Neuroinflammatory Mechanisms Research Articles

Repurposing drugs against Alzheimer's disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs.

The Potential Benefits of Quercetin for Brain Health: A Review of Anti-Inflammatory and Neuroprotective Mechanisms.

Neuroinflammation is a critical factor in developing and progressing numerous brain diseases, including neurodegenerative diseases. Chronic or excessive neuroinflammation can lead to neurotoxicity, causing brain damage and contributing to the onset and progression of various brain diseases. Therefore, understanding neuroinflammation mechanisms and developing strategies to control them is crucial for treating brain diseases. Studies have shown that neuroinflammation plays a vital role in the progression of neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD), and stroke. Additionally, the effects of PM2.5 pollution on the brain, including neuroinflammation and neurotoxicity, are well-documented. Quercetin is a flavonoid, a plant pigment in many fruits, vegetables, and grains. Quercetin has been studied for its potential health benefits, including its anti-inflammatory, antioxidant, and anti-cancer properties. Quercetin may also have a positive impact on immune function and allergy symptoms. In addition, quercetin has been shown to have anti-inflammatory and neuroprotective properties and can activate AMP-activated protein kinase (AMPK), a cellular energy sensor that modulates inflammation and oxidative stress. By reducing inflammation and protecting against neuroinflammatory toxicity, quercetin holds promise as a safe and effective adjunctive therapy for treating neurodegenerative diseases and other brain disorders. Understanding and controlling the mechanisms of NF-κB and NLRP3 inflammasome pathways are crucial for preventing and treating conditions, and quercetin may be a promising tool in this effort. This review article aims to discuss the role of neuroinflammation in the development and progression of various brain disorders, including neurodegenerative diseases and stroke, and the impact of PM2.5 pollution on the brain. The paper also highlights quercetin's potential health benefits and anti-inflammatory and neuroprotective properties.

HIPK2 mediates M1 polarization of microglial cells via STAT3: A new mechanism of depression-related neuroinflammation.

This study aimed to investigate the role of protein kinase HIPK2 in depression and its associated mechanism. The chronic unpredictable mild stress (CUSM) model was constructed to simulate mice with depression to detect the mouse behaviors. Moreover, by using mouse microglial cells BV2 as the model. After conditional knockdown of HIPK2, the depressive behavior disorder of mice was improved, meanwhile, neuroinflammation was alleviated, and the M1 cell proportion was reduced. Similar results were obtained after applying the HIPK2 inhibitor tBID or ASO-HIPK2 treatment. HIPK2 was overexpressed in BV2 cells, which promoted M1 polarization of cells, while tBID suppressed the effect of HIPK2 and reduced the M1 polarized level in BV2 cells. Pull-down assay results indicated that HIPK2 bound to STAT3 and promoted STAT3 phosphorylation. We found that HIPK2 can bind to STAT3 to promote its phosphorylation, which accelerates M1 polarization of microglial cells, aggravates the depressive neuroinflammation, and leads to abnormal behaviors. HIPK2 is promising as the new therapeutic target of depression.

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway

Epilepsy is a neurological disease and approximately 30% of patients have failed to respond to current anti-epilepsy drugs. The neuroinflammation mechanism has raised increasing concerns and been regarded as the novel treatment strategy in epilepsy, but the target molecules require further research. Pyruvate kinase isoform 2 (PKM2) is well studied in peripheral inflammation, but its role in epilepsy neuroinflammation remains unclear. We knocked down microglia PKM2 in the hippocampus using a stereotaxic adeno-associated virus (AAV) microinjection and established a pilocarpine-induced status epilepticus (PISE) model. Racine score was used to evaluate the seizure grade. Next, we used WB, Multiplex tyramide signal amplification (TSA) staining and other methods to determine neuroinflammation and the complement component 3 (C3)-C3aR interaction in primary microglia. Results showed that microglia PKM2 knockdown reduced epilepsy grade and rescued neuron loss. Mechanistically, PKM2 knockdown inhibited microglia activation and inflammation factor secretion through suppressing p65 expression and phosphorylation. The reduced microglia C1q, TNF-α, and IL-1α were responsible for the decreased astrocyte C3 expression and the following neuron damage caused by the C3-C3aR interaction. Our data suggest that microglia PKM2 inhibition ameliorates neuroinflammation and neuron loss through C3-C3aR interaction in epilepsy, which provides an attractive target for the intervention of damaged neuron-glia crosstalk in epilepsy.

