Changes In Brain Tissue Research Articles

Morphofunctional changes in the neuronal environment in suicide

For many years, the topic of the development of suicidal behavior has remained relevant. Every year, there are more reports of new morphological changes in brain tissue, with particular emphasis on the effects of changes and the microenvironment on the functional activity of neurons and the relationship with the development of certain mental diseases. Because morphological changes are not always visible and apparent, immunohistochemical examination for glial fibrillary acid protein might be an additional diagnostic method.
 The presented literature review is an analytical evaluation of the current status of the topic of studying the morphology of macroglia, astrocytes, oligodendrocytes, and the bloodbrain barrier in suicide. According to generalized data, the most characteristic localizations of changes in the development of suicidal behavior are the suture nucleus and prefrontal and anterior cingulate cortex. There is evidence of a correlation between the development of suicidal behavior and an increase in inflammatory cytokines in the prefrontal cortex, a disruption in the connection between astrocytes and oligodendrocytes in the anterior cingulate cortex, and an indication of the involvement of the shell, striatum, preclinium, and wedge, orbitofrontal cortex in suicidal behavior formation.
 When examining the causes of death, determining the characteristic morphology of suicide death can potentially constitute an evidence base for confirming or excluding factors of suicide development.
 Further research is needed to form a clearer picture of the changes in relation to the practice of forensic medical examination; nonetheless, immunohistochemical analysis might be considered a potential method of evidence-based understanding suicide factors.

Transcriptomic profiling of Parkinson's disease brains reveals disease stage specific gene expression changes

Parkinson´s disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms. Aggravation of symptoms is mirrored by accumulation of protein aggregates mainly composed by alpha-synuclein in different brain regions, called Lewy bodies (LB). Previous studies have identified several molecular mechanisms as autophagy and inflammation playing a role in PD pathogenesis. Increased insights into mechanisms involved in early disease stages and driving the progression of the LB pathology are required for the development of disease-modifying strategies. Here, we aimed to elucidate disease stage-specific transcriptomic changes in brain tissue of well-characterized PD and control donors. We collected frontal cortex samples from 84 donors and sequenced both the coding and non-coding RNAs. We categorized our samples into groups based on their degree of LB pathology aiming to recapitulate a central aspect of disease progression. Using an analytical pipeline that corrected for sex, age at death, RNA quality, cell composition and unknown sources of variation, we found major disease stage-specific transcriptomic changes. Gene expression changes were most pronounced in donors at the disease stage when microscopic LB changes first occur in the sampled brain region. Additionally, we identified disease stage-specific enrichment of brain specific pathways and immune mechanisms. On the contrary, we showed that mitochondrial mechanisms are enriched throughout the disease course. Our data-driven approach also suggests a role for several poorly characterized lncRNAs in disease development and progression of PD. Finally, by combining genetic and epigenetic information, we highlighted two genes (MAP4K4 and PHYHIP) as candidate genes for future functional studies. Together our results indicate that transcriptomic dysregulation and associated functional changes are highly disease stage-specific, which has major implications for the study of neurodegenerative disorders.

Microstructural brain tissue changes contribute to cognitive and mood deficits in adults with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) patients show brain tissue changes in mood and cognitive regulatory sites, but the nature and extent of tissue injury and their associations with symptoms are unclear. Our aim was to examine brain tissue damage in T2DM over controls using mean diffusivity (MD) computed from diffusion tensor imaging (DTI), and assess correlations with mood and cognitive symptoms in T2DM. We collected DTI series (MRI), mood, and cognitive data, from 169 subjects (68 T2DM and 101 controls). Whole-brain MD-maps were calculated, normalized, smoothed, and compared between groups, as well as correlated with mood and cognition scores in T2DM subjects. Type 2 diabetes patients showed altered cognitive and mood functions over control subjects. Multiple brain sites in T2DM patients showed elevated MD values, indicating chronic tissue changes, including the cerebellum, insula, and frontal and prefrontal cortices, cingulate, and lingual gyrus. Associations between MD values and mood and cognition scores appeared in brain sites mediating these functions. Type 2 diabetes patients show predominantly chronic brain tissue changes in areas mediating mood and cognition functions, and tissue changes from those regions correlate with mood and cognitive symptoms suggesting that the microstructural brain changes may account for the observed functional deficits.

