: The mechanisms underlying heterogeneous neurological functional outcomes following recombinant tissue plasminogen activator (rtPA) therapy in acute ischemic stroke (AIS) remain elusive. This exploratory study...
OBJECTIVES: The mechanisms underlying heterogeneous neurological functional outcomes following recombinant tissue plasminogen activator (rtPA) therapy in acute ischemic stroke (AIS) remain elusive. This exploratory study aimed to explore proteomic signatures associated with rtPA response using data-independent acquisition (DIA) mass spectrometry. METHODS: We performed plasma proteomic profiling on 10 AIS patients (6 with favorable outcomes [90-day mRS ≤ 2], 4 with unfavorable outcomes [90-day mRS > 2]) and 6 healthy controls. Differential protein expression analysis, functional enrichment (GO, KEGG), and weighted gene co-expression network analysis (WGCNA) were applied to identify outcome-related proteins and pathways. RESULTS: AIS induced significant perturbations in energy metabolism, inflammatory responses, and oxidative stress responses, with more pronounced proteomic dysregulation observed in unfavorable-outcome patients. The differentially expressed proteins (DEPs) associated with rtPA therapy (such as CP, CA1, CA2, ABCC2, COL1A2) were functionally linked to oxidative stress, metabolic transport, and transforming growth factor (TGF)-β receptor signaling. Pathway analysis revealed enrichment in porphyrin metabolism, nitrogen metabolism, and ABC transporter pathways. Additionally, DEPs between patients with distinct outcomes demonstrated significant enrichment in NF-κB signaling pathway and ABC transporters. CONCLUSIONS: This exploratory study suggests that rtPA may influence acid-base balance, redox homeostasis, and TGF-β signaling. The association of NF-κB signaling and ABC transporters with outcome heterogeneity highlights their potential for further investigation as therapeutic targets. These findings provide preliminary mechanistic insights that warrant validation in larger cohorts.
Transient effects in corticospinal and reticulospinal tract excitability induced by motor skill and isometric resistance training.
Hawthorn R, Phelps N, Atkinson C … +4 more , Keesey R, Seitz Z, Nie H, Seáñez I
Brain Res · 2026 Mar · PMID 41482176 · Full text
Coordinated movement relies on the proper integration of multiple neural circuits. Motor training can alter the excitability of neural circuits controlling movement, but the pathway-specific effects to the lower limb of...
Coordinated movement relies on the proper integration of multiple neural circuits. Motor training can alter the excitability of neural circuits controlling movement, but the pathway-specific effects to the lower limb of motor skill versus isometric resistance training remain unclear. Here, we tested how single 30-minute sessions of cue-paced motor skill and isometric resistance training modulate corticospinal, reticulospinal, and spinal excitability in unimpaired adults (N = 23). Using motor-evoked potentials via transcranial magnetic stimulation, we found motor skill training increased corticospinal excitability, while isometric resistance training did not. In contrast, by assessing reticulospinal tract excitability by StartReact responses and measuring spinal excitability with H/M ratios, F-wave response amplitude, and persistence, we found that each tract's excitability remained largely unchanged. These results suggest that short-term motor skill training selectively enhances corticospinal tract excitability without a measurable impact on spinal or reticulospinal circuits. These results highlight the influence of task complexity on distal lower limb excitability and provide a framework for evaluating neural adaptations across corticospinal, reticulospinal, and spinal circuits.
The impact of NGF overexpression on proteome profile in WJ-MSC cultures.
Borkowska P, Krawczyk A, Kowalczyk M … +4 more , Zielinska A, Kusmierz D, Rother MB, Paul-Samojedny M
Brain Res · 2026 Mar · PMID 41482175 · Publisher ↗
BACKGROUND: Neurological disorders cause over 11 million deaths annually worldwide, highlighting the urgent need for new therapeutic strategies to improve current treatment outcomes. Nerve growth factor (NGF) is a key re...