Modern research progress in external application of traditional Chinese medicine to acupoints

Traditional Chinese medicine(TCM) has a long history and abundant experience in external therapy, which marks human wisdom. In the early history of human, people found that fumigation, coating, and sticking of some tree branches and herb stems can help alleviate scabies and remove parasites in productive labor, which indicates the emergence of external therapy. Pathogen usually enters the body through the surface, so external therapy can be used to treat the disease. External therapy is among the major characteristic of surgery of TCM. As one of the external therapies in TCM, external application to acupoints smooths the zang-fu organs through meridians and collaterals, thereby harmonizing yin and yang. This therapy emerged in the early society, formed the Spring and Autumn Period and the Warring States Period, improved in the Song and Ming dynasties, and matured in the Qing dynasty. With the efforts of experts in history, it has had a mature theory. According to modern research, it can avoid the first-pass effect of liver and the gastrointestinal irritation and improve the bioavailability of Chinese medicine. Based on the effect of Chinese medicine and the theory of meridian and collateral, it can stimulate the acupoints, exert regulatory effect on acupoints, and give full play to the efficacy of TCM and the interaction of the two. Thereby, it can regulate qi and blood and balance yin and yang, thus being widely used in the treatment of diseases. In this paper, the use of external application to acupoints, the effect on skin immunity, the regulation of neuro-inflammatory mechanism, the relationship between acupoint application and human circulation network, and the development of its dosage form were summarized through literature review. On this basis, this study is expected to lay a foundation for further research.

Neuroinflammation related to the blood-brain barrier and sphingosine-1-phosphate in a pre-clinical model of periodontal diseases and depression in rats.

To explore the potential mechanisms of neuroinflammation (microglia, blood-brain barrier [BBB] permeability, and the sphingosine-1-phosphate [S1P] pathways) resulting from the association between periodontitis and depression in rats. This pre-clinical in vivo experimental study used Wistar rats, in which experimental periodontitis (P) was induced by using oral gavages with Porphyromonas gingivalis and Fusobacterium nucleatum. Then, a chronic mild stress (CMS) model was implemented to induce a depressive-like behaviour, resulting in four groups: P with CMS (P+CMS+), P without CMS (P+CMS-), CMS without P (P-CMS+), and control (P-CMS-). After harvesting brain samples, protein/mRNA expression analyses and fluorescence immunohistochemistry were performed in the frontal cortex (FC). Results were analysed by ANOVA. CMS exposure increased the number of microglia (an indicator of neuroinflammation) in the FC. In the combined model (P+CMS+), there was a decrease in the expression of tight junction proteins (zonula occludens-1 [ZO-1], occludin) and an increase in intercellular and vascular cell adhesion molecules (ICAM-1, VCAM-1) and matrix metalloproteinase 9 (MMP9), suggesting a more severe disruption of the BBB. The enzymes and receptors of S1P were also differentially regulated. Microglia, BBB permeability, and S1P pathways could be relevant mechanisms explaining the association between periodontitis and depression.

Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer's Disease Progression.

Aging is the most prominent risk factor for late-onset Alzheimer's disease. Aging associates with a chronic inflammatory state both in the periphery and in the central nervous system, the evidence thereof and the mechanisms leading to chronic neuroinflammation being discussed. Nonetheless, neuroinflammation is significantly enhanced by the accumulation of amyloid beta and accelerates the progression of Alzheimer's disease through various pathways discussed in the present review. Decades of clinical trials targeting the 2 abnormal proteins in Alzheimer's disease, amyloid beta and tau, led to many failures. As such, targeting neuroinflammation via different strategies could prove a valuable therapeutic strategy, although much research is still needed to identify the appropriate time window. Active research focusing on identifying early biomarkers could help translating these novel strategies from bench to bedside.

