Search Results (86)

Background/Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor marked by diffuse infiltration into surrounding brain tissue. The peritumoral zone often appears normal on imaging yet harbors microscopic invasion. While perfusion-based studies, such as arterial spin labeling (ASL), have profiled this region, longitudinal radiomic monitoring remains limited. This study investigates delta radiomics using multiparametric MRI (mpMRI) in a GBM mouse model to track subtle peritumoral changes over time. Methods: A G7 GBM xenograft model was established in nine nude mice, imaged at 9- and 12 weeks post-implantation using MRI (T1W, T2W, T2 mapping, DWI-ADC, FA, and ASL) and co-registered histopathology (H&E, HLA staining). Tumor and peritumoral regions were manually segmented, and 107 radiomic features (shape, first-order, texture) were extracted per sequence and histology. The delta features were calculated and compared between timepoints. Results: The robust T2W texture and T2 map first-order features demonstrated the greatest sensitivity and reproducibility in capturing temporal peritumoral brain zone changes, distinguishing between time points used by K-mean. Conclusions: Delta radiomics offers added value over static analysis for early monitoring of peritumoral brain zone changes. The first-order and texture features of radiomics could serve as robust biomarkers of peritumoral invasion. These findings highlight the potential of longitudinal MRI-based radiomics to characterize glioblastoma progression and inform translational research. Full article

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast cell and SH-SY5Y human neuroblastoma cells). Oral administration of HY7715 (1 × 10⁹ CFU/kg/day) alleviated anxiety-like behaviors significantly, as shown by increased central exploration in the open field test and prolonged open-arm activity in the elevated plus maze. HY7715 reduced serum norepinephrine levels elevated by stress, and restored hippocampal expression of brain-derived neurotrophic factor, while suppressing pro-inflammatory (NF-κB, IL-6) and pro-apoptotic (BAX, caspase-3) markers. It also increased expression of mitochondrial regulatory genes (SIRT1, mTOR), and decreased that of cytochrome c, in brain tissue. Histological analysis revealed that HY7715 preserved neuronal integrity in the CA1 and CA3 hippocampal regions. In vitro, HY7715 attenuated oxidative stress-induced cytotoxicity, decreased intracellular ROS accumulation, maintained mitochondrial activity, and inhibited apoptosis of both neuronal cell types, showing greater efficacy than the strain type L. plantarum KCTC3108. These findings suggest that HY7715 exerts neuroprotective effects by modulating oxidative stress/apoptosis/mitochondrial pathways, and highlight its potential as a psychobiotic for stress-related neuropsychiatric disorders. Full article

Studying the morphological changes in dendrites and dendritic spines during the early postnatal period is essential for unraveling the development of neural circuits and synaptic connectivity. Structural alterations in the dendritic arborization and spine morphology of medium spiny neurons (MSNs) have been closely linked to various neurodevelopmental disorders (NDDs). While Golgi-Cox staining remains a powerful technique for visualizing individual neurons, existing protocols are predominantly optimized for adult rodent brains only. This has limited our insight into MSNs development during the early postnatal stages, largely due to difficulties in maintaining tissue integrity during processing and the absence of standardized methods specific to neonatal brains. In this study, we present a reliable, cost-effective, and easily reproducible Golgi-Cox staining protocol suitable for use in standard histology laboratories. This protocol is specifically adapted for neonatal and early postnatal mouse brain tissue but is also applicable to adult brains. It enables consistent and detailed analysis of dendritic and spine morphology across developmental time points and provides a valuable tool for investigating the disrupted neuronal maturation observed in the mouse models of NDDs. Full article

Prion diseases are classically attributed to the accumulation of protease-resistant prion protein (PrP^Sc); however, recent evidence suggests that alternative misfolded prion conformers and systemic inflammatory factors may also contribute to neurodegeneration. This study investigated whether recombinant moPrP^Res, generated by incubating wild-type mouse PrP^C with bacterial lipopolysaccharide (LPS), can induce prion-like disease in FVB/N female mice, whether LPS alone causes neurodegeneration, and how LPS modulates disease progression in mice inoculated with the Rocky Mountain Laboratory (RML) strain of prions. Wild-type female FVB/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrP^Res, moPrP^Res + LPS, RML, and RML + LPS. Animals were monitored longitudinally for survival, body weight, and clinical signs. Brain tissues were analyzed histologically and immunohistochemically for vacuolar degeneration, PrP^Sc accumulation, reactive astrogliosis, and amyloid-β plaque deposition. Recombinant moPrP^Res induced a progressive spongiform encephalopathy characterized by widespread vacuolation and astrogliosis, yet with no detectable PrP^Sc by Western blot or immunohistochemistry. LPS alone triggered a distinct neurodegenerative phenotype, including cerebellar amyloid-β plaque accumulation and terminal-stage spongiosis, with approximately 40% mortality by the end of the study. Co-administration of moPrP^Res and LPS resulted in variable regional pathology and intermediate survival (50% at 750 days post-inoculation). Interestingly, RML + LPS co-treatment led to earlier clinical onset and mortality compared to RML alone; however, vacuolation levels were not significantly elevated and, in some brain regions, were reduced. These results demonstrate that chronic endotoxemia and non-infectious misfolded PrP conformers can independently or synergistically induce key neuropathological hallmarks of prion disease, even in the absence of classical PrP^Sc. Targeting inflammatory signaling and toxic prion intermediates may offer novel therapeutic strategies for prion and prion-like disorders. Full article