BACKGROUND: Neurological disorders cause over 11 million deaths annually worldwide, highlighting the urgent need for new therapeutic strategies to improve current treatment outcomes. Nerve growth factor (NGF) is a key regulator of neuronal survival, and modifying mesenchymal stem cells (MSC) to enhance their neurotrophic activity is a promising therapeutic strategy. However, the broader molecular consequences of NGF overexpression in MSC remain unclear. This study examined how NGF overexpression affects neurotrophin secretion and apoptosis-related protein expression in Wharton's jelly MSC (WJ-MSC). METHODS: WJ-MSC were lentivirally transduced to overexpress NGF and differentiated for 12 days. NGF, BDNF, TrkA, TrkB, IL-13, and TNF-α were quantified using ELISA (n = 3 biological replicates; assays in duplicate). Thirty-five apoptosis-related proteins were assessed using the Proteome Profiler Human Apoptosis Array (assays in duplicate). Data were analyzed using one-way ANOVA or multiple t-test. RESULTS: NGF overexpression increased extracellular NGF (↑∼220 %, p < 0.0001) and reduced BDNF secretion (↓∼35 %, p < 0.05). Soluble phosphorylated TrkA/TrkB increased significantly in supernatants (↑30-60 %, p < 0.05). IL-13 rose modestly without statistical significance, and TNF-α remained undetectable. Early proteome changes showed upregulation of pro-apoptotic proteins (p21 ↑97 %, phospho-p53 ↑30 %) with concurrent reductions in anti-apoptotic markers (BCL2 ↓66 %, HSP60 ↓58 %). After 12 days, the apoptotic profile remained predominantly pro-apoptotic, despite selective increases in BCLXL (↑92 %), clusterin (↑102 %), and survivin (↑38 %) indicating only partial compensatory responses. CONCLUSIONS: NGF overexpression enhances neurotrophin-related signaling but produces a sustained pro-apoptotic shift in WJ-MSC, suggesting limited benefit for cell survival. These findings require confirmation using functional apoptosis assays and in vivo models.
Identification of hub genes and signaling pathways as possible therapeutic targets in human glioblastoma: evidenced by bioinformatics analysis.
Beygi HS, Shahraki A, Sheervalilou R
Brain Res · 2026 Mar · PMID 41478499 · Publisher ↗
BACKGROUND AND AIM: Glioblastoma (GBM) is a lethal brain cancer demanding novel therapeutic targets. This study integrated bioinformatics to identify hub genes and dysregulated pathways in GBM. METHODS: Gene expression p...
BACKGROUND AND AIM: Glioblastoma (GBM) is a lethal brain cancer demanding novel therapeutic targets. This study integrated bioinformatics to identify hub genes and dysregulated pathways in GBM. METHODS: Gene expression profiles (GSE108474: 221 GBM, 28 normal samples) were analyzed using R (Limma, clusterProfiler, BioBase). Differentially expressed genes (DEGs) were defined by |logFC| > 1 and adjusted p < 0.01. Gene Ontology (GO) and KEGG pathway enrichment (p < 0.05), protein-protein interaction network construction (STRING/Cytoscape), and hub gene validation using TCGA-GBM/GTEx data (GEPIA2; 163 tumor, 207 normal) were performed. Immune infiltration (xCell algorithm; 64 cell types) and prognostic significance (Kaplan-Meier/log-rank tests) were assessed. RESULTS: We identified 5,710 DEGs, significantly enriched in actin cytoskeleton regulation. Eleven hub genes were validated: upregulated (PECAM1, PXDN, RPL27, RPL12, EIF3B, ENG, TGFB2, THBS1) and downregulated (CAMK2B, FGF22, RASGRF1). Hub genes correlated strongly with immunosuppressive cells: FGF22 and CAMK2B negatively correlated with M2 macrophages, while PECAM1, PXDN, RPL27, and ENG positively correlated. Consistent correlations were observed with B cells and regulatory T cells. Survival analysis revealed high THBS1 expression associated with poorer overall survival (HR = 1.4, p < 0.05) and disease-free survival (HR = 1.9, p < 0.05). Elevated ENG also reduced disease-free survival (HR = 1.7, p < 0.05). CONCLUSION: THBS1 and ENG are significant prognostic biomarkers and potential therapeutic targets in GBM. Their strong correlation with immunosuppressive M2 macrophage infiltration implicates actin cytoskeleton remodeling pathways in GBM-mediated immune evasion. Targeting these hub genes may disrupt critical tumor microenvironment interactions, offering new avenues for therapy.
Can thermotherapy mitigate depression? A review of physiological adaptations and clinical evidence.
