Serum S-100beta as a possible marker of blood-brain barrier disruption

Two brain-specific proteins, S-100β and neuron-specific enolase (NSE), are released systemically after cerebral lesions, but S-100β levels sometimes rise in the absence of neuronal damage. We hypothesized that S-100β is a marker of blood–brain barrier (BBB) leakage rather than of neuronal damage. We measured both proteins in the plasma of patients undergoing iatrogenic BBB disruption with mannitol, followed by chemotherapy. Serum S-100β increased significantly after mannitol infusion (P<0.05) while NSE did not. This suggests that S-100β is an early marker of BBB opening that is not necessarily related to neuronal damage.     

A pilot study on the effects of early use of valproate sodium on neuroinflammation after traumatic brain injury北大核心CSCD

Objective To study the effect of early use of sodium valproate on neuroinflammation after traumatic brain injury (TBI). Methods A total of 45 children who visited in Xuzhou Children's Hospital Affiliated to Xuzhou Medical University from August 2021 to August 2022 were enrolled in this prospective study, among whom 15 healthy children served as the healthy control group, and 30 children with TBI were divided into a sodium valproate treatment group and a conventional treatment group using a random number table (n=15 each). The children in the sodium valproate treatment group were given sodium valproate in addition to conventional treatment, and those in the conventional group were given an equal volume of 5% glucose solution in addition to conventional treatment. The serum concentrations of nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3), high-mobility group box 1 (HMGB1), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) were measured in the healthy control group on the day of physical examination and in the children with TBI on days 1, 3, and 5 after admission. Glasgow Outcome Scale-Extended (GOS-E) score was evaluated for the children with TBI 2 months after discharge. Results Compared with the healthy control group, the children with TBI had significantly higher serum concentrations of NLRP3, HMGB1, TNF- α, and IL-1β on day 1 after admission (P<0.017). The concentration of NLRP3 on day 5 after admission was significantly higher than that on days 1 and 3 after admission in the children with TBI (P<0.017). On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of NLRP3 than the conventional treatment group (P<0.05). For the conventional treatment group, there was no significant difference in the concentration of HMGB1 on days 1, 3, and 5 after admission (P>0.017), while for the sodium valproate treatment group, the concentration of HMGB1 on day 5 after admission was significantly lower than that on days 1 and 3 after admission (P<0.017). On day 5 after admission, the sodium valproate treatment group had a significantly lower concentration of HMGB1 than the conventional treatment group (P<0.05). For the children with TBI, the concentration of TNF-α on day 1 after admission was significantly lower than that on days 3 and 5 after admission (P<0.017). On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of TNF-α than the conventional treatment group (P<0.05). The concentration of IL-1β on day 3 after admission was significantly lower than that on days 1 and 5 after admission (P<0.017) in the children with TBI. On days 3 and 5 after admission, the sodium valproate treatment group had a significantly lower concentration of IL-1β than the conventional treatment group (P<0.05). The GOS-E score was significantly higher in the sodium valproate treatment group than that in the conventional treatment group 2 months after discharge (P<0.05). Conclusions Early use of sodium valproate can reduce the release of neuroinflammatory factors and improve the prognosis of children with TBI. © 2023 Xiangya Hospital of CSU. All rights reserved.     

A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke, but how to control the overactive neuroinflammation is still a long-standing challenge. Here, we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia, which were abolished by silencing SIRT6. RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811 stimulation and is required for the anti-inflammatory effects of MDL-811. We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation. Moreover, our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS, but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery. Importantly, MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients, underlying an interesting translational perspective. Taken together, MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.     

Novel compound FLZ alleviates rotenone-induced PD mouse model by suppressing TLR4/MyD88/NF-κB pathway through microbiota–gut–brain axis

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota–gut–brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood–brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota–gut–brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.     

Microglial dysfunction in brain aging and Alzheimer's disease

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial “activation” and “neuroinflammation” are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.     

从发病机制概述针刺治疗血管性痴呆的研究进展

血管性痴呆是脑血管病变后所引起的认知功能障碍,是临床中较为常见的痴呆类型。其发病机制源于血管系统损害引起低脑血流灌注、氧化应激等一系列病理过程。针灸作为一种非药物疗法,在脑血管病及相关疾病中有较为广泛的临床应用,许多研究都显示了针灸对认知功能的改善作用,并涉及细胞凋亡、氧化应激、神经炎症、神经递质通路等方面的调节作用。因此,现从血管性痴呆的发病机制角度探讨针刺的治疗作用,以期为进一步揭示针灸在血管性痴呆治疗中的潜在机制提供参考。     

“通督启神”针法治疗AD的动物实验研究进展

阿尔茨海默病(AD)是一种以记忆与认知功能障碍为主要临床表现的中枢神经系统退行性疾病,其病因复杂且发病机制尚未明确,具有高发病率、高致残率和高医疗成本的特点,成为当今公共卫生的一大难题。本研究立足于“通督启神”针法治疗AD的基础研究,对近5年“通督启神”针法治疗AD的动物实验相关文献进行整理,从提高脑能量代谢和脑血流量、抑制神经胶质细胞活化和神经炎症反应、良性调节Aβ生成与清除、抗衰老与抗氧化4个方面总结“通督启神”针法的实验效应及作用机制。最后指出未来可结合胆碱能神经、胰岛素信号转导、线粒体结构和功能以及手针、脉冲电针和音乐电针的异同深入研究,为今后“通督启神”针法治疗AD的基础研究提供新的思路与方法。