Vascular dementia (VD), characterized by cognitive decline and behavioral disorders, has seen a rapid increase in prevalence in recent years. However, effective treatments for VD remain unavailable. Due to its regenerative potential, stem cell therapy has garnered attention as a promising approach for VD treatment, yet it has shown limited effects on cognitive and behavioral impairments caused by the disease. To address this limitation, this study aimed to develop a novel treatment using human embryonic stem cell-derived multipotent mesenchymal stem cells (MMSCs). The therapeutic efficacy of MMSCs was evaluated using a vascular dementia mouse model induced by bilateral carotid artery stenosis (BCAS). The effects of MMSCs were assessed through behavioral tests and postmortem brain tissue analysis, including mRNA expression analysis and hematoxylin and eosin (H&E) staining. MMSCs treatment significantly improved both working memory and long-term memory. Histological analysis revealed enhanced angiogenesis, preservation of blood–brain barrier integrity, and improved hippocampal organization. Furthermore, MMSCs treatment reduced the expression of Rock1/2, indicating suppression of neuroinflammatory and apoptotic pathways. These findings suggest that MMSCs offer a sustainable and effective therapeutic approach for vascular dementia. Full article

Background: Manganese porphyrin, MnTnBuOE-2-PyP⁵⁺ (BMX-001), improves neurologic deficits in experimental ischemic stroke and has the potential to serve as an adjunct with thrombolysis or thrombectomy in stroke patients. In 10–30% of stroke patients following thrombolysis, the hemorrhagic transformation, associated with iron release, occurs. This study aimed to examine the neurologic outcome following the BMX-001 treatment in a mouse intracerebral hemorrhage (ICH) model with relevance to prospective ischemic stroke clinical trials. Methods: Twenty C57Bl6 mice were randomly assigned to groups after surgery and received vehicle or BMX-001 treatment immediately following stereotaxic left striatum collagenase injection. Post-ICH body weight, the Corner test, neurological deficit score, and Rotarod test were examined. Six sham surgery mice serve as a control group. At 72 h, the brain histological evaluation was performed, including hemorrhage size, Prussian blue staining, and the activation of macrophages. Data were collected by a researcher who was blind to groups. Results: No significant difference in body weight, neurological deficits, and hemorrhage size was found between groups. However, BMX-001 reduced the number of macrophages in the hemorrhagic area (48 ± 10 in vehicle, 33 ± 8 in BMX-001, p = 0.008) and the number of cells stained with Prussian blue—an indicator of iron released during hemorrhage (65 ± 22 in vehicle and 41 ± 15 in BMX-001, p = 0.027). Conclusions: The results support the safe use of BMX-001 in stroke patients in combination with thrombolysis or thrombectomy and, moreover, indicate the beneficial anti-inflammatory effect of BMX-001, alike to that previously reported in stroke studies of analogous, similarly redox-active, Mn porphyrins. Full article

