Proactive M2 blockade prevents cognitive decline in GRK5-deficient APP transgenic mice via enhancing cholinergic neuronal resilience.

Alzheimer's disease (AD) poses an immense challenge in healthcare, lacking effective therapies. This study investigates the potential of anthranilamide derivative (AAD23), a selective M2 receptor antagonist, in proactively preventing cognitive impairments and cholinergic neuronal degeneration in G protein-coupled receptor kinase-5-deficient Swedish APP (GAP) mice. GAP mice manifest cognitive deficits by 7 months and develop senile plaques by 9 months. A 6-month AAD23 treatment was initiated at 5 months and stopped at 11 months before behavioral assessments without the treatment. AAD23-treated mice exhibited preserved cognitive abilities and improved cholinergic axonal health in the nucleus basalis of Meynert akin to wildtype mice. Conversely, vehicle-treated GAP mice displayed memory deficits and pronounced cholinergic axonal swellings in the nucleus basalis of Meynert. Notably, AAD23 treatment did not alter senile plaques and microgliosis. These findings highlight AAD23's efficacy in forestalling AD-related cognitive decline in G protein-coupled receptor kinase-5-deficient subjects, attributing its success to restoring cholinergic neuronal integrity and resilience, enhancing resistance against diverse degenerative insults.

Antiretroviral drug dolutegravir induces inflammation at the mouse brain barriers.

Integrase strand transfer inhibitors (INSTIs) based antiretroviral therapy (ART) is currently used as first-line regimen to treat HIV infection. Despite its high efficacy and barrier to resistance, ART-associated neuropsychiatric adverse effects remain a major concern. Recent studies have identified a potential interaction between the INSTI, dolutegravir (DTG), and folate transport pathways at the placental barrier. We hypothesized that such interactions could also occur at the two major blood-brain interfaces: blood-cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB). To address this question, we evaluated the effect of two INSTIs, DTG and bictegravir (BTG), on folate transporters and receptor expression at the mouse BCSFB and the BBB in vitro, ex vivo and in vivo. We demonstrated that DTG but not BTG significantly downregulated the mRNA and/or protein expression of folate transporters (RFC/SLC19A1, PCFT/SLC46A1) in human and mouse BBB models in vitro, and mouse brain capillaries ex vivo. Our in vivo study further revealed a significant downregulation in Slc19a1 and Slc46a1 mRNA expression at the BCSFB and the BBB following a 14-day DTG oral treatment in C57BL/6 mice. However, despite the observed downregulatory effect of DTG in folate transporters/receptor at both brain barriers, a 14-day oral treatment of DTG-based ART did not significantly alter the brain folate level in animals. Interestingly, DTG treatment robustly elevated the mRNA and/or protein expression of pro-inflammatory cytokines and chemokines (Cxcl1, Cxcl2, Cxcl3, Il6, Il23, Il12) in primary cultures of mouse brain microvascular endothelial cells (BBB). DTG oral treatment also significantly upregulated proinflammatory cytokines and chemokine (Il6, Il1ß, Tnfα, Ccl2) at the BCSFB in mice. We additionally observed a downregulated mRNA expression of drug efflux transporters (Abcc1, Abcc4, and Abcb1a) and tight junction protein (Cldn3) at the CP isolated from mice treated with DTG. Despite the structural similarities, BTG only elicited minor effects on the markers of interest at both the BBB and BCSFB. In summary, our current data demonstrates that DTG but not BTG strongly induced inflammatory responses in a rodent BBB and BCSFB model. Together, these data provide valuable insights into the mechanism of DTG-induced brain toxicity, which may contribute to the pathogenesis of DTG-associated neuropsychiatric adverse effect.

Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [11C]PBR28 PET correlates with vascular disease measures.

The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.

Brain-Thymus Connections in Chagas Disease.

