Brain Research最新文献

Ischemic stroke, caused by diminished or interrupted cerebral blood flow, triggers the activation of microglial cells and subsequent inflammatory responses. Formononetin (FMN) has been observed to inhibit BV2 microglial cell activation and alleviate ensuing neuroinflammatory reactions. Despite extensive research, the precise underlying mechanism remains unclear. To investigate the neuroinflammatory response following FMN-mediated inhibition of BV2 microglial activation, we employed an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model. BV2 microglial cells were categorized into four groups: control, FMN, OGD/R, and OGD/R+FMN. Cell viability was assessed using the CCK-8 assay, while flow cytometry assessed M1 and M2 cell populations within BV2 cells. Immunofluorescence was utilized to detect the expression levels of apoptosis-inducing factor (AIF), p53, Toll-like receptor 4 (TLR4), and NF-κB p65. Western blotting (WB) was conducted to quantify p65/p-p65, IκB-α/p-IκB-α, and TLR4 protein levels in each group. Additionally, ELISA was employed to measure IL-1β and TNF-α levels in cell supernatants from each group. The results revealed a significant increase in the proportion of iNOS/CD206-positive M1/M2 cells in the OGD/R group compared to the control group (p < 0.05). There was also a notable increase in nuclear translocation of NF-κB p65 and elevated expression of inflammatory factors IL-1β and TNF-α in cell supernatants. Moreover, levels of p-p65, p-IκB-α, and TLR4 proteins were significantly elevated in the OGD/R group (p < 0.05). However, the addition of FMN reversed these effects. Specifically, FMN administration notably attenuated cell death and inflammation in BV2 microglia induced by OGD/R through modulation of the TLR4/NF-κB signaling pathway.These findings suggest that FMN may serve as a potential therapeutic agent against neuroinflammation associated with ischemic stroke by targeting microglial activation pathways.

Irisin is a glycosylated protein formed from the hydrolysis of fibronectin type III domain-containing protein 5 (FNDC5). Irisin is widely involved in the regulation of glucose and lipid metabolism. In addition, recent studies have demonstrated that Irisin can inhibit inflammation, restrain oxidative stress and have neuroprotective effects, which suggests that Irisin may have a good therapeutic effect on central nervous system diseases. Therefore, this review summarizes the role of Irisin in central nervous system diseases, including its signal pathways and possible mechanisms, etc. Irisin may be a potential candidate drug for the treatment of central nervous system diseases.

Neuroinflammation caused by the chronic periodontal pathogen Porphyromonas gingivalis is growing regarded as as a key factor in the pathogenesis of Alzheimer’s disease (AD). Alantolactone (AL), a sesquiterpene lactone isolated from the root of Inula racemosa Hook. f, has been proven to provide various neuroprotective effects. However, whether AL can improve cognitive impairment caused by P. gingivalis infection remains unclear. In this research, a rat model of P. gingivalis infection was used to examine the neuroprotective benefits of AL. The results revealed that 6 weeks of AL treatment (50 and 100 mg/kg) shortened escape latency and increased the number of crossings over the platform location and time spent in the target quadrant of P. gingivalis-infected rats in the Morris water maze experiment. By activating the Nrf2/HO-1 pathway, AL suppressed malondialdehyde (MDA) levels and simultaneously increased the activity of total superoxide dismutase (T-SOD). Furthermore, AL lowered the presence of IL-6, IL-1β, and TNFα in the hippocampal and cortical tissues of P. gingivalis-infected rats by inhibiting astrocyte and microglial activation and NF-κB phosphorylation. AL also significantly reduced Aβ levels in the cortical and hippocampus tissues of rats infected with P. gingivalis. In conclusion, AL improved cognitive impairment in P. gingivalis-infected rats by inhibiting neuroinflammation, reducing Aβ1-42 level, and exerting antioxidative stress effects.