Saponin of Aralia taibaiensis promotes angiogenesis through VEGF/VEGFR2 signaling pathway in cerebral ischemic mice

Ethnopharmacological relevanceAralia taibaiensis is known for its ability to promote blood circulation and dispel blood stasis, activate meridians and remove arthralgia. The saponins of Aralia taibaiensis (sAT) are the main active components that are often used to treat cardiovascular and cerebrovascular diseases. However, it has not been reported whether sAT can improve ischemic stroke (IS) by promoting angiogenesis. Aim of the studyIn this study, we investigated the potential of sAT to promote post-ischemic angiogenesis in mice and determined the underlying mechanism through in vitro experiments. MethodsTo establish the middle cerebral artery occlusion (MCAO) mice model in vivo. First of all, we examined the neurological function, brain infarct volume, and degree of brain swelling in MCAO mice. We also observed pathological changes in brain tissue, ultrastructural changes in blood vessels and neurons, and the degree of vascular neovascularization. Additionally, we established the oxygen-glucose deprivation/reoxygenation (OGD/R) -human umbilical vein endothelial cells (HUVECs) model in vitro to detect the survival, proliferation, migration and tube formation of OGD/R HUVECs. Finally, we verified the regulatory mechanism of Src and PLCγ1 siRNA on sAT promoting angiogenesis by cell transfection technique. ResultsIn the cerebral ischemia-reperfusion mice, sAT distinctly improved the cerebral infarct volume, brain swelling degree, neurological dysfunction, and brain histopathological morphology due to cerebral ischemia/reperfusion injury. It also increased the double positive expression of BrdU and CD31 in brain tissue, promoted the release of VEGF and NO and decreased the release of NSE and LDH. In the OGD/R HUVECs, sAT significantly improved cell survival, proliferation, migration and tube formation, promoted the release of VEGF and NO, and increased the expression of VEGF, VEGFR2, PLCγ1, ERK1/2, Src and eNOS. Surprisingly, the effect of sAT on angiogenesis was inhibited by Src siRNA and PLCγ1 siRNA in OGD/R HUVECs. ConclusionThe results proved that sAT promotes angiogenesis in cerebral ischemia-reperfusion mice and its mechanism is to regulate VEGF/VEGFR2 and then regulate Src/eNOS and PLCγ1/ERK1/2.

Artificial intelligence and radiation effects on brain tissue in glioblastoma patient: preliminary data using a quantitative tool.

The quantification of radiotherapy (RT)-induced functional and morphological brain alterations is fundamental to guide therapeutic decisions in patients with brain tumors. The magnetic resonance imaging (MRI) allows to define structural RT-brain changes, but it is unable to evaluate early injuries and to objectively quantify the volume tissue loss. Artificial intelligence (AI) tools extract accurate measurements that permit an objective brain different region quantification. In this study, we assessed the consistency between an AI software (Quibim Precision® 2.9) and qualitative neruroradiologist evaluation, and its ability to quantify the brain tissue changes during RT treatment in patients with glioblastoma multiforme (GBM). GBM patients treated with RT and subjected to MRI assessment were enrolled. Each patient, pre- and post-RT, undergoes to a qualitative evaluation with global cerebral atrophy (GCA) and medial temporal lobe atrophy (MTA) and a quantitative assessment with Quibim Brain screening and hippocampal atrophy and asymmetry modules on 19 extracted brain structures features. A statistically significant strong negative association between the percentage value of the left temporal lobe and the GCA score and the left temporal lobe and the MTA score was found, while a moderate negative association between the percentage value of the right hippocampus and the GCA score and the right hippocampus and the MTA score was assessed. A statistically significant strong positive association between the CSF percentage value and the GCA score and a moderate positive association between the CSF percentage value and the MTA score was found. Finally, quantitative feature values showed that the percentage value of the cerebro-spinal fluid (CSF) statistically differences between pre- and post-RT. AI tools can support a correct evaluation of RT-induced brain injuries, allowing an objective and earlier assessment of the brain tissue modifications.