Neuroinflammation of traumatic brain injury: Roles of extracellular vesicles.

Traumatic brain injury (TBI) is a major cause of neurological disorder or death, with a heavy burden on individuals and families. While sustained primary insult leads to damage, subsequent secondary events are considered key pathophysiological characteristics post-TBI, and the inflammatory response is a prominent contributor to the secondary cascade. Neuroinflammation is a multifaceted physiological response and exerts both positive and negative effects on TBI. Extracellular vesicles (EVs), as messengers for intercellular communication, are involved in biological and pathological processes in central nervous system (CNS) diseases and injuries. The number and characteristics of EVs and their cargo in the CNS and peripheral circulation undergo tremendous changes in response to TBI, and these EVs regulate neuroinflammatory reactions by activating prominent receptors on receptor cells or delivering pro- or anti-inflammatory cargo to receptor cells. The purpose of this review is to discuss the possible neuroinflammatory mechanisms of EVs and loading in the context of TBI. Furthermore, we summarize the potential role of diverse types of cell-derived EVs in inflammation following TBI.

Correction of gut dysbiosis as a promising direction in the prevention of neuroinflammation and cognitive impairment

In recent years new data have been obtained on the role of intestinal dysbiosis in the pathogenesis mechanisms of neuroinflammation and neurodegeneration in Alzheimer's disease (AD), as well as on the influence of dietary patterns (Mediterranean diet, MIND diet) and probiotics on the correction of dysbiosis and slowing down the development of cognitive disorders. It seems reasonable to draw the attention of practicing physicians to the need to prevent cognitive dysfunction through dietary correction, probiotics and prebiotics intake. The purpose of the research was to study the possibility of using certain dietary patterns, as well as intake of probiotics and prebiotics for the correction of dysbiosis and early prevention of cognitive dysfunction, basing on the analysis of published data on the bidirectional communication between the colon microbiota and the brain and microbiota changes in patients with cognitive dysfunction and AD. Material and methods. We searched domestic and foreign literature devoted to gut microbiota, the "gut-brain" axis, microbiota disorders in AD patients; mechanisms of neuroinflammation and neurodegeneration; the role of dietary patterns, in particular MIND diet, pre- and probiotics in the prevention of cognitive dysfunction - via PubMed search engine, SemanticScholar Google Internet search platform and domestic scientific electronic library Cyberleninka. 72 literature sources were analyzed. Results. Intestinal dysbiosis and disruption of intestinal barrier integrity play an important role in the pathogenesis of neuroinflammation and neurodegeneration. Changes in the microbiota in patients with cognitive impairment and AD are associated with disease severity and are generally characterized by increased numbers of Gram-negative microorganisms in Bacteroidetes and Proteobacteria phyla and decreased numbers of Gram-positive microorganisms in Firmicutes and Actinobacteria phyla. An increase in gram-negative microorganisms abundance leads to elevated release of lipopolysaccharides (LPS) that disrupt the integrity of the intestinal mucous barrier and, through a series of steps, initiate neuroinflammation. Course application of probiotics containing representatives of Bifidobacterium and Lactobacillus genera, in particular, Bifidobacterium breve A1 и Lactobacillus plantarum С29 strains, leads to improved cognitive function, which can be explained by anti-inflammatory and antioxidant effects. Long-term prospective studies of the effects of dietary patterns such as the Mediterranean diet and the MIND diet clearly show delayed regression of cognitive function in older adults without initial dementia as well as in patients with AD. For example, according to various studies, individuals who have strictly adhered to the Mediterranean diet for 6-9 years have a 23-39% lower risk of developing cognitive impairment. Adherence to the MIND diet for 6 years has a statistically significant association with higher verbal memory scores. Correction of gut dysbiosis, including through the administration of probiotics, prebiotics and bringing the diet to the MIND diet pattern, is the most affordable and rational method for early prevention of cognitive dysfunction. Conclusion. A promising strategy in the early prevention of neuroinflammation, cognitive impairment and dementia is to maintain the balance of the gut microbiota. The solution to this problem is achieved by adjusting the dietary pattern, increasing the use of dietary fiber and prebiotics and reasonable use of probiotics.

