Changes In Brain Tissue Research Articles

The Role of Cystathionine-β-Synthase, H2S, and miRNA-377 in Hypoxic-Ischemic Encephalopathy: Insights from Human and Animal Studies.

We aimed to investigate the mechanism underlying the roles of miRNA-377, Cystathionine-β-synthase (CBS), and hydrogen sulfide (H2S) in the development of hypoxic-ischemic encephalopathy (HIE). We investigated the relationship between CBS, H2S, and miR-377 in both humans with HIE and animals with hypoxic-ischemic insult. An animal model of fetal rats with hypoxic-ischemic brain injury was established, and the fetal rats were randomly assigned to control and hypoxic-ischemic groups for 15min (mild) and 30min (moderate) groups. Human samples were collected from children diagnosed with HIE. Healthy or non-neurological disease children were selected as the control group. Hematoxylin-eosin (HE) staining, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot were used to conduct this study. Hypoxia-ischemia induced pathological alterations in brain tissue changes were more severe in groups with severe hypoxic insult. miRNA-377 expression levels were upregulated in brain tissue and serum of fetal rats and human samples with HIE compared to controls. Conversely, CBS and H2S expression levels were significantly decreased in both human and animal samples compared to controls. Our findings suggest that CBS is a target gene of miR-377 which may contribute to the development of HIE by regulating CBS/H2S. H2S has a protective effect against hypoxic damage in brain tissue. The study provides new insights into the potential mechanisms underlying the protective role of H2S in hypoxic brain damage and may contribute to the development of novel therapies for HIE.

Sesamol defends neuronal damage following cerebral ischemia/reperfusion: a crosstalk of autophagy and Notch1/NLRP3 inflammasome signaling

ObjectiveSesamol (SES) is a phenolic compound found in sesame seed oil. Several studies have revealed its anti-inflammatory and antioxidant properties. However, its complete underlying mechanistic perspective about cerebral ischemia/reperfusion (I/R) lesions has not yet been disclosed. Consequently, we aimed to scrutinize its neuroprotective mechanism against cerebral injury during a global cerebral I/R in a rat model, considering its impact on autophagy and Notch1/NLRP3 inflammasome signaling regulation.MethodsTo affirm our purpose, adult Wistar rats were allotted into five groups: sham and the other four groups in which transient global cerebral ischemia was induced by bilateral common ligation (2VO) for 1 h, then reperfusion for either 24 h or 5 days: I/R (1/24), I/R (1/5), SES + I/R (1/24), and SES + I/R (1/5). In treated groups, SES (100 mg/kg, p.o., for 21 days) was administered before cerebral I/R induction. The assessment of histopathological changes in brain tissues, immunohistochemistry, biochemical assays, ELISA, and qRT-PCR were utilized to investigate our hypothesis.ResultsAdvantageously, SES halted the structural neuronal damage with lessened demyelination induced by cerebral I/R injury. Restoring oxidant/antioxidant balance was evident by boosting the total antioxidant capacity and waning lipid peroxidation. Furthermore, SES reduced inflammatory and apoptosis markers. Additionally, SES recovered GFAP, Cx43, and autophagy signaling, which in turn switched off the Notch-1/NLRP3 inflammasome trajectory.ConclusionsOur results revealed the neuroprotective effect of SES against cerebral I/R injury through alleviating injurious events and boosting autophagy, consequently abolishing Notch1/NLRP3 inflammasome signaling.

Effect of intranasal and oral administration of levetiracetam onthe temporal and spatial distributions of SV2A in the KA-induced rat model of SE.