Background

Observational studies have reported changes in the brain white matter (WM) microstructure in patients with inflammatory bowel disease (IBD); however, it remains uncertain whether the relationship between them is causative. The aim of this study is to reveal the potential causal relationship between IBD and WM microstructure through a bidirectional two-sample Mendelian randomization (MR) analysis. Methods: We extracted genome-wide association study (GWAS) summary statistics for IBD and WM microstructure from published GWASs. Two-sample MR analysis was conducted to explore the bidirectional causal associations between IBD and WM microstructure, followed by a series of sensitivity analyses to assess the robustness of the results. Results: Although forward MR analysis results showed no evidence of causality from microstructural WM to IBD, reverse MR showed that genetically predicted IBD, consisting of ulcerative colitis and Crohn’s disease, has a significant causal effect on the orientation dispersion index (OD) of the right tapetum (β = −0.029, 95% CI = −0.045 to −0.013, p = 3.63 × 10⁻⁴). Further sensitivity analysis confirmed the robustness of the association. Conclusion: Our results suggested the potentially causal association of IBD with reduced OD in the right tapetum.

Previous studies have indicated a close association between cognitive impairment in patients with neurodegenerative diseases, such as Alzheimer’s disease (AD), and synaptic damage. Diazepam (DZP), a benzodiazepine class drug, is used to control symptoms such as seizures, anxiety, and sleep disorders. These symptoms can potentially manifest throughout the entire course of AD. Therefore, DZP may be utilized in the treatment of AD to manage these symptoms. However, the specific role and mechanisms of DZP in AD remain unclear. In this study, we discovered that long-term administration of a low dose of DZP (0.5  mg/kg) improved cognitive function and protected neurons from damage in APP/PS1 mice. Mechanistic investigations revealed that DZP exerted its neuroprotective effects and reduced Aβ deposition by modulating GluA1 (glutamate AMPA receptor subunit) to influence synaptic function. In conclusion, these findings highlight the potential benefits of DZP as a novel therapeutic approach, suggesting that long-term use of low-dose DZP in early-stage AD patients may be advantageous in slowing disease progression.

Depression and concussion are highly prevalent neuropsychological disorders that often occur simultaneously. However, due to the high degree of symptom overlap between the two events, including but not limited to headache, sleep disturbances, appetite changes, fatigue, and difficulty concentrating, they may be treated in isolation. Thus, clinical awareness of additive symptom load may be missed. This study measures neuropsychological and electroencephalography (EEG) alpha band coherence differences in collegiate student-athletes with history of comorbid depression and concussion, in comparison to those with a single morbidity and healthy controls (HC). 35 collegiate athletes completed neuropsychological screenings and EEG measures. Participants were grouped by concussion and depression history. Differences in alpha band coherence were calculated using two-way ANOVA with post hoc correction for multiple comparisons. Comorbid participants scored significantly worse on neuropsychological screening, BDI-FS, and PCSS than those with a single morbidity and HC. Two-way ANOVA by group revealed significant main effects of alpha band coherence for concussion, depression, and their interaction term. Post-hoc analysis showed that comorbid participants had more abnormal alpha band coherence than single morbidity, when compared to HC. Comorbidity of concussion and depression increased symptom reporting and revealed more altered alpha band coherence than single morbidity, compared to HC. The abnormalities of the comorbid group exclusively showed decreased alpha band coherence in comparison to healthy controls. The comorbidity of depression and SRC has a compounding effect on depression symptoms, post-concussion symptoms, and brain functional connectivity. This research demonstrates a promising objective measure in comorbid individuals, previously only measured via subjective symptom reporting.

Parkinson’s disease (PD) is indeed a complex neurodegenerative disorder recognized by the progressive depletion of dopaminergic neurons in the brain, particularly in the substantia nigra region, leading to motor impairments and other symptoms. But at the molecular level, the study about PD still lacks. As the number of cases worldwide continues to increase, it is critical to focus on the cellular and molecular mechanisms of the disease’s presentation and neurodegeneration to develop novel therapeutic approaches. At the molecular level, the complexity is more due to the involvement of vacuolar protein sorting 35 (VPS35) and sonic hedgehog (SHH) signaling in PD (directly or indirectly), leading to one of the most prominent hallmarks of the disease, which is an accumulation of α-synuclein. This elevated pathogenesis may result from impaired autophagy due to mutation in the case of VPS35 and impairment in SHH signaling at the molecular level. The traditional understanding of PD is marked by the disruption of dopaminergic neurons and dopaminergic signaling, which exacerbates symptoms of motor function deficits. However, the changes at the molecular level that are being disregarded also impact the overall health of the dopaminergic system. Gaining insight into these two unique mechanisms is essential to determine whether they give neuroprotection or have no effect on the health of neurons. Hence, here we tried to simplify the understanding of the role of VPS35 and SHH signaling to comprehend it in one direction.