Neuropsihijatrijski lupus - dva lica jedne bolesti (prikaz dva slučaja)

Introduction: Neuropsychiatric lupus (neuropsychiatric systemic lupus erythematosus - NPSLE) is a form of a systemic autoimmune disease - systemic lupus erythematosus (SLE), with dominant central and peripheral nervous system involvement. Nuclear magnetic resonance imaging (NMRI) of the brain is considered the gold standard for diagnosing patients with NPSLE. Treatment of NPSLE includes the following: high doses of corticosteroids, methylprednisolone pulse therapy, intravenous immunoglobulins, plasmapheresis, immunosuppressants (cyclophosphamide, azathioprine, mycophenolate mofetil), and biological therapy - rituximab. Case reports: In this paper, we present two patients diagnosed with neuropsychiatric lupus, with different clinical manifestations of the disease, as well as the diagnostics performed, and the good clinical outcomes of immunosuppressive therapy achieved in both patients. Conclusion: The pathogenesis of NPSLE involves neuroinflammatory (autoimmune) and ischemic mechanisms. Neuroimaging has shown good results in differentiating patients with SLE from controls. The goal of SLE treatment is to achieve remission or low disease activity and to prevent episodes of exacerbation. Treatment with intravenous cyclophosphamide as well as with systemic corticosteroids has shown significantly positive results in patients with NPSLE. There is great need, in the future, for new biomarkers in the serum and cerebrospinal fluid (CSF), as well as for more innovative radiological procedures. Additional clinical trials that would lead to new therapeutic options for the treatment of NPSLE are necessary.

Inhibition of CCR2 attenuates neuroinflammation and neuronal apoptosis after subarachnoid hemorrhage through the PI3K/Akt pathway

BackgroundNeuroinflammation and neuronal apoptosis are closely associated with a poor prognosis in patients with subarachnoid hemorrhage (SAH). We investigated the role of C–C motif chemokine receptor 2 (CCR2) in SAH.MethodsPre-processed RNA-seq transcriptome datasets GSE167110 and GSE79416 from the Gene Expression Omnibus (GEO) database were screened for genes differentially expressed between mice with SAH and control mice, using bioinformatics analysis. The endovascular perforation model was performed to establish SAH. RS504393 (a CCR2 antagonist) and LY294002 (PI3K inhibitor) were administered to explore the mechanism of neuroinflammation after SAH. SAH grading, neurological scoring, brain water content and blood–brain barrier (BBB) permeability determination, enzyme-linked immunosorbent assay (ELISA), western blotting, and immunofluorescence were performed. An in vitro model of SAH was induced in H22 cells by hemin treatment. The protective mechanism of CCR2 inhibition was studied by adding RS504393 and LY294002. Clinical cerebrospinal fluid (CST) samples were detected by ELISA.ResultsExpression of CCR2 was upregulated in both datasets and was identified as a hub gene. CCR2 expression was significantly upregulated in the cytoplasm of neurons after SAH, both in vitro and in vivo. RS significantly reduced the brain water content and blood–brain barrier permeability, alleviated neuroinflammation, and reduced neuronal apoptosis after SAH. Additionally, the protective effects of CCR2 inhibition were abolished by LY treatment. Finally, the levels of CCR2, inflammatory factors, and apoptotic factors were elevated in the CSF of patients with SAH. CCR2 levels were associated with patient outcomes at the 6-month follow-up.ConclusionCCR2 expression was upregulated in both in vitro and in vivo SAH models. Additionally, inhibition of CCR2, at least partly through the PI3K/AKT pathway, alleviated neuroinflammation and neuronal apoptosis in vivo and in vitro. CCR2 levels in the CSF have a moderate diagnostic value for 6-month outcome prediction in patients with SAH.