Background/Objectives: Minimal hepatic encephalopathy (MHE) is a clinical condition characterized by neurological impairments, including brain inflammation, arising from the accumulation of toxic metabolites associated with liver dysfunction and leaky gut. This study investigated the pharmacological activity of a new phytocomplex extracted from red orange by-products (AL0042) using hydrodynamic cavitation and consisting of a mixture of pectin, polyphenols, and essential oils. Methods: Preliminary in vitro studies evaluated the impact on the epithelial integrity (TEER) of enterocytes challenged by a pro-inflammatory cocktail. The effect of AL0042 was then evaluated in a model of thioacetamide (TAA)-treated mice that mimics MHE. A group of 8–10-week-old male C57BL/6 mice was intraperitoneally injected with TAA to establish the MHE model. The intervention group received TAA along with AL0042 (20 mg/kg, administered orally once daily for 7 days). At the end of the treatment, the rotarod test was conducted to evaluate motor ability, along with the evaluation of blood biochemical, liver, and brain parameters. Results: In vitro, AL0042 (250 μg/mL) partially recovered the TEER values, although anti-inflammatory mechanisms played a negligible role. In vivo, compared with the control group, the test group showed significant behavioral differences, together with alterations in plasma ammonia, serum TNF-α, ALT, AST, corticosterone levels, and SOD activity. Moreover, histological data confirmed the anti-inflammatory effect at liver and brain level. Conclusions: AL0042 treatment revealed a significant therapeutic effect on the TAA-induced MHE mouse model, curbing oxidative stress and peripheral and central inflammation, thus suggesting that its pharmacological activity deserves to be further investigated in clinical studies. Full article

Toxoplasma gondii is an obligate intracellular protozoan that infects humans and other mammals. The C57BL/6J mouse strain is regarded as an ideal model organism for studying T. gondii due to its susceptibility to T. gondii infection and its other advantages over other laboratory animals. However, systematic studies on the response dynamics of the susceptible C57BL/6J mice after oral infection with T. gondii cysts are lacking. To address this research gap, we investigated the spatiotemporal dynamics of infection, colonization, and antibody fluctuations in susceptible C57BL/6J mice orally infected with Type II T. gondii ME49 strain cysts. Mice were orally challenged with T. gondii cysts to examine the infection dynamics. Daily monitoring was conducted for 60 days post-infection (dpi) to assess animals’ clinical signs and survival rates. The parasite burden in various organs was quantified using qPCR targeting the T. gondii B1 gene. The serum antibody responses were evaluated using ELISA. The cyst burden in the mouse brain was assessed via histology and immunofluorescence. T. gondii infection induced clinical symptoms in the mice, including fever and weight loss. T. gondii rapidly invaded the mice’s small intestine, spleen, lungs, liver, and heart via the bloodstream within 1–5 dpi. T. gondii had breached the blood–brain barrier and colonized the brain by 7 dpi. The levels of Toxoplasma-specific IgG antibodies increased and stabilized for two months (until the experiment ended). Systemic parasite dissemination occurred rapidly, infiltrating most tissues and organs, leading to pronounced enteritis and multi-organ damage due to inflammation. The tachyzoites differentiated into bradyzoites when T. gondii infection progressed from the acute to the chronic phase in mice, forming tissue cysts in organs, including the muscles and brain. As a result, the predilection site of T. gondii in mice is the brain, which is where the cysts persisted for the host’s lifetime and continuously induced meningitis. These findings provide valuable insights into the spatiotemporal diffusion, colonization, predilection sites, temporal antibody dynamics, pathogen detection methodologies, and histopathological changes in C57BL/6J mice following oral infection with T. gondii cysts. These insights are important for elucidating T. gondii’s pathogenesis and host–T. gondii interaction. Full article

Background/Objectives: Glioblastoma (GBM) is the deadliest type of brain tumor and photodynamic therapy (PDT) is a promising treatment modality of GBM. However, insufficient photosensitizer distribution in the GBM critically limits the success of PDT. To address this obstacle, we propose tumoritropic neutrophils (NE) as active carriers for photosensitizer delivery to achieve GBM-targeted PDT. Methods: Isolated mouse NE were loaded with functionalized hexagonal boron nitride nanoparticles carrying the photosensitizer chlorin e6 (BNPD-Ce6). In vitro experiments were conducted to determine drug release from the loaded NE (BNPD-Ce6@NE) to mouse GBM cells and consequential photo-cytotoxicity. In vivo experiments were performed on mice bearing intracranial graft GBMs to demonstrate GBM-targeted drug delivery and the efficacy of anti-GBM PDT mediated by BNPD-Ce6@NE. Results: BNPD-Ce6@NE displayed good viability and migration ability, and rapidly released BNPD-Ce6 to co-cultured mouse GBM cells, which then exhibited marked reactive oxygen species (ROS) generation and cytotoxicity following 808 nm laser irradiation (LI). In the in vivo study, a single intravenous bolus injection of BNPD-Ce6@NE resulted in pronounced Ce6 distribution in intracranial graft GBMs 4 h post injection, which peaked around 8 h post injection. A PDT regimen consisting of multiple intravenous BNPD-Ce6@NE injections each followed by one extracranial tumor-directed LI 8 h post injection significantly slowed the growth of intracranial graft GBMs and markedly improved the survival of host animals. Histological analysis revealed massive tumor cell damage and NE infiltration in the PDT-treated GBMs. Conclusions: NE are efficient carriers for GBM-targeted photosensitizer delivery to achieve efficacious anti-GBM PDT. Full article