To investigate the effectiveness of nasal delivery of levetiracetam (LEV) on the distributions of synaptic vesicle protein 2 isoform A (SV2A) in epileptic rats with injection of kainic acid (KA) into amygdala. A total of 138 rats were randomly divided into four groups, including the Sham surgery group, the epilepsy group (EP), and the LEV oral administration (LPO) and nasal delivery (LND) groups. The rat intra-amygdala KA model of epilepsy was constructed. Pathological changes of rat brain tissue after status epilepticus (SE) were detected using haematoxylin and eosin staining. Expression of SV2A in rat hippocampus after SE was evaluated using the western blotting analysis. Expression and distribution of SV2A in rat hippocampus after SE were detected based on immunofluorescence staining. The EP group showed evident cell loss and tissue necrosis in the CA3 area of hippocampus, whereas the tissue damage in both LPO and LND groups was significantly reduced. Western blotting analysis showed that the expressions of SV2A in the hippocampus of both EP and LND groups were significantly decreased 1 week after SE, increased to the similar levels of the Sham group in 2 weeks, and continuously increased 4 weeks after SE to the level significantly higher than that of the Sham group. Results of immunofluorescence revealed largely the same expression patterns of SV2A in the CA3 area of hippocampus as those in the entire hippocampus. Our study revealed the same antiepileptic and neuronal protective effects by the nasal and oral administrations of LEV, without changing the expression level of SV2A.

Tract-wise microstructural analysis informs on current and future disability in early multiple sclerosis

ObjectivesMicrostructural characterization of patients with multiple sclerosis (MS) has been shown to correlate better with disability compared to conventional radiological biomarkers. Quantitative MRI provides effective means to characterize microstructural brain tissue changes both in lesions and normal-appearing brain tissue. However, the impact of the location of microstructural alterations in terms of neuronal pathways has not been thoroughly explored so far. Here, we study the extent and the location of tissue changes probed using quantitative MRI along white matter (WM) tracts extracted from a connectivity atlas.MethodsWe quantified voxel-wise T1 tissue alterations compared to normative values in a cohort of 99 MS patients. For each WM tract, we extracted metrics reflecting tissue alterations both in lesions and normal-appearing WM and correlated these with cross-sectional disability and disability evolution after 2 years.ResultsIn early MS patients, T1 alterations in normal-appearing WM correlated better with disability evolution compared to cross-sectional disability. Further, the presence of lesions in supratentorial tracts was more strongly associated with cross-sectional disability, while microstructural alterations in infratentorial pathways yielded higher correlations with disability evolution. In progressive patients, all major WM pathways contributed similarly to explaining disability, and correlations with disability evolution were generally poor.ConclusionsWe showed that microstructural changes evaluated in specific WM pathways contribute to explaining future disability in early MS, hence highlighting the potential of tract-wise analyses in monitoring disease progression. Further, the proposed technique allows to estimate WM tract-specific microstructural characteristics in clinically compatible acquisition times, without the need for advanced diffusion imaging.

Psychological factors and brain magnetic resonance imaging metrics associated with fatigue in persons with multiple sclerosis

BackgroundBesides demographics and clinical factors, psychological variables and brain-tissue changes have been associated with fatigue in persons with multiple sclerosis (pwMS). Identifying predictors of fatigue could help to improve therapeutic approaches for pwMS.Therefore, we investigated predictors of fatigue using a multifactorial approach. Methods136 pwMS and 49 normal controls (NC) underwent clinical, neuropsychological, and magnetic resonance imaging examinations. We assessed fatigue using the “Fatigue Scale for Motor and Cognitive Functions”, yielding a total, motor, and cognitive fatigue score. We further analyzed global and subcortical brain volumes, white matter lesions and microstructural changes (examining fractional anisotropy; FA) along the cortico striatal thalamo cortical (CSTC) loop. Potential demographic, clinical, psychological, and magnetic resonance imaging predictors of total, motor, and cognitive fatigue were explored using multifactorial linear regression models. Results53% of pwMS and 20% of NC demonstrated fatigue. Besides demographics and clinical data, total fatigue in pwMS was predicted by higher levels of depression and reduced microstructural tissue integrity in the CSTC loop (adjusted R2 = 0.52, p < 0.001). More specifically, motor fatigue was predicted by lower education, female sex, higher physical disability, higher levels of depression, and self-efficacy (adjusted R2 = 0.54, p < 0.001). Cognitive fatigue was also predicted by higher levels of depression and lower self-efficacy, but in addition by FA reductions in the CSTC loop (adjusted R2 = 0.45, p < 0.001). ConclusionsOur results indicate that depression and self-efficacy strongly predict fatigue in MS. Incremental variance in total and cognitive fatigue was explained by microstructural changes along the CSTC loop, beyond demographics, clinical, and psychological variables.