Høydal ØA, Notøy RRG, Høydal KL
Brain Res · 2026 Feb · PMID 41461279 · Publisher ↗
With a rising prevalence of the major mood disorders, recent years have seen a growing interest in the potential therapeutic value of lifestyle practises such as exercise and thermotherapy. While the beneficial effects o...
With a rising prevalence of the major mood disorders, recent years have seen a growing interest in the potential therapeutic value of lifestyle practises such as exercise and thermotherapy. While the beneficial effects of exercise on mental health are now well documented, the potential benefits of thermotherapyare less studied. Similarly to exercise, passive heat- and cold exposure may induce physiological responses which counteract the pathophysiological underpinnings of mood disorders such as depression and anxiety. Thus, for prevention or treatment of mood disorders, thermotherapy could complement exercise or be a viable alternative for people with injuries or disability. Here, we first review physiological adaptations to passive heat- or cold treatment in the context of hypotheses for thepathogenesis of depression. Next, we review clinical interventions investigating effects of passive heat- or cold treatment on depressive disorder, before ending with a discussion of future directions.
Neurodevelopmental origins of neurodegeneration: a lifespan perspective on brain vulnerability.
Kopalli SR, Vadia N, Varma P … +12 more , Mishra S, Joshi N, Bansal P, Al-Hasnaawei S, Chauhan AS, Jain H, Nathiya D, Devi A, Jayasingh Chellammal HS, Gupta P, Wal P, Koppula S
Brain Res · 2026 Feb · PMID 41456636 · Publisher ↗
Neurodegenerative disorders-including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis-are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines...
Neurodegenerative disorders-including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis-are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines how genetic, epigenetic, and environmental factors impact brain development during critical periods, predisposing individuals to neurodegeneration later in life. Prenatal and early-life exposures such as maternal stress, malnutrition, infection, and environmental toxins can alter key developmental processes, leading to long-term vulnerability. Mechanistic pathways linking early-life disruptions to neurodegenerative outcomes include persistent mitochondrial dysfunction, chronic neuroinflammation, increased oxidative stress, and aberrant synaptic pruning, all of which contribute to progressive neuronal damage and dysfunction. The gut-brain axis is also discussed as a key intermediary, where early microbiota dysbiosis alters neuroimmune signaling and inflammatory responses, modulating susceptibility to age-related neurological disorders. In this context, the review highlights emerging molecular and imaging biomarkers capable of detecting subtle neurodevelopmental deviations that may precede clinical symptoms by decades. The paper emphasizes the need for early-life interventions, including maternal nutritional optimization, management of prenatal stress, and microbiome-targeted strategies, as potential tools to reduce long-term neurological risk. Furthermore, it proposes the integration of precision medicine approaches aimed at individualized risk assessment and therapeutic targeting of developmental pathways. Adopting a lifespan perspective, this review argues for a paradigm shift from reactive to preventive strategies in neurology. Understanding the developmental roots of neurodegeneration opens new avenues for research and intervention, enabling resilience and reducing disease burden through early diagnostics and tailored therapeutics across the lifespan.
Daily temporal organization of inflammation and cognition-related factors and antioxidant enzymes are modified by an intracerebroventricular injection of amyloid-beta peptide (1-42) aggregates in the rat temporal cortex.
Coria-Lucero C, Lopez M, Gomez-Mejiba S … +8 more , Ramirez D, Delsouc MB, Casais M, Alba R, Leporatti J, Delgado S, Anzulovich AC, Navigatore-Fonzo L
Brain Res · 2026 Mar · PMID 41453554 · Publisher ↗
Alzheimer's dementia (AD) is a neurodegenerative disorder that causes memory loss and dementia in older adults. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, oxidative damage, ne...