Impaired Pain Processing at a Brainstem Level Is Involved in Maladaptive Neuroplasticity in Patients with Chronic Complex Regional Pain Syndrome

Neuroinflammatory mechanisms and maladaptive neuroplasticity underlie the progression of complex regional pain syndrome (CRPS), which is prototypical of central neuropathic pain conditions. While cortical maladaptive alterations are well described, little is known about the contribution of the brainstem to the pathophysiology. This study investigates the role of pain-modulatory brainstem pathways in CRPS using the nociceptive blink reflex (nBR), which not only provides a direct read-out of brainstem excitability and habituation to painful stimuli but may also be suitable for use as a diagnostic biomarker for CRPS. Thirteen patients with CRPS and thirteen healthy controls (HCs) participated in this prospective case-control study investigating the polysynaptic trigemino-cervical (R2) nBR response. The R2 area and its habituation were assessed following repeated supraorbital electrical stimulation. Between-group comparisons included evaluations of diagnostic characteristics as a potential biomarker for the disease. Patients with CRPS showed a substantial decrease in habituation on the stimulated (Cohen's d: 1.3; p = 0.012) and the non-stimulated side (Cohen's d: 1.1; p = 0.04). This is the first study to reveal altered nBR habituation as a pathophysiological mechanism and potential diagnostic biomarker in CRPS. We confirmed previous findings of altered nBR excitability, but the diagnostic accuracy was inferior. Future studies should investigate the nBR as a marker of progression to central mechanisms in CRPS and as a biomarker to predict treatment response or prognosis.

Gut microbiota regulates neuroinflammation and progression of neurodegeneration in a mouse model of tauopathy

AbstractBackgroundAlthough mounting evidence supports that an unbalanced gut microbiota (GM) is linked to amyloid‐β deposition, the contribution of the GM to tau‐mediated neurodegeneration (TN) is poorly characterized. Our preliminary data have shown that the GM manipulations, using either treatment with a combination of antibiotics (ABX) or raising animals in germ‐free (GF) conditions, regulate TN (Seo, et al., AAIC 2021). However, further investigation is needed to sort out the underlying mechanisms that are involved in the interaction between GM and TN. Here, we explore neuroinflammation as a potential mediator in the interaction between GM and TN.MethodP301S tau transgenic mice were crossed with human ApoE knock‐in mice (ApoE3 or ApoE4) or ApoE knockout mice (EKO) to generate P301S::ApoE3/E3, ApoE4/E4, or P301S/EKO mice, termed TE3F, TE4F, and TEKO, respectively. Each group was gavaged with either ABX or H2O from postnatal day 16‐22, housed in a specific pathogen‐free facility, and euthanized at 9.5 months of age. A separate group of TE4F mice was housed under GF conditions. Collected brains were sectioned and used for immunohistochemistry analysis.ResultsIn agreement with brain atrophy measurements that we previously reported, TE3F mice treated with a short‐term ABX showed significantly lower phosphorylated tau (p‐tau) staining compared to the H2O‐treated group (p < 0.01), but not TE4F and TEKO mice treated with ABX. GF‐TE4F mice also showed a marked decrease in p‐tau staining compared to conventionally‐raised animals (p < 0.01). Further quantification of gliosis, as measured by GFAP and Iba1 immunostaining, did not reveal any ABX treatment effects. However, when we assessed the expression of clec7a+ microglia, which marks reactive microglia, ABX treated animals showed significantly lower clec7a+ staining across the different APOE isoform groups (p < 0.01). Furthermore, microglial morphology analysis revealed that ABX treatment drive microglia to a more homeostatic‐like state in TE3F mice, but not in TE4F nor TEKO mice. Remarkably, GF‐TE4F mice showed a marked decrease in both GFAP and Iba1 expression compared to the control TE4F mice (p < 0.05).ConclusionOur results support the hypothesis that GM manipulation modulates tau‐mediated neurodegeneration via influencing a neuroinflammatory mechanism.