The protective effect and mechanism of mangiferin on D‐galactose‐induced oxidative stress and cognitive impairment in aging mice by an integrated network pharmacology and experimental validation strategy

AbstractMangiferin (MAN) was a natural bioactive xanthone with remarkable antioxidative, anti‐inflammatory, and antiapoptotic effects. The purpose of this study to determine the protective influence of MAN on D‐galactose (D‐gal)‐induced aging and cognitive impairment, together with its underlying molecular mechanism. The network pharmacology molecular docking analysis revealed that MAN has a potential binding with aging‐related oxidative stress and apoptosis proteins. In D‐gal‐induced aging mice, MAN could significantly reduce D‐gal‐induced histopathological changes of liver and brain tissues. Moreover, MAN administration obviously increased activities of antioxidant enzymes (SOD, T‐AOC, GSH‐Px, and CAT) and decreased levels of AChE and MDA in the serum, liver, or brain tissues. Additionally, MAN alleviated learning and memory disorders and improved the exploration ability. Western blotting and immunohistochemical analysis results revealed that MAN could regulate the expressions of PI3K/Akt/Nrf2 signaling pathway‐related proteins and apoptotic‐related proteins (Bax, Bcl‐2, and Caspase‐9) in the liver tissues. Therefore, these findings suggested that MAN can be used as a potent dietary supplement in functional foods for the protection against aging‐related impairments.

Feasibility Analysis of Brain Perfusion Using Polyaspartic Acid Surface-Modified Superparamagnetic Contrast Agent

This research was aimed to construct polyaspartic acid (PASP) surface-modified magnetic resonance imaging (MRI) contrast agent nanoparticles (NPs) and preliminarily demonstrate the feasibility of using the NPs for MRI cerebral perfusion. Ultrasmall superparamagnetic iron oxide (USPIO) NPs were fabricated by a one-step chemical coprecipitation methodology, and surface modification of USPIO NPs was performed using PASP as the surface modifier to prepare PASP-USPIO NPs. The physicochemical properties of the NPs were detected, and their specific structural ability with HUVECs was visualized by Prussian blue staining. With the contrast agent gadolinium-diethylene triamine pentaacetate (Gd-DTPA) as the control group, the intravenous bolus of USPIO and PASP-USPIO was analyzed and a brain MRI scan of New Zealand white rabbits was performed. The relative cerebral blood volume (rCBV) and maximum signal reduction ratio (SRRmax) values of cerebral gray matter and white matter were calculated based on the plotted time-signal intensity. The results showed that the USPIO and PASP-USPIO NPs were successfully prepared. The average particle sizes were 40.1±5.5 nm and 42.7±6.9 nm, respectively, and the specific saturation magnetization was 86.9 A m2 ·kg−1 and 51.3 A m2 ·kg−1, respectively. Relative to USPIO, human umbilical vein endothelial cells (HUVECs) stained with Prussian blue positively in vitro in the PASP-USPIO group were notably increased, while the rate of change in the signal-to-noise ratio of imaging in vivo was substantially decreased. The time-signal intensity curves were plotted, and it was found that the rCBV of gray matter, rCBV of white matter, SRRmax of gray matter, and SRRmax of white matter in the USPIO group and PASP-USPIO group were greatly increased relative to control group (P &lt; 0.05), while the SRRmax ratio of gray matter to white matter was decreased (P &lt; 0.05). Additionally, the rCBV in the gray matter and rCBV in the white matter of the PASP-USPIO group were drastically increased in contrast to the USPIO group (P &lt; 0.05). In short, the constructed PASP surface-modified USPIO NPs can become a novel MRI contrast agent for monitoring hemodynamic changes in brain tissue.