Alzheimer's dementia (AD) is a neurodegenerative disorder that causes memory loss and dementia in older adults. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, oxidative damage, neuroinflammation, synaptic loss and neuronal cell death. The accumulation of Aβ in the brain plays a key role in the pathogenesis of AD. Elevated levels of Aβ causes an increase in oxidative damage and neuroinflammation both are considered key factors in the progression of AD. Also patients with Alzheimer's show alterations in their circadian rhythms. Our objectives were (a) to analyze whether inflammation and cognition-related factors exhibit a day-night variation, (b) to verify whether antioxidant enzymes expression and activity exhibit a daily rhythm in the rat temporal cortex and (c) to evaluate the effects of an intracerebroventricular injection of Aβ-amyloid (1-42) aggregates on those temporal profiles. Four-month old males Holtzman rats were used in this study. Groups were defined as: 1) control 2) Aβ-injected. Rats were maintained under 12 h-Light:12 h-Dark conditions with food ad-libitum. Our results showed temporal patterns of nitrites, iNOS, catalase and glutathione peroxidase expression and activity, as well as Rc3 and Gap-43 mRNA, in the rat temporal cortex. An i.c.v. injection of Aβ abolishes the temporal pattern of Rc3 and Gap-43 mRNA. Also increased the rhythm's mesor of NO and iNOS levels, reduced the mesor of CAT activity rhythms, and changed the phase of GPx activity patterns. These alterations in the temporal patterns of inflammation and redox status-related factors would affect cellular clock activity and consequently cognitive performance.
Molecular and neurochemical underpinnings of altered intrinsic neural timescales in Parkinson's disease: a multimodal imaging and transcriptomics study.
Wen Z, He YZ, Hu ZX … +2 more , Huang X, Xie BJ
Brain Res · 2026 Feb · PMID 41448446 · Publisher ↗
Parkinson's disease (PD) is characterized by widespread motor and non-motor impairments; however, the temporal dynamics underlying these functional disruptions remain unclear. The intrinsic neural timescale (INT), a nove...
Parkinson's disease (PD) is characterized by widespread motor and non-motor impairments; however, the temporal dynamics underlying these functional disruptions remain unclear. The intrinsic neural timescale (INT), a novel neuroimaging metric that reflects the capacity of brain regions to integrate information over time, provides new insights into cortical hierarchy and dysfunction. In this study, we examined voxel-wise and network-level alterations in INT among PD patients using resting-state fMRI and integrated their molecular correlates with transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. Our analysis revealed localized reductions in INT in the left insula, Rolandic operculum, and middle temporal gyrus in PD, while large-scale network hierarchies remained preserved. Partial least squares regression analysis indicated that changes in INT were significantly associated with spatial gene expression gradients, particularly those involving immune-metabolic stress and synaptic maintenance. Furthermore, cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Notably, INT alterations correlated with cortical GABAA receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits. These findings highlight a multiscale pathophysiological framework linking functional brain dynamics, molecular architecture, and neurochemical modulation in PD.
A systematic review of the effect of pulse parameters of next-generation TMS devices on corticospinal excitability and neuroplasticity.
Agboada D, Rethwilm R, Kuder M … +2 more , Mack W, Seiberl W
Brain Res · 2026 Feb · PMID 41435978 · Publisher ↗
BACKGROUND: Conventional TMS devices are limited in the number of variations of pulse parameters they produce, which limits the extension of TMS application. Recently, however, successful attempts have been made to intro...
BACKGROUND: Conventional TMS devices are limited in the number of variations of pulse parameters they produce, which limits the extension of TMS application. Recently, however, successful attempts have been made to introduce next-generation (next-gen) TMS devices with adjustable pulse parameters. Although research using these devices is still in its infancy, a systematic synthesis of the direction of results is valuable to identify the current progress and some limitations of these technologies which can guide further studies in the field. OBJECTIVE: This review aims to investigate the influence of pulse parameters (width, shape, and current direction) of next-gen TMS devices on corticospinal excitability and the induction of neuroplasticity. METHODS: Using the PRISMA method of reporting systematic reviews, we searched major biomedical databases - PubMed (n = 84), Web of Science (n = 141), Scopus (n = 111) and APA PsychInfo (n = 27) for literature, with 21 studies included in this review. RESULTS: Compared to conventional TMS devices, next-generation TMS devices were more efficient in many neurophysiological measurements. For plasticity inducing protocols, both inhibitory and facilitatory protocols showed enhanced respective inhibitory and excitatory after-effects with increasing pulse width. The new near-rectangular pulse shape moreover induced stronger inhibitory after-effects compared to conventional pulses. CONCLUSIONS: Next-generation devices expand the parameter space of TMS. Further studies are however needed to explore the full potential of these next-gen devices, especially in non-motor brain regions. SIGNIFICANCE: Next-gen TMS devices do hold a promise in the optimization of the neuromodulatory effects of TMS.
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