Retinal microglia and aging: Changes in the healthy and experimental glaucoma mouse model

AbstractGlaucoma is an age‐related neurodegenerative pathology, characterized by retinal ganglion cells (RGCs) death, which leads to irreversible blindness. Clinical studies have shown that one of the risk factors for glaucoma is high intraocular pressure (IOP). The only therapeutic strategy currently used in this pathology is the reduction of IOP, which does not always reverse neurodegeneration and stop the progression of the disease. However, there is another more important risk factor for glaucoma than IOP, which is aging. It has been observed that aging can increase the vulnerability of the central nervous system to damage. Changes that occur with aging can make RGCs more vulnerable to damage in the glaucomatous neurodegeneration process. The effects of oxidative stress and chronic exposure to light and inflammation mainly cause alterations in the retina due to aging.In glaucomatous neurodegeneration, as in most neurodegenerative diseases, the immune system is involved. Glial cells are immune cells of the retina and optic nerve. When damage occurs, these cells respond quickly, becoming activated, to help restore tissue homeostasis and ensure the immune privilege of nerve tissue. In addition, with aging, a state of chronic parainflammation occurs, leading to the activation of the microglia and release of cytotoxic factors, such as TNF‐α, nitric oxide and other molecules, that which could significantly exacerbate glaucomatous neurodegeneration.One of the main models for raising IOP is the unilateral model of laser‐induced ocular hypertension (OHT). Studies have analysed RGC death and the neuroinflammatory process (focusing on glial cell changes) in this unilateral laser‐induced OHT model in young adult mice. Considering that glaucoma is an age‐related pathology, and that age is the main risk factor, aged in these studies should have been considered a determinate factor.We have used 15‐month‐old mice, which is the beginning point of the aging process of the mice, which is well established from 18 months. In this study, we found morphological signs of microglial activation and changes in the expression of MHCII, CD68 and P2RY12 in the naïve eyes of 15‐month‐old mice (early stage of aging), compared to young naïve adults.On this study we have also analysed the microglial behaviour in response to an increase in IOP in 15‐month‐old mice in a unilateral laser‐induced OHT mouse model of both OHT and contralateral eyes. We also found microglial morphologic alterations and changes in the expression of MHCII, CD68 and P2RY12 in the eyes of 15‐month‐old OHT mice and in the eyes contralateral to them, compared to the eyes of young adult OHT mice and the eyes contralateral to them.In neurodegenerative diseases associated with aging, such as glaucoma, the neuroinflammatory mechanisms induced by microglial cells have an important implication in the development of disease. The use of aging models to analyses the age‐related retinal pathologies could help to improve our understanding of the progression of these pathologies.

Effects of early electroacupuncture on the expression of Iba-1 and TNF-α in Parkinson's disease mice