HDAC-Mediated Glial Crosstalk Mediates Radiation Induced Memory Changes from Whole Brain Radiation in a Mouse Model

Prior work demonstrated radiation sensitivity can be regulated via Class III HDAC-mediated intracellular DNA damage response coordinated with Wnt-beta catenin signaling. We hypothesized that radiation induced functional alterations in HDAC mediated glial crosstalk in the CNS produce intercellular signaling alterations leading to phenotypic changes in cognition following whole brain radiation exposure. Primary human astrocytes, human astrocytoma (U251), and immortalized human microglia (HMC3) were examined in vitro in response to treatment with conditioned media isolated from irradiated glial cells. Prior to treatment with either single-dose or fractionated radiation schedules, cells were transfected with siRNA expression vector for Sirt2, a class III HDAC, versus scrambled controls. Quantitative PCR and immunoblots for neurotransmitters, metabolism, and inflammatory markers were obtained. Cells exposed to conditioned media were examined by immunofluorescence for cytoskeletal alterations and changes in junctional proteins. The findings were correlated with in vivo qPCR and immunohistochemical changes in brain tissue and functional memory changes in Sirt2 knockout versus wild type mice after whole brain radiation using novel object recognition testing at 2 weeks and 6 month post radiation timepoints. Statistical analysis was performed using paired Students T test between treated and control groups. Cells treated with conditioned media produced from irradiated U251, astrocytes and microglia produced increased expression of inflammatory cytokines IL-6, IL-8, GM-CSF and VEGF. However, immunofluorescence of cells treated with conditioned media from irradiated Sirt2 knockdown microglia and primary astrocytes demonstrated qualitative disruptions in glutamate neurotransmitter metabolism and actin cytoskeletal alterations with changes in pseudopodia and lamellipodia after staining with phalloidin and neurofilament L, suggesting altered intercellular communication. Connexin 43 in gap junctions was increased >2-fold (p<0.05) after exposure to conditioned media, whereas E-cadherin in adherens junctions was not significantly affected. Novel object recognition testing of Sirt2 knockout mice demonstrated resistance to radiation induced memory decline from whole brain radiation at pre radiation day 5 versus post radiation days 5 and 185 compared to controls (p<0.05). Glial crosstalk can be mediated via elimination of a Class III HDAC and appears to be a key mediator of radiation induced disruptions of intercellular communication in the CNS, connecting radiation to structural changes on the cell surface to synaptic activity and neurotransmitter metabolism, leading to functional disputations in recognition memory similar to what is experienced by patients receiving brain radiotherapy. These data suggest glial cross talk as a new therapeutic avenue to combat radiation induced cognitive dysfunction.

Low-intensity ultrasound combined with arsenic trioxide induced apoptosis of glioma via EGFR/AKT/mTOR

AimsThis study aimed to explore whether low-intensity ultrasound (LIUS) combined with low-concentration arsenic trioxide (ATO) could inhibit the proliferation of glioma and, if so, to clarify the potential mechanism. Main methodsThe effects of ATO and LIUS alone or in combination on glioma were examined by CCK8, EdU, and flow cytometry assays. Western blot analysis was used to detect changes in expression of apoptosis-related proteins and their effects on the EGFR/AKT/mTOR pathway. The effects of ATO and LIUS were verified in vivo in orthotopic xenograft models, and tumor size, arsenic content in brain tissue, survival, and immunohistochemical changes were observed. Key findingsLIUS enhanced the inhibitory effect of ATO on the proliferation of glioma, and EGF reversed the proliferation inhibition and protein changes induced by ATO and LIUS. The anti-glioma effect of ATO combined with LIUS was related to downstream AKT/mTOR pathway changes caused by inhibition of EGFR activation, which enhanced apoptosis of U87MG and U373 cells. In vivo experiments showed significant increases in arsenic content in brain tissue, as well as decreased tumor sizes and longer survival times in the combined treatment group compared with other groups. The trends of immunohistochemical protein changes were consistent with the in vitro results. SignificanceThis study showed that LIUS enables ATO to exert anti-glioma effects at a safe dose by inhibiting the activation of EGFR and the downstream AKT/mTOR pathway to regulate apoptosis. LIUS in combination with ATO is a promising novel method for treating glioma and could improve patient prognosis.