Sanwei DouKou Decoction ameliorate Alzheimer disease by increasing endogenous neural stem cells proliferation through the Wnt/β-catenin signalling pathway.

Sanwei DouKou decoction (SDKD) is a traditional Chinese medicine (TCM) prescription derived from the Tibetan medical book "Si Bu Yi Dian" and is clinically used for the treatment of Alzheimer's disease (AD). However, the potential mechanism of SDKD treatment for AD remains elusive. This study aims to explore the potential mechanism by which SDKD alleviates AD. Extracts of SDKD were identified with Gas chromatograph-mass spectrometer (GC-MS). 5×FAD mice were treated with SDKD for 8 weeks. The efficacy of SDKD against AD was evaluated by in-vivo experiments. Morris water maze and contextual fear conditioning tests were used to detect the learning and memory ability of mice. Hematoxylin-eosin staining (H&E) staining was used to observe the pathological changes of brain tissue. Immunohistochemistry was used to detect the positive expression of Nestin in hippocampus. In in-vitro experiments, the Cell Counting Kit 8 (CCK-8) technique was used to detect cell viability, the proliferation of neural stem cells was detected by immunofluorescence staining, the intracellular protein expression was detected by Western Blot. The results of this study suggested that SDKD may ameliorate AD. SDKD significantly shortened the escape latency of mice in the Morris water maze experiment, increased the number of times the mice crossed the target quadrant, and prolonged freezing time in the contextual fear memory experiment. SDKD also improved neuronal pathology in the hippocampus, decreased neuronal loss, and increased Nestin protein levels. Furthermore, in in-vitro experiments, SDKD could significantly increase Neural stem cells (NSCs) viability, promoted NSCs proliferation, and also effectively activated the Wnt/β-catenin signalling pathway, increased Wnt family member 3A (Wnt3a), β-catenin and CyclinD1 protein levels, activated the NSCs proliferation pathways in AD model mouse brain tissue. The present study demonstrated that sanwei doukou decoction can ameliorate AD by increasing endogenous neural stem cells proliferation through the Wnt/β-catenin signalling pathway. Our observations justify the traditional use of SDKD for a treatment of AD in nervous system.

Changes in Brain Tissue Following Administration of Adipose-Derived Stem Cells

Changes in Brain Tissue Following Administration of Adipose-Derived Stem Cells

TIMP2 facilitates CIRI through activating NLRP3-mediated pyroptosis.

This study aimed to investigate the underlying mechanisms of cerebral ischemia-reperfusion injury (CIRI) in mice using CIR and hypoxia/reoxygenation (H/R) cell models. The study evaluated brain tissue weight, pathological injury, and changes in the expression levels of TIMP2, p-ERK1/2 and NLRP3-mediated pyroptosis-related proteins in brain tissues and hippocampal neurons of CIR mice using established methods such as dry/wet weight measurement, HE staining, qPCR, TUNEL assay, and Western blotting. The results demonstrated a significant increase in brain water content and neuronal apoptosis rate in the experimental groups compared with those in the control group. In particular, the I/R+TIMP2 group showed the highest increase. Additionally, the control group exhibited a clear brain tissue structure, neatly and densely arranged cells with normal morphology, and evenly stained and clear hippocampal tissues. However, the I/R group showed hippocampal structure disorders, interstitial edema, deep nuclear staining, karyopyknosis, and karyorrhexis in brain tissues. The study results further revealed that TIMP2 could aggravate the pathological damage of brain tissues in the I/R+TIMP2 group compared with the I/R group and significantly reduced it in the TIMP2-KD group. Furthermore, the Western blotting results demonstrated that the protein expression levels of TIMP2, p-ERK1/2, t-ERK1/2, NLRP3, IL-1β, IL-18, GSDMD, Caspase-1, and ASC in brain tissues and hippocampal neurons were significantly higher in the experimental groups than those in the control group. The I/R+TIMP2 group displaying the highest increase and the TIMP2-KD group showing a significant decrease. In conclusion, TIMP2 can contribute to the occurrence and progression of CIRI by activating NLRP3-mediated pyroptosis.