To observe the effect of early electroacupuncture(EA) intervention on ionized calcium binding adapter molecule 1 (Iba-1), tyrosine hydroxylase (TH) and tumor necrosis factor-α (TNF-α) in Parkinson's disease (PD) mice, so as to explore its neuroinflammation mechanism in treating PD. A total of 24 male C57BL/6J mice (9 weeks old) were randomly divided into control, model and EA groups, with 8 mice in each group. The PD model was established by long-term low dose subcutaneous injection of rotenone. Started at the same time with modeling, EA (2 Hz/100 Hz, 1 mA) was applied to "Shenting"(GV24), bilateral "Tianshu"(LI11), "Quchi"(ST25), and "Shangjuxu"(ST37) for 15 min, once a day for 8 weeks. The motor function was assessed by rotorod test and step length test. The expression levels of Iba-1 and TH proteins in substantia nigra pars compacta (SNpc) was detected by Western blot and immunohistochemistry. The expression level of TNF-α protein in colon tissue was examined by Western blot and immunofluorescence staining. Compared with the control group, the fall latency shortened at 4, 6, and 8 weeks after modeling (P<0.01) and the step length of hind limbs shortened at 5 and 7 weeks after modeling (P<0.01), the expression levels of Iba-1 in SNpc and TNF-α in colon tissue were increased (P<0.01), and the expression level of TH in SNpc was decreased (P<0.01) in the model group. Compared with the model group, the fall latency prolonged at 6 and 8 weeks after modeling (P<0.01) and the step length of hind limbs prolonged at 5 and 7 weeks after modeling (P<0.01), the expression levels of Iba-1 in SNpc and TNF-α in colon tissue were decreased (P<0.01, P<0.05), and the expression level of TH in SNpc was increased (P<0.05, P<0.01) in the EA group. Early EA intervention can delay the occurring time of motor disfunction, alleviated the loss of substantia nigra dopaminergic neurons, and exerted a good neuroprotective effect on the degenerative changes in rotenone-induced PD mice, which may be related to its effects in alleviating the intestinal inflammation, inhibiting the activation of microglia, thereby reducing the neuroinflammation.

Research Progress of Targeting Neuro-Immune Inflammation in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by extracellular senile plaques and the formation of intracellular neurofibrillary tangles. The accumulation of toxic beta-amyloid (Aβ) induces the overproduction of reactive oxygen species (ROS), nitric oxide (NO) and pro-inflammatory cytokines. Accumulating studies suggest that neuroinflammatory mechanism plays an important role in the occurrence and development of AD. Microglia, astrocytes, macrophages, mast cells and T cells are involved in the pathogenesis of AD through neuroimmune mechanisms and inflammatory reactions. In recent years, many new drugs have been developed for the treatment of AD targeting neuroimmune and inflammatory mechanisms. Although some drugs failed in the Ⅲ phase of clinical trial, they made sense on subsequent research. This paper mainly discusses the positive effects on AD according to immunotherapy, anti-inflammatory treatment and regulation of immune inflammation by traditional Chinese medicine, in order to benefit for prevention or treatment of AD in the future.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration

BackgroundThe excessive activation of the microglia leads to the release of inflammatory factors that contribute to neuronal cell loss and neurodegeneration in Parkinson's Disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) that belongs to a newly found neurotrophic factors (NTFs) family has been reported to promote neuronal survival in the PD models. However, the effects of the MANF on neuroinflammation in PD remain unclear. MethodsAAV8-MANF virus was constructed to determine whether the high expression of MANF can protect the neuroinflammation-induced dopaminergic neurodegeneration in rats with 6-OHDA-induced PD. Rotarod performance test, immunofluorescent staining and western bolt were employed to evaluate the behavioral dysfunction, dopaminergic neurodegeneration, microglia activation, and signal activation. 6-OHDA treated SH-SY5Y cells and LPS treated BV-2 cells were used as the in vitro model for MANF neuroprotective and neuroinflammation mechanisms. Cell vitality and apoptosis were evaluated with MTT, CCK-8 and flow cytometric analysis. The AKT/GSK3β-Nrf2 signaling and the TNF-α/IL6 expression were measured by Western Blot. ResultsOur findings indicated that the elevated MANF expression by the AAV8-MANF administration ameliorated the motor dysfunction and protected the dopaminergic neurons in the 6-OHDA treated rats. The upregulated CD11b in the rat SN caused by the 6-OHDA administration was significantly attenuated by the pretreatment of the AAV8-MANF. Furthermore, the levels of p-AKT, p-GSK3β, BCL-2, and Nrf-2 were upregulated by the high expression of the MANF. Under the oxidative stress of the 6-OHDA, the MANF significantly reduced the apoptotic effect of the TNF-α on the SH-SY5Y cells. In the LPS treated BV-2 cells, the MANF reduced the production of the TNF-α and IL-6, via enhancing the Nrf-2, p-Akt, p-GSK3β, and p-NF-κβ level. ConclusionsThese results suggested that the MANF prevented the dopaminergic neurodegeneration caused by the microglia activation in PD via activation of the AKT/GSK3β-Nrf-2 signaling axis.