In-depth proteome analysis of brain tissue from Ewsr1 knockout mouse by multiplexed isobaric tandem mass tag labeling

EWS RNA binding protein 1 (EWSR1) is a multifunctional protein whose epigenetic signatures contribute to the pathogenesis of various human diseases, such as neurodegenerative disorders, skin development, and tumorigenic processes. However, the specific cellular functions and physiological characteristics of EWSR1 remain unclear. In this study, we used quantitative mass spectrometry-based proteomics with tandem mass tag labeling to investigate the global proteome changes in brain tissue in Ewsr1 knockout and wild-type mice. From 9115 identified proteins, we selected 118 differentially expressed proteins, which is common to three quantitative data processing strategies including only protein level normalizations and spectrum-protein level normalization. Bioinformatics analysis of these common differentially expressed proteins revealed that proteins up-regulated in Ewsr1 knockout mouse are mostly related to the positive regulation of bone remodeling and inflammatory response. The down-regulated proteins were associated with the regulation of neurotransmitter levels or amino acid metabolic processes. Collectively, these findings provide insight into the physiological function and pathogenesis of EWSR1 on protein level. Better understanding of EWSR1 and its protein interactions will advance the field of clinical research into neuronal disorders. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD026994.

Neuroprotective and Cardiometabolic Role of Vitamin E: Alleviating Neuroinflammation and Metabolic Disturbance Induced by AlCl3 in Rat Models.

Cardiovascular diseases (CVDs) and neurodegenerative disorders, such as diabetes mellitus and Alzheimer's disease, share a common pathophysiological link involving insulin resistance (IR), inflammation, and hypertension. Aluminium chloride (AlCl3), a known neurotoxicant, has been associated with neurodegeneration, cognitive impairment, and various organ dysfunctions due to the production of reactive oxygen species (ROS) and oxidative stress. In this study, we aimed to investigate the potential protective effects of metformin and vitamin E against AlCl3-induced neuroinflammation and cardiometabolic disturbances in rat models. Rats were divided into five groups: a normal control group, an AlCl3-treated diseased group without any treatment, and three groups exposed to AlCl3 and subsequently administered with metformin (100 mg/kg/day) alone, vitamin E (150 mg/kg/day) orally alone, or a combination of metformin (100 mg/kg/day) and vitamin E (150 mg/kg/day) for 45 days. We analyzed serum biomarkers and histopathological changes in brain, heart, and pancreatic tissues using H&E and Masson's trichrome staining and immunohistochemistry (IHC). Electrocardiogram (ECG) patterns were observed for all groups. The AlCl3-treated group showed elevated levels of inflammatory biomarkers, MDA, and disturbances in glycemic and lipid profiles, along with reduced insulin levels. However, treatment with the combination of metformin and vitamin E resulted in significantly reduced glucose, cholesterol, LDL, and TG levels, accompanied by increased insulin and HDL levels compared to the individual treatment groups. Histopathological analyses revealed that combination therapy preserved neuronal structures, muscle cell nuclei, and normal morphology in the brain, heart, and pancreatic tissues. IHC demonstrated reduced amyloid plaques and neurofibrillary tangles in the combination-treated group compared to the AlCl3-treated group. Moreover, the combination group showed a normal ECG pattern, contrasting the altered pattern observed in the AlCl3-treated group. Overall, our findings suggest that metformin and vitamin E, in combination, possess neuroprotective and cardiometabolic effects, alleviating AlCl3-induced neuroinflammation and metabolic disturbances.

Overexpression of miR-199a-5p improves brain injury in newborn rats with intrauterine infection via inhibition of astrocyte activation

White matter injury is the most common form of brain injury in preterm infants. In addition to hypoxia ischemia, intrauterine infection is most closely related to brain white matter injury. Our study aimed to explore the mechanism of the miR-199a-5p/HIF-1α axis on astrocyte activation and brain injury in newborn rats caused by intrauterine infection.The animal/cell model was established via escherichia coli infection/lipopolysaccharide induction, followed by the measurement of body weight, brain weight, and the pathological changes in brain tissues of newborn rats, and the pathological changes in placenta and uterus wall of pregnant rats. Also, the levels of GFAP, TNF-α, MDA, GSH, SOD, miR-199a-5p, and HIF-1α were detected though corresponding assays or kits. In vitro, cell viability and apoptosis and the levels of IL-6 and TNF-α were evaluated in astrocytes. Moreover, the targeting relationship between miR-199a-5p and HIF-1α was verified.miR-199a-5p was lowly expressed in the brain tissues of newborn rats with intrauterine infection. Overexpression of miR-199a-5p relieved the injury of placenta and uterus wall in pregnant rats and brain injury in newborn rats, accompanied by decreased HIF-1α, GFAP, TNF-α, and MDA levels and increased GSH and SOD levels. Results from cell models showed that miR-199a-5p overexpression inhibited astrocyte activation, shown by enhanced cell viability, weakened cell apoptosis, and decreased GFAP, IL-6, and TNF-α. Mechanistically, miR-199a-5p targeted HIF-1α to decrease its expression.Collectively, miR-199a-5p inhibited astrocyte activation and alleviated brain injury in newborn rats with intrauterine infection by reducing HIF-1α expression.