Characterizing the penumbras of white matter hyperintensities in patients with cerebral small vessel disease

PurposeThe white matter hyperintensity penumbra (WMH-P) is the subtly changed normal-appearing white matter (NAWM) that surrounds white matter hyperintensities (WMHs). The goal of this study was to define WMH-P in cerebral small vessel disease (CSVD) by arterial spin labeling (ASL) and diffusion tensor imaging (DTI)/diffusion kurtosis imaging (DKI).Materials and methodsWe prospectively analyzed 42 patients with CSVD. To determine the range of cerebral blood flow (CBF) and DTI/DKI penumbras around white matter hyperintensities, we generated NAWM layer masks from periventricular WMHs (PVWMHs) and deep WMHs (DWMHs). Mean values of CBF, fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity, mean kurtosis, axial kurtosis, and radial kurtosis within the WMHs and their corresponding NAWM layer masks were analyzed. Paired sample t tests were used for analysis, and differences were considered statistically significant if the associated p value was ≤ 0.05.ResultsFor DWMHs, the CBF penumbras were 13 mm, and the DTI/DKI penumbras were 8 mm. For PVWMHs, the CBF penumbras were 14 mm, and the DTI/DKI penumbras were 14 mm.ConclusionsOur findings revealed that DTI/DKI and ASL can show structural and blood flow changes in brain tissue surrounding WMHs. In DWMHs, the blood flow penumbra was larger than the structural penumbra, while in PVWMHs, the blood flow penumbra was almost the same as the structural penumbra.

Characterization of diffusion MRI using the mean apparent propagator model in hemodialysis patients: A pilot study

To better understand documented cognitive decline in hemodialysis (HD) patients, diffusion MRI (dMRI) has been used to characterize brain anatomical deficits relative to controls. Studies to this point have primarily used diffusion tensor imaging (DTI) to model the three-dimensional diffusion of water in HD patients, with DTI parameters reflecting underlying microstructural changes of brain tissue. Since DTI has some limitations in characterizing tissue microstructure, some of which may be complicated by HD, we explored the use of the mean apparent propagator (MAP) model to describe diffusion in HD patients. We collected anatomical T1 and T2 FLAIR MRIs as well as multi-shell dMRI in ten HD participants and ten age-matched controls. The T1 and T2 FLAIR MRIs were used for tissue segmentation and identification of white matter hyperintensity, respectively. Multi-shell dMRI data were used to estimate MAP and DTI diffusion models. Each model was then used to characterize the differences between the HD cohort and the age-matched controls in normal appearing white matter, subcortical gray matter, corpus callosum (CC) and bilateral radiata (Rad). As expected, parameters of both DTI and MAP models of dMRI were significantly different in HD participants compared to controls. However, some MAP parameters suggested additional tissue microstructural changes in HD participants, such as increased axonal diameter. Measurements of non-Gaussianity indicated that MAP provided better a diffusion estimate than DTI, and MAP appeared to provide a more accurate measure of anisotropy in Rad, based on measures of the Rad/CC ratio. In conclusion, parameters of the MAP and DTI models were both sensitive to changes in diffusivity in HD participants compared to controls; however, the MAP model appeared to provide additional detailed information about changes in brain tissue microstructure.

Platycodin D stimulates AMPK activity to inhibit the neurodegeneration caused by reactive oxygen species-induced inflammation and apoptosis.