Neurodegeneration is a progressive event leading to specific neuronal loss due to the accumulation of aberrant proteins. These pathologic forms of proteins further worsen and interfere with normal physiologic mechanisms, which can lead to abnormal proliferation of immune cells and subsequent inflammatory cascades and ultimately neuronal loss. Recently, immunotherapies targeting abnormal, pathologic forms of protein have shown a promising approach to modify the progression of neurodegeneration. Recent advances in immunotherapy have led to the development of novel antibodies against the proteinopathies which can eradicate aggregations of protein as evident from preclinical and clinical studies. Nonetheless, only a few of them have successfully received clinical approval, while others have been discontinued due to a lack of clinical efficacy endpoints. The current review discusses the status of investigational antibodies under clinical trials, their targets for therapeutic action, and evidence for failure or success.

Ischemic stroke is characterized by high morbidity and mortality and a lack of effective therapeutic interventions. Leptin plays an important role in regulating oxidative stress, angiogenesis, hematopoiesis, etc. Although recent studies have found a neuroprotective effect of leptin, little is known about its role in cerebral ischemia. This study explores the possible roles and potential preventative mechanisms of leptin in cerebral ischemia–reperfusion injury (CIRI). An in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model was used to replicate the CIRI model, low (0.5 mg/kg), medium (1 mg/kg) and high (2 mg/kg) concentrations of leptin were injected intraperitoneally immediately after inserting the embolic line. After 1.5 h of ischemia and 24 h of reperfusion, we examined the neural function of the mice, collected brain tissue for histological examination, and screened for the optimal concentrations of leptin intervention. On this basis, we observed the changes of cortical apoptosis injury, intracellular calcium fluorescence intensity and astrocyte glial fibrillary acidic protein (GFAP) expression and morphological changes. In addition, we also tested the expression of transporters and metabolism-related enzymes (VGLUT-1, VGLUT-2, GLAST, GLT-1, GS, ATP1α1), the expression of inflammatory factors and the content of glutamate (Glu). Compared with the I/R group, we found that leptin improved neurological deficits, reduced the area of infarcts, maintained the normal morphology of astrocytes (AST), downregulated the expression of VGLUT-1, and upregulates the expression of GLT-1 and GLAST, thereby reducing the content of Glu in the synaptic cleft. Our studies suggest that leptin may have a neuroprotective effect by decreasing the excitotoxicity of glutamate.

Prenatal infection increases the risk for neurodevelopmental disorders including autism spectrum disorder and schizophrenia. To better understand this link, a number of maternal immune activation (MIA) rodent models have been studied. However, the majority of these studies focus on adult behavioural outcomes that mirror adult symptoms related to neurodevelopmental disorders. There is little research reporting the effects of MIA on early postnatal development and even fewer using outbred mouse strains. Here, we use a modified version of the Fox scale to assess the effects of two MIA models, a bacterial model (LPS) and a viral model (PolyIC), on overall mouse pup sensorimotor development in CD-1 mice. Surprisingly, both bacterial and viral MIA models resulted in early reflex development when compared with control pups. To better characterize potential factors related to these changes, we examined indicators of sickness/inflammation in the immune-activated dams and in their pups. Sickness behaviour in the dams resulting from immune activation was assessed using a telemetry implant that allowed for continuous recording of temperature and activity in dams exposed to bacterial or viral immune activation. Although MIA dams showed reduced activity on the day immediately following MIA compared to controls, there was no evidence of fever. All dams showed elevated cytokines/chemokines associated with parturition, but this resolved by day 10 post-parturition and was unaffected by previous immune activation. Although circulating cytokines/chemokines in the dams were similar across MIA treatments, there were differences in the amount of interleukin-12p70 and interleukin-13 present in milk taken from milk bands in MIA pups, and interleukin-4 was overall decreased in LPS pup brain. These findings demonstrate that bacterial and viral models of MIA can result in similar precocious development in mice but differing long-term effects on inflammatory markers in both the milk provided to the pups and in their brains.