Mechanistic Assessment of Anise Seeds and Clove Buds against the Neurotoxicity Caused by Metronidazole in Rats: Possible Role of Antioxidants, Neurotransmitters, and Cytokines.

Long-term use of the nitroimidazole-derived antibiotic metronidazole has been associated with neuronal damage due to its ability to cross the blood-brain barrier. Polyphenol-rich plants, such as anise seeds and clove buds, are suggested to have neuroprotective effects. However, their intracellular protective pathway against metronidazole-induced neurotoxicity remains unexplored. This study aims to evaluate the potential neuroprotective benefits of anise seeds and clove buds and elucidate the proposed metronidazole-induced neurotoxicity mechanism. This study divided rats into six groups, each containing six rats. In Group I, the control group, rats were administered saline orally. Group II rats received 200 mg/kg of metronidazole orally. Group III rats received 250 mg/kg b.w. of anise seed extract and metronidazole. Group IV rats received 500 mg/kg b.w. of anise seed extract (administered orally) and metronidazole. Group V rats received 250 mg/kg b.w. of clove bud extract (administered orally) and metronidazole. Group VI rats were administered 500 mg/kg b.w. of clove bud extract and metronidazole daily for 30 consecutive days. The study evaluated the phenolic compounds of anise seeds and clove buds. Moreover, it assessed the inflammatory and antioxidant indicators and neurotransmitter activity in brain tissues. A histological examination of the brain tissues was conducted to identify neuronal degeneration, brain antioxidants, and apoptotic mRNA expression. The study found that metronidazole treatment significantly altered antioxidant levels, inflammatory mediators, and structural changes in brain tissue. Metronidazole also induced apoptosis in brain tissue and escalated the levels of inflammatory cytokines. Oral administration of metronidazole resulted in a decrease in GABA, dopamine, and serotonin and an increase in ACHE in brain tissue. Conversely, oral administration of anise and clove extracts mitigated the harmful effects of metronidazole. The neurotoxic effects of metronidazole appear to stem from its ability to reduce antioxidants in brain tissue and increase nitric oxide production and apoptosis. The study concludes that neuronal damage caused by metronidazole is significantly mitigated by treatment with anise and clove extracts.

Relationship between reduced scattering coefficient and intracranial pressure in clinical patients under different brain edema states

AbstractThere is a lack of a safe and effective technology to monitor intracranial pressure accurately and non‐destructively. In this paper, the relationship between reduced scattering coefficient and intracranial pressure in clinical patients under different brain edema states was studied. First, the brain edema MC simulation model was constructed based on different types of brain edema. The results laid a foundation for clinical ICP detection. Second, the changes of ICP and reduced scattering coefficient caused by brain edema were studied in clinical application. It was found that when the patient developed brain edema, the reduced scattering coefficient and ICP showed corresponding changes. Finally, the mathematical model of invasive ICP and reduced scattering coefficient was established. It was found that the sensitivity of 834 nm light to brain tissue changes was higher than that of 692 nm light, which could be used to reflect the changes of brain tissue physiological state.

Flunitrazepam induces neurotoxicity in zebrafish through microbiota-gut-brain axis