Alzheimer's disease (AD) was considered to be a neurodegenerative disease that caused cognitive impairment. Reactive Oxidative stress (ROS) was considered to be one of a major cause of the onset and progression of AD. Platycodin D (PD), a representative saponin from Platycodon grandiflorum, has conspicuous antioxidant activity. However, whether PD could protect nerve cell against oxidative injury remains unknown. This study investigated the regulatory effects of PD on neurodegeneration caused by ROS. To determine whether PD could play its own antioxidant role in neuronal protection. First, PD(2.5, 5mg/kg) ameliorated the memory impairment induced by AlCl3 (100mg/kg) combined with D-galactose (D-Gal) (200mg/kg) in mice, using the radial arm maze (RAM) test, and neuronal apoptosis in the hippocampus was evaluated by hematoxylin and eosin staining (HE). Next, the effects of PD (0.5, 1, and 2μM) on okadaic-acid (OA) (40nM) -induced apoptosis and inflammation of HT22cells were investigated. Mitochondrial ROS production was measured by fluorescence staining. The potential signaling pathways were identified through Gene Ontology enrichment analysis. The role of PD in regulating AMP-activated protein kinase (AMPK) was assessed using siRNA silencing of genes and an ROS inhibitor. In vivo, PD improved memory in mice, and recovered the morphological changes of brain tissue and nissl bodies. In vitro experiment, PD increased cell viability (p<0.01; p<0.05;p<0.001), decreased apoptosis (p<0.01), reduced excessive ROS and MDA, rised SOD and CAT content(p<0.01; p<0.05). Morover, it can block the inflammatory response caused by ROS. Be important, PD strengthen antioxidant ability by elevating AMPK activation both in vivo and in vitro. Furthermore, molecular docking suggested a good likelihood of PD-AMPK binding. AMPK activity is vital for the neuroprotective effect of PD, suggesting that PD may be a potential pharmaceutical agent to treat ROS-induced neurodegeneration.

Dihydromyricetin suppresses inflammatory injury in microglial cells to improve neurological behaviors of Alzheimer's disease mice via the TLR4/MD2 signal.

We analyzed the role and mechanism of dihydromyricetin (DHM) in suppressing inflammatory injury in microglial cells via targeting MD2. In vitro, BV2 cells were used as the objects of study to induce inflammatory injury with LPS+ATP, then the cell apoptosis level was identified, inflammatory factor levels were measured by ELISA, TLR4 and MD2 were stained with fluorescence staining, and protein expression was determined using Western-blot (WB) assay. Afterwards, MD2 expression was knocked down n BV2 cells to construct the BV2-MD2-/- cell line, so as to detect the role of DHM on BV2-MD2-/-. Moreover, the binding of DHM to MD2 was analyzed via mall molecule-protein docking and pull-down assays. In-vivo, wild-type (WT) C67BL/6 mice and APP/PS1 (AD) mice were used as the objects of study, which were intervened with DHM to detect the changes in mouse cognition. In addition, the pathological changes of brain tissues were analyzed with H&E staining. In addition, the inflammatory factor and protein levels in brain tissues were also detected. DHM suppressed inflammatory injury in BV2 cells, reduced the cell apoptosis rate and inflammatory factor levels, and suppressed the level of TLR4 and MD2. After MD2 knockdown, DHM was unable to further suppress BV2 cell injury. Results of small molecule-protein docking and pull-down assays suggested that DHM bound to MD2 to suppress the formation of TLR4 complex. In AD mice, DHM improved the cognitive disorder in mice, suppressed inflammatory injury in brain tissues and lowered the expression of TLR4 protein. DHM targeted MD2 to suppress the formation of TLR4 protein complex, thereby suppressing inflammatory injury in microglial cells and improving the cognition in AD mice.

CSF metabolomics alterations after aneurysmal subarachnoid hemorrhage: what do we know?

The purpose of this mini review is to describe metabolomics in cerebrospinal fluid (CSF) and its potential in aneurysmal subarachnoid hemorrhage (aSAH). In brain injury, patients' micro dialysis enables detecting biochemical change in brain tissue. Indicators for ischemia were detected such as lactate, pyruvate, glucose, and glutamate. In aSAH patients, the pathophysiology and the factor for poor outcome are not completely understood yet. Routine use of biomarkers in CSF, particularly in aSAH patients, is still lacking. This mini review was performed on the role of metabolomics alterations after aneurysmal subarachnoid hemorrhage. We identified five clinical studies that addressed metabolomics in patients with aneurysmal subarachnoid hemorrhage. There is increasing evidence suggesting that biomarkers can give insight in the pathogenesis and can serve as an outcome predictor. In this mini review, we present a brief overview of metabolomics profiling in neuroscience and wish to discuss the predictive and therapeutic value in aSAH patients.

Standardized extract of Sanguisorba minor attenuates injury in aging rat model via the Nrf2/HO‑1 pathway.