Abnormalities in the mammalian target of the rapamycin (mTOR) pathway have been implicated in numerous developmental brain disorders. While the molecular and histological abnormalities have been described, less is known about alterations in membrane and synaptic excitability with chronic changes in the mTOR pathway. In the present study, we used a conditional mouse model with a deletion of the phosphatase and tensin homologue (Pten^-/-, a negative regulator of mTOR) from cortical pyramidal neurons (CPNs). Whole-cell patch clamp recordings in ex vivo slices examined the intrinsic and synaptic membrane properties of layer II/III CPNs in normal mice treated with rapamycin for four weeks, and Pten^-/- mice with and without chronic treatment with rapamycin. Compared with control mice, CPNs from Pten^-/- mice demonstrated increased membrane capacitance and time constant in association with increased neuronal somatic size, reduced neuronal firing, and decreased frequency of spontaneous and miniature inhibitory postsynaptic currents, consistent with decreased pre-synaptic GABA release. Rapamycin treatment for four weeks prevented these changes in Pten^-/- mice. CPNs from normal mice chronically treated with rapamycin, compared with CPNs from naïve mice, showed reduced capacitance and time constant, increased input resistance, and changes in inhibitory synaptic inputs, consistent with increased pre-synaptic GABA release. These results support the concept that Pten deletion results in significant changes in inhibitory inputs onto CPNs, and these alterations can be prevented with chronic rapamycin treatment. In addition, normal mice treated with rapamycin also display altered membrane and synaptic properties. These findings have potential implications for the treatment of neurological disorders associated with mTOR pathway dysfunction, such as epilepsy and autism. Full article

In this time series study, the temporal sequences of postmortem changes in brains kept at different temperatures were investigated in different areas of mouse brains. Fixation of tissues kept at different storage temperatures (4 °C, 22 °C, 37 °C) was delayed for four time points (24, 120, 168, 336 h). Histological and immunohistochemical investigations were carried out to determine how postmortem autolysis may affect the cellular morphology and the expression of neural cell epitopes. Results showed that the autolytic changes started earlier in brains at 22 °C and 37 °C and in the grey matter compared to the white matter, with the cerebellum and hippocampus showing the earliest postmortem changes. The cellular antigens were differently affected by the autolytic process overtime: NeuN and Olig2 immunoreactivity was gradually lost at the nuclear site and diffused into the cytoplasm; increased background staining was observed with SMI-32; GFAP showed an increase in immunolabeling, whereas 2F11 immunoreactivity decreased. This study suggests that the morphological analysis and immunohistochemical investigation of the brain tissue could be satisfactorily applied to forensic cases, providing useful data for the estimation of the postmortem interval. Full article

(1) Background: Impeded resolution of inflammation contributes substantially to the pathogenesis of Alzheimer’s disease (AD); consequently, resolving inflammation is pivotal to the amelioration of AD pathology. This can potentially be achieved by the treatment with specialized pro-resolving lipid mediators (SPMs), which should resolve neuroinflammation in brains. (2) Methods: Here, we report the histological effects of long-term treatment with an SPM, maresin-like 1 (MarL1), on AD pathogenesis in a transgenic 5xFAD mouse model. (3) Results: MarL1 treatment reduced Aβ overload, curbed the loss of neurons in brains especially cholinergic neurons associated with cleaved-caspase-3-associated apoptotic degeneration, reduced microgliosis and the pro-inflammatory M1 polarization of microglia, curbed the AD-associated decline in anti-inflammatory Iba1⁺Arg-1⁺-M2 microglia, inhibited phenotypic switching to pro-inflammatory N1 neutrophils, promoted the blood–brain barrier-associated tight-junction protein claudin-5 and decreased neutrophil leakage in 5xFAD brains, and induced the switch of neutrophils toward the inflammation-resolving N2 phenotype. (4) Conclusions: Long-term administration of MarL1 mitigates AD-related neuropathogenesis in brains by curbing neuroinflammation and neurodegeneration, based on the histological results. These findings provide preclinical leads and mechanistic insights for the development of MarL1 into an effective modality to ameliorate AD pathogenesis. Full article