The abuse of psychoactive substances has led to their frequent detection in the environment, with unknown effects on the nervous system. In this study, zebrafish were exposed to benzodiazepine drug flunitrazepam (FLZ, 0.2 and 5 μg/L) for 30 days to assess its neurotoxicity. Results revealed that FLZ disrupted the balance of gut microbiota and caused an increase in pathogenic bacteria, such as Paracoccus and Aeromonas, leading to pathological damage to the intestine. The upregulation of intestinal pro-inflammatory factors, IL-1β and TNF-α, by 2.4 and 6.3 times, respectively, along with the downregulation of tight junction proteins, Occludin and zonula occludens 1 (ZO-1), by 80 % and 50 %, increased in intestinal permeability. Moreover, untargeted metabolomics demonstrated that FLZ interfered with intestinal nucleotide metabolism and amino acid biosynthesis. FLZ could also increase the levels of lipopolysaccharide (LPS) and malondialdehyde (MDA) in the brain by 0.9 and 3.4 times, respectively, leading to pathological changes in brain tissue. Furthermore, FLZ significantly disturbed nucleotide metabolism and amino acid biosynthesis and metabolism pathways in the brain. Correlation analysis between gut microbiota and neurochemicals confirmed that FLZ can induce neurotoxicity through the microbiota-gut-brain axis. These findings elucidate the molecular mechanisms of psychoactive drugs on microbiota-gut-brain axis and provide a theoretical basis for the ecological environmental risk assessment of various psychoactive substances.

Compilation of reported protein changes in the brain in Alzheimer’s disease

Proteomic studies of human Alzheimer’s disease brain tissue have potential to identify protein changes that drive disease, and to identify new drug targets. Here, we analyse 38 published Alzheimer’s disease proteomic studies, generating a map of protein changes in human brain tissue across thirteen brain regions, three disease stages (preclinical Alzheimer’s disease, mild cognitive impairment, advanced Alzheimer’s disease), and proteins enriched in amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. Our dataset is compiled into a searchable database (NeuroPro). We found 848 proteins were consistently altered in 5 or more studies. Comparison of protein changes in early-stage and advanced Alzheimer’s disease revealed proteins associated with synapse, vesicle, and lysosomal pathways show change early in disease, but widespread changes in mitochondrial associated protein expression change are only seen in advanced Alzheimer’s disease. Protein changes were similar for brain regions considered vulnerable and regions considered resistant. This resource provides insight into Alzheimer’s disease brain protein changes and highlights proteins of interest for further study.

Neuroprotective anticonvulsant and anxiolytic effects of octreotide in wistar rats

Somatostatin interneurons exhibited anti-epileptic activity. As a result, somatostatin agonists appear to be a promising target for antiepileptic drug development (AEDs). In this regard, we investigated the effects of octreotide, a somatostatin analog, on pentylenetetrazol (PTZ)-induced seizures in male Wistar rats. Animals were given octreotide at doses of 50 or 100 µg/kg for seven days. The anxiolytic effects of octreotide were then evaluated using open field and elevated plus-maze tests. Following that, mice were intraperitoneally given a single convulsive dosage of PTZ (60 mg/kg) and then monitored for 30 min for symptoms of seizures. Finally, the antioxidant capacity of brain tissue and histopathological changes in the hippocampus were investigated. Octreotide therapy for seven days at 50 or 100 µg/kg was more effective than diazepam in preventing acute PTZ-induced seizures (P < 0.05). Furthermore, both octreotide dosages revealed substantial anxiolytic effects in open-field and elevated plus-maze tests compared to untreated rats. Nonetheless, octreotide's anxiolytic impact was less effective than diazepam's. On the other hand, octreotide also suppressed neuronal apoptosis and attenuated oxidative stress. Our results suggest that chronic administration of octreotide has anticonvulsant, anxiolytic, and antioxidant activity in the male Wistar rat model.

Ubiquitin-specific protease 8 regulates cognitive dysfunction of mice with sepsis-associated encephalopathy through SIRT1 deubiquitination.