Acrylamide Induces Neurotoxicity in SH-SY5Y Cells via NLRP3-mediated Pyroptosis.

Acrylamide (ACR), a soft electrophile, is a typical environmental and food contaminant that presents potential health hazards and, consequently, is attracting increasing attention in the quest for its control. ACR neurotoxicity has been widely reported in experimental animals and attributed to neuroinflammation; however, the mechanisms involved therein require clarification. In this study, we used a neuron cell model to investigate the mechanisms of ACR-induced neuroinflammation and pyroptosis. The results showed that ACR treatment induced lytic cell death morphologically under both the canonical pyroptotic pathway (NOD-like receptor protein 3 (NLRP3)-apoptosis-associated speck-like protein containing CARD (ASC)-cysteinyl aspartate specific proteinase 1 (caspase-1)-gasdermin D (GSDMD)-interleukin-1β (IL-1β)/interleukin-18 (IL-18)) and an alternative pyroptotic pathway (cysteinyl aspartate specific proteinase 3 (caspase-3)-gasdermin E (GSDME)-IL-1β/IL-18) in SH-SY5Y cells. Moreover, the lactate dehydrogenase (LDH) production, cytokines release, and lytic cell death induced by ACR were diminished by caspase-1 and -3 inhibitors. Furthermore, the knockdown of caspase-1 by small interfering RNA attenuated ACR-induced lytic cell death, suggesting that canonical pyroptosis (the NLRP3-caspase 1-GSDMD-IL-1β signaling axis) played a primary role in the ACR-induced pyroptosis. Of the two pyroptotic-related pathways, the NLRP3 inflammasome cascade was activated first within the 6-h period of ACR exposure, while the activation of the alternative pyroptotic pathway was delayed. Collectively, these results indicate that ACR mainly induces NLRP3-related neuroinflammation and pyroptosis in SH-SY5Y cells, which is, thus, suggestive of an alternative mechanism for ACR-induced neurotoxicity.

Neuroprotective effect of alpha-kinase 1 knockdown against cerebral ischemia through inhibition of the NF-κB pathway and neuroinflammation

BackgroundActivation of the nuclear factor B (NF-κB) signaling pathway by pattern recognition receptors (PRRs) is regarded as a crucial mechanism of neuroinflammation and brain injury after acute ischemic stroke. The stimulation of alpha-kinase 1 (ALPK1), a newly identified PRR, triggers NF-κB activation and an inflammatory response. Longitudinal population-based genetic epidemiological studies suggest that the ALPK1 gene is a susceptible site to ischemic stroke. However, the function of ALPK1 in the central nervous system remains unclear. The present study explored the role of ALPK1 in acute ischemic stroke. MethodsBV2 microglial cells were stimulated with conditioned medium (CM) that was collected from oxygen and glucose deprivation (OGD)-treated HT22 neurons, and a murine brain ischemia model was established to detect the changes of ALPK1 expression. We used lentivirus to knockdown ALPK1 to explore the effects of ALPK1 in cerebral ischemia models in vitro and in vivo. ResultsWe observed a significant increase of ALPK1 expression in BV2 cells that were stimulated with OGD CM. The knockdown of ALPK1 inhibited the phosphorylation of tumor necrosis factor receptor associated factor-interacting protein with a forkhead-associated domain (TIFA), the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), the activation of NF-κB, and the levels of proinflammatory factors in the BV2 cells. We also verified a neuroprotective effect of ALPK1 knockdown against ischemic brain injury through inhibition of the TIFA/TRAF6/NF-κB pathway and neuroinflammation in mice. ConclusionsThis study demonstrates that ALPK1 is implicated in sterile inflammatory injury after acute brain ischemia, which provides first evidence for the therapeutic potential of ALPK1 inhibition in ischemic stroke.