The effects of Lactiplantibacillus plantarum 1008 (LP1008) on age-related cognitive impairment and skeletal muscle atrophy have been reported previously. However, its role in obesity- and age-related hypogonadism has yet to be explored. This study investigates the therapeutic efficacy of low- and high-dose LP1008 in a high-fat-diet-fed male mouse model. Mice at 37 weeks of age were fed a standard diet (n = 8) or a 45% high-fat diet for 28 weeks, and the high-fat-diet-fed mice were divided into vehicle, low-dose and high-dose LP1008 groups (n = 8 per group) on the basis of the treatment administered for an additional 8 weeks. We found that LP1008 suppressed the increases in total cholesterol levels and liver function parameters and alleviated histological changes in the brain, ileum, gastrocnemius muscle and testes. In terms of reproductive function, LP1008 attenuated the decreases in sperm quality, sperm maturity, testosterone levels and levels of enzymes involved in testosterone biosynthesis. Furthermore, LP1008 altered impairments in spatial learning and memory and induced slight alterations in the gut microbiota. Moreover, LP1008 exerted antioxidant, anti-inflammatory and anti-apoptotic effects in aged, obese male mice. LP1008 reversed diet-induced obesity, age-related reproductive dysfunction and pathological damage by increasing testosterone levels and altering the gut microbiome through the regulation of mediators involved in oxidative stress, apoptosis and inflammation. Full article

Background/Objectives: The biological basis for behavioral manifestations of Alzheimer’s disease remains unclear. Emotional and behavioral alterations of Alzheimer’s disease can result in substantial caregiver burden and lack effective management. This study expands upon previous work investigating behavioral alterations in mice with Alzheimer’s disease and a potential treatment of increasing brain-derived neurotrophic factor (BDNF) using repetitive transcranial magnetic stimulation (rTMS). Methods: A total of 47 3xTg-AD (Alzheimer’s) and 53 B6 (wildtype) mice were administered ANA12 (an antagonist of TrkB receptor) or Vehicle (saline) and then rTMS or Sham treatment daily. After 14 days of treatments and injections, mouse behavior was assessed under various behavioral cognitive tests. Mice were then perfused, and brain samples were processed for histology and protein assays. Brain homogenates were analyzed for BDNF and its downstream signaling molecules. Results: Open field testing demonstrated that 3xTg-AD mice spent more time in the center than B6 mice. 3xTg-AD-Sham mice injected with ANA12 were the only group to travel significantly less distance than B6-ANA12-Sham or B6-Vehicle-Sham mice (p < 0.05), while 3xTg-AD-rTMS mice (irrespective of injection) were not significantly different from B6 mice. 3xTg-AD mice had significantly greater measured levels of BDNF and TrkB than the wild-type mice. Conclusions: Treatment of Alzheimer’s disease using rTMS positively affects elements of hypoactivity, but not all behavioral abnormalities. rTMS shifted 3xTg-AD open field behavioral test measures, generating significant differences between untreated 3xTg-AD and B6 genotypes. Despite its benefit, further investigation of rTMS as a treatment for Alzheimer’s disease as well as its biological underpinnings are needed. Full article

The increasing prevalence of age-related neurodegenerative disorders owing to the aging population worldwide poses substantial challenges. This study investigated the neuroprotective effects of protocatechuic acid (PCA), a compound found in various fruits, vegetables, and grains, using a scopolamine-induced hypomnesia mouse model. Six-week-old male C57BL/6J mice were orally administered PCA at doses of 10 and 100 mg/kg body weight per day for two weeks, along with intraperitoneal injections of scopolamine. Learning and memory abilities were assessed using the passive avoidance, Morris water maze, and Y-maze behavioral assays. Biochemical analyses evaluated the levels of oxidative stress markers, including 8-hydroxydeoxyguanosine (8-OHdG) in the blood and malondialdehyde (MDA) in the brain, as well as phase II antioxidant proteins in the hippocampus. Histological examination was conducted to determine hippocampal integrity. Our results demonstrated that PCA administration at 10 mg/kg body weight per day or higher for two weeks (i) significantly ameliorated scopolamine-induced learning and memory impairments, as evidenced by improved performance in behavioral tasks, (ii) reduced plasma 8-OHdG levels and cerebral MDA levels in a dose-dependent manner, (iii) increased antioxidant protein expressions in the hippocampal tissue, and (iv) mitigated histological damage in the hippocampal region of the brain. These findings suggest that oral administration of PCA provides neuroprotective effects against oxidative stress-induced learning and memory impairments, possibly through upregulating antioxidant machinery. Therefore, PCA may serve as a promising dietary supplement for mitigating cognitive deficits associated with neurodegenerative diseases. Full article