Sepsis-associated encephalopathy (SAE) is the most severe complication of sepsis. Ubiquitin-specific protease 8 (USP8) could improve cognitive and motor disorders in SAE. This study explored the mechanism of USP8 in SAE mice to provide new therapeutic targets for SAE. C57BL/6 mice were selected to establish SAE models by caecal ligation and puncture (CLP) and injected with lentivirus overexpressing USP8 one week before SAE modeling. Mouse weight changes were monitored, cognitive and learning abilities were tested by the Morris water maze test, behaviors were evaluated by open-field tests, and pathological changes in brain tissue were analyzed by H&E staining. Levels of USP8, TNF-α, IL-1β, IL-6, and IL-10, and SOD, GSH-Px activities, and MDA levels were detected by Western blot, ELISA, and kits. Co-immunoprecipitation assay verified the interaction between USP8 and SIRT1 and SIRT1 ubiquitination level. In CLP mice, the body weight, cognitive function, and learning ability were decreased, along with motor disorder, abnormal morphological structure of neurons, and obvious inflammatory infiltration. USP8 protein in brain tissue was decreased, the levels of TNF-α, IL-1β, and IL-6 were increased, IL-10 was decreased, SOD and GSH-Px activities were decreased, and MDA level was increased. USP8 treatment improved cognitive dysfunction and inhibited inflammation and oxidative stress in CLP mice. USP8 promoted SIRT1 expression by direct deubiquitination. SIRT1 knockdown partially reversed the regulation of USP8 on SAE mice. USP8 can directly deubiquitinate SIRT1 and inhibit inflammatory reactions and oxidative stress, thus improving cognitive dysfunction in SAE mice.

The Effects of Whole Body Gamma Irradiation on Mice, Age-Related Behavioral, and Pathophysiological Changes.

We designed a study with the objective to determine the long-term radiation effects of gamma rays, originating from a single shot of Co60 at a dose of 2Gy on the 7-month-old male mice of the ICR line in 30days after the irradiation. The aim of this study was to characterize the behavior of animals using the Open Field test, immuno-hematological status, and morpho-functional changes in the central nervous system of mice. Irradiated animals displayed significantly different behavior in the OF in comparison with the control group. The radiation damage was confirmed by assessing the ratio of leukocytes in the peripheral blood of mice at a later date after exposure to Co60. After irradiation, a decrease in the glioneuronal complex was observed in the irritated group as well as histological changes of brain cells. To sum up, not only was the hematological status of mice altered upon the total gamma irradiation, but also their behavior, which was most probably due to significant alterations in the CNS. Study of influence of ionizing radiation on female mice, comparison between different age groups. Open Field test on the 30days after 2Gy of γ-rays and histological analysis indicated changes in behavioral patterns, leucocytes, and brain tissue.

Effect of Xiaoxuming Decoction on synaptic plasticity following acute cerebral ischemia-reperfusion in rats

This study aims to explore the effect of Xiaoxuming Decoction on synaptic plasticity in rats with acute cerebral ischemia-reperfusion. A rat model of cerebral ischemia-reperfusion injury was established by middle cerebral artery occlusion(MCAO). Rats were randomly assigned into a sham group, a MCAO group, and a Xiaoxuming Decoction(60 g·kg~(-1)·d~(-1)) group. The Longa score was rated to assess the neurological function of rats with cerebral ischemia for 1.5 h and reperfusion for 24 h. The 2,3,5-triphenyltetrazolium chloride(TTC) staining and hematoxylin-eosin(HE) staining were employed to observe the cerebral infarction and the pathological changes of brain tissue after cerebral ischemia, respectively. Transmission electron microscopy was employed to detect the structural changes of neurons and synapses in the ischemic penumbra, and immunofluorescence, Western blot to determine the expression of synaptophysin(SYN), neuronal nuclei(NEUN), and postsynaptic density 95(PSD95) in the ischemic penumbra. The experimental results showed that the modeling increased the Longa score and led to cerebral infarction after 24 h of ischemia-reperfusion. Compared with the model group, Xiaoxuming Decoction intervention significantly decreased the Longa score and reduced the formation of cerebral infarction area. The modeling led to the shrinking and vacuolar changes of nuclei in the brain tissue, disordered cell arrangement, and severe cortical ischemia-reperfusion injury, while the pathological damage in the Xiaoxuming Decoction group was mild. The modeling blurred the synaptic boundaries and broadened the synaptic gap, while such changes were recovered in the Xiaoxuming Decoction group. The modeling decreased the fluorescence intensity of NEUN and SYN, while the intensity in Xiaoxuming Decoction group was significantly higher than that in the model group. The expression of SYN and PSD95 in the ischemic penumbra was down-regulated in the model group, while such down-regulation can be alleviated by Xiaoxuming Decoction. In summary, Xiaoxuming Decoction may improve the synaptic plasticity of ischemic penumbra during acute cerebral ischemia-reperfusion by up-regulating the expression of SYN and PSD95.