Aging promotes damage to vulnerable organs like brain and liver. Sanguisorba minor has been traditionally used to cure various ailments. Few studies have reported pharmacological activities of this medicinal plant. This research aimed to investigate the effects of Sanguisorba minor extract (SME) on brain and liver injury in aging rats and identify the underlying mechanisms. The aging model was developed by subcutaneously injecting D‑galactose and simultaneously treating them with SME. After biochemical and pathological assessments, mRNA expression levels of nuclear factor‑erythroid factor 2‑related factor 2 (Nrf2) and Nrf2‑ regulated gene, heme oxygenase‑1 (HO‑1), in the brain and liver tissues were determined. As a result, malondialdehyde and acetylcholinesterase levels were elevated while total thiol content and superoxide dismutase were reduced in the aging rats. Treatment with the extract remarkably attenuated oxidative injury and pathological changes in liver and brain tissues. Concomitantly, the extract up‑regulated Nrf2 and HO‑1 genes. Our findings exhibited SME may improve the aging‑related brain and liver damage through the Nrf2‑HO‑1 pathway.

Comparison of differential metabolites in brain tissue of aged marmosets and serum of elderly patients after prolonged anesthesia.

To compare the differential metabolites in the brain tissue of aged marmosets after long-term anesthesia (≥ 6 h) and the serum of elderly patients by metabolomics methods. Six aged marmosets (≥ 8 years old) were divided into two groups: anesthesia and control. The aged monkeys in the anesthesia group were induced with 6-8% sevoflurane and 100% oxygen (2 l/min) for 1-2 min and maintained with 1.5-2.5% sevoflurane and 100% oxygen (2 l/min) for 6 h. In the control group (n = 3), anesthesia was only induced under the same conditions for 1-2 min. The prefrontal cortex tissues of the two groups of aged marmosets were collected for metabolomics detection. Twenty-nine elderly patients (≥ 65 years old) who had undergone surgical anesthesia for more than 6 h were enrolled. Serum samples were collected before and on the first day after surgery for metabolomics analysis. Differential metabolites were compared between human serum and marmoset brain tissue. The changes in lactate and xanthurenic acid in the serum of elderly patients were consistent with those in the brain tissue of aged marmoset monkeys, that is, lactate was up-regulated and xanthurenic acid was down-regulated. However, serum levels of 5-methylterahydrofolic acid and leucine were down-regulated in elderly patients after anesthesia. In contrast, 5-methylterahydrofolic acid and leucine levels were up-regulated in the prefrontal cortex of aged marmosets compared with control marmosets. Furthermore, glycolysis/gluconeogenesis and pentose phosphate pathway were both significantly enriched in the prefrontal cortex of aged marmosets and serum of elderly patients after surgery. The changes of serum metabolites in elderly patients are not exactly the same as the metabolic changes of brain tissues in aged marmosets. The metabolic changes in serum lactate and xanthurenic acid levels can reflect brain tissue metabolism. The enrichment pathways of differential metabolites in the serum of elderly patients and the brain tissue of aged marmosets were partially the same.

Neuroprotective Effect of Vitamin D on Behavioral and Oxidative Parameters of Male and Female Adult Wistar Rats Exposed to Mancozeb (manganese/zinc ethylene bis-dithiocarbamate)

The constant exposure of rural workers to pesticides is a serious public health problem. Mancozeb (MZ)is a pesticide linked to hormonal, behavioral, genetic, and neurodegenerative effects, mainly related to oxidative stress. Vitamin D is a promising molecule that acts as a protector against brain aging. This study aimed to evaluate the neuroprotective role of vitamin D in adult male and female Wistar rats exposed to MZ. Animals received 40mg/kg of MZ i.p. and 12.5μg/kg or 25μg/kg vitamin D by gavage, twice a week, for 6weeks. The concentration of manganese had a significant increase in the hippocampus of both sexes and in the striatum of females, unlike zinc, which did not show a significant increase. MZ poisoning led to mitochondrial changes in brain tissues and promoted anxiogenic effects, especially in females. Alterations in antioxidant enzymes, mainly in the catalase activity were observed in intoxicated rats. Taken together, our results showed that exposure to MZ leads to the accumulation of manganese in brain tissues, and the behavior and metabolic/oxidative impairment were different between the sexes. Furthermore, the administration of Vitamin D was effective in preventing the damage caused by the pesticide.

Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia

Recent postmortem transcriptomic studies of schizophrenia (SCZ) have shown hundreds of differentially expressed genes. However, the extent to which these gene expression changes reflect antipsychotic drug (APD) exposure remains uncertain. We compared differential gene expression in the prefrontal cortex of SCZ patients who tested positive for APDs at the time of death with SCZ patients who did not. APD exposure was associated with numerous changes in the brain transcriptome, especially among SCZ patients on atypical APDs. Brain transcriptome data from macaques chronically treated with APDs showed that APDs affect the expression of many functionally relevant genes, some of which show expression changes in the same directions as those observed in SCZ. Co-expression modules enriched for synaptic function showed convergent patterns between SCZ and some of the APD effects, while those associated with inflammation and glucose metabolism exhibited predominantly divergent patterns between SCZ and APD effects. In contrast, major cell-type shifts inferred in SCZ were primarily unaffected by APD use. These results show that APDs may confound SCZ-associated gene expression changes in postmortem brain tissue. Disentangling these effects will help identify causal genes and improve our neurobiological understanding of SCZ.

Bombyx Batryticatus extract promotes microglia polarization to improve neuron injury and behaviors of cerebral ischemia/reperfusion rats

This study aims to investigate the effect of Bombyx Batryticatus extract(BBE) on behaviors of rats with global cerebral ischemia reperfusion(I/R) and the underlying mechanism. The automatic coagulometer was used to detect the four indices of human plasma coagulation after BBE intervention for quality control of the extract. Sixty 4-week-old male SD rats were randomized into sham operation group(equivalent volume of normal saline, ip), model group(equivalent volume of normal saline, ip), positive drug group(900 IU·kg~(-1) heparin, ip), and low-, medium-, and high-dose BBE groups(0.45, 0.9, and 1.8 mg·g~(-1)·d~(-1) BBE, ip). Except the sham operation group, rats were subjected to bilateral common carotid artery occlusion followed by reperfusion(BCCAO/R) to induce I/R. The administration lasted 7 days for all the groups. The behaviors of rats were examined by beam balance test(BBT). Morphological changes of brain tissue were observed based on hematoxylin-eosin(HE) staining. Immunofluorescence method was used to detect common leukocyte antigen(CD45), leukocyte differentiation antigen(CD11b), and arginase-1(Arg-1) in cerebral cortex(CC). The protein expression of interleukin-1β(IL-1β), interleukin-4(IL-4), interleukin-6(IL-6), and interleukin-10(IL-10) was detected by enzyme-linked immunosorbent assay(ELISA). The non-targeted metabonomics was employed to detect the levels of metabolites in plasma and CC of rats after BBE intervention. The results of quality control showed that the BBE prolonged the activated partial thromboplastin time(APTT), prothrombin time(PT), and thrombin time(TT) of human plasma, which was similar to the anticoagulation effect of BBE obtained previously. The results of behavioral test showed that the BBT score of the model group increased compared with that of the sham operation group. Compared with the model group, BBE reduced the BBT score. As for the histomorphological examination, compared with the sham operation group, the model group showed morphological changes of a lot of nerve cells in CC. The nerve cells with abnormal morphology in CC decreased after the intervention of BBE compared with those in the model group. Compared with the sham operation group, the model group had high average fluorescence intensity of CD45 and CD11b in the CC. The average fluorescence intensity of CD11b decreased and the average fluorescence intensity of Arg-1 increased in CC in the low-dose BBE group compared with those in the model group. The average fluorescence intensity of CD45 and CD11b decreased and the average fluorescence intensity of Arg-1 increased in medium-and high-dose BBE groups compared with those in the model group. The expression of IL-1β and IL-6 was higher and the expression of IL-4 and IL-10 was lower in the model group than in the sham operation group. The expression of IL-1β and IL-6 was lower and the expression of IL-4 and IL-10 was higher in the low-dose, medium-dose, and high-dose BBE groups than in the model group. The results of non-targeted metabonomics showed that 809 metabolites of BBE were identified, and 57 new metabolites in rat plasma and 45 new metabolites in rat CC were found. BBE with anticoagulant effect can improve the behaviors of I/R rats, and the mechanism is that it promotes the polarization of microglia to M2 type, enhances its anti-inflammatory and phagocytic functions, and thus alleviates the damage of nerve cells in CC.

Time-course effects and mechanisms of hypobaric hypoxia on nervous system in mice

ObjectiveThe aim of this study was to investigate the effect of time course on neurological impairment after acute hypobaric hypoxia exposure in mice and clarify the mechanism of acclimatization, so as to provide a suitable mice model and identify potential target against hypobaric hypoxia for further drug research. MethodMale C57BL/6J mice were exposed to hypobaric hypoxia at a simulated altitude of 7000 m for 1, 3, and 7 days (1HH, 3HH and 7HH respectively). The behavior of the mice was evaluated by novel object recognition (NOR) and morris water maze test (MWM), then, the pathological changes of mice brain tissues were observed by H&E and Nissl staining. In addition, RNA sequencing (RNA-Seq) was performed to characterize the transcriptome signatures, and enzyme-linked immunosorbent assay (ELISA), Real-time polymerase chain reaction (RT-PCR), and western blot (WB) were used to verify the mechanisms of neurological impairment induced by hypobaric hypoxia. ResultThe hypobaric hypoxia condition resulted in impaired learning and memory, decreased new object cognitive index, and increased escape latency to the hidden platform in mice, with significant changes seen in the 1HH and 3HH groups. Bioinformatic analysis of RNA-seq results of hippocampal tissue showed that 739 differentially expressed genes (DEGs) appeared in the 1HH group, 452 in the 3HH group, and 183 in the 7HH group compared to the control group. There were 60 key genes overlapping in three groups which represented persistent changes and closely related biological functions and regulatory mechanisms in hypobaric hypoxia-induced brain injuries. DEGs enrichment analysis showed that hypobaric hypoxia-induced brain injuries were associated with oxidative stress, inflammatory responses, and synaptic plasticity. ELISA and WB results confirmed that these responses occurred in all hypobaric hypoxic groups while attenuated in the 7HH group. VEGF-A-Notch signaling pathway was enriched by DEGs in hypobaric hypoxia groups and was validated by RT-PCR and WB. ConclusionThe nervous system of mice exposed to hypobaric hypoxia exhibited stress followed by gradual habituation and thus acclimatization over time, which was reflected in the biological mechanism involving inflammation, oxidative stress, and synaptic plasticity, and accompanied by activation of the VEGF-A-Notch pathway.

Puerarin protects against sepsis-associated encephalopathy by inhibiting NLRP3/Caspase-1/GSDMD pyroptosis pathway and reducing blood-brain barrier damage

Puerarin (Pue), an isoflavone compound extracted from Pueraria, has been shown to inhibit inflammation and reduce cerebral edema. The neuroprotective effect of puerarin has attracted much attention in recent years. Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that causes damage to the nervous system. This study aimed to investigate the effect of puerarin on SAE and elucidate the potential underlying mechanisms. A rat model of SAE was established by cecal ligation and puncture, and puerarin was injected intraperitoneally immediately after the operation. Puerarin was found to improve the survival rate and neurobehavioral score of SAE rats, alleviate symptoms, inhibit the level of brain injury markers NSE and S100β, and improve the pathological changes in rat brain tissue. Puerarin was also found to inhibit the level of factors related to the classical pathway of pyroptosis, such as NLRP3, Caspase-1, GSDMD, ASC, IL-1β, and IL-18. Puerarin also reduced the brain water content and penetration of Evan’s Blue dye in SAE rats, and reduced the expression of MMP-9. In the in vitro experiments, we further confirmed the inhibitory effect of puerarin on neuronal pyroptosis by establishing a pyroptosis model in HT22 cells. Our findings suggest that puerarin may improve SAE by inhibiting the classical pathway of NLRP3/Caspase-1/GSDMD-mediated pyroptosis and reducing blood-brain barrier damage, thus playing a role in brain protection. Our study may provide a novel therapeutic strategy for SAE.