BACKGROUND: The brain and the immune systems represent the two primary adaptive systems within the body. Both are involved in a dynamic process of communication, vital for the preservation of mammalian homeostasis. This interplay involves two major pathways: the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. SUMMARY: The establishment of infection can affect immunoneuroendocrine interactions, with functional consequences for immune organs, particularly the thymus. Interestingly, the physiology of this primary organ is not only under the control of the central nervous system (CNS) but also exhibits autocrine/paracrine regulatory circuitries mediated by hormones and neuropeptides that can be altered in situations of infectious stress or chronic inflammation. In particular, Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), impacts upon immunoneuroendocrine circuits disrupting thymus physiology. Here, we discuss the most relevant findings reported in relation to brain-thymic connections during T. cruzi infection, as well as their possible implications for the immunopathology of human Chagas disease. KEY MESSAGES: During T. cruzi infection, the CNS influences thymus physiology through an intricate network involving hormones, neuropeptides, and pro-inflammatory cytokines. Despite some uncertainties in the mechanisms and the fact that the link between these abnormalities and chronic Chagasic cardiomyopathy is still unknown, it is evident that the precise control exerted by the brain over the thymus is markedly disrupted throughout the course of T. cruzi infection.

Peri-implantitis with a potential axis to brain inflammation: an inferential review.

Peri-implantitis (PI) is a chronic, inflammatory, and infectious disease which affects dental implants and has certain similarities to periodontitis (PD). Evidence has shown that PD may be related to several types of systemic disorders, such as diabetes and insulin resistance, cardiovascular diseases, respiratory tract infections, adverse pregnancy outcomes, and neurological disorders. Furthermore, some types of bacteria in PD can also be found in PI, leading to certain similarities in the immunoinflammatory responses in the host. This review aims to discuss the possible connection between PI and neuroinflammation, using information based on studies about periodontal disorders, a topic whose connection with systemic alterations has been gaining the interest of the scientific community. Literature concerning PI, PD, and systemic disorders, such as neuroinflammation, brain inflammation, and neurological disorder, was searched in the PubMed database using different keyword combinations. All studies found were included in this narrative review. No filters were used. Eligible studies were analyzed and reviewed carefully. This study found similarities between PI and PD development, maintenance, and in the bacterial agents located around the teeth (periodontitis) or dental implants (peri-implantitis). Through the cardiovascular system, these pathologies may also affect blood-brain barrier permeability. Furthermore, scientific evidence has suggested that microorganisms from PI (as in PD) can be recognized by trigeminal fiber endings and start inflammatory responses into the trigeminal ganglion. In addition, bacteria can traverse from the mouth to the brain through the lymphatic system. Consequently, the immune system increases inflammatory mediators in the brain, affecting the homeostasis of the nervous tissue and vice-versa. Based on the interrelation of microbiological, inflammatory, and immunological findings between PD and PI, it is possible to infer that immunoinflammatory changes observed in PD can imply systemic changes in PI. This, as discussed, could lead to the development or intensification of neuroinflammatory changes, contributing to neurodegenerative diseases.

Partial MCT1 invalidation protects against diet-induced non-alcoholic fatty liver disease and the associated brain dysfunction.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has been associated with mild cerebral dysfunction and cognitive decline, although the exact pathophysiological mechanism remains ambiguous. Using a diet-induced model of NAFLD and monocarboxylate transporter-1 (Mct1+/-) haploinsufficient mice, which resist high-fat diet-induced hepatic steatosis, we investigated the hypothesis that NAFLD leads to an encephalopathy by altering cognition, behaviour, and cerebral physiology. We also proposed that global MCT1 downregulation offers cerebral protection. METHODS: Behavioural tests were performed in mice following 16 weeks of control diet (normal chow) or high-fat diet with high fructose/glucose in water. Tissue oxygenation, cerebrovascular reactivity, and cerebral blood volume were monitored under anaesthesia by multispectral optoacoustic tomography and optical fluorescence. Cortical mitochondrial oxygen consumption and respiratory capacities were measured using ex vivo high-resolution respirometry. Microglial and astrocytic changes were evaluated by immunofluorescence and 3D reconstructions. Body composition was assessed using EchoMRI, and liver steatosis was confirmed by histology. RESULTS: NAFLD concomitant with obesity is associated with anxiety- and depression-related behaviour. Low-grade brain tissue hypoxia was observed, likely attributed to the low-grade brain inflammation and decreased cerebral blood volume. It is also accompanied by microglial and astrocytic morphological and metabolic alterations (higher oxygen consumption), suggesting the early stages of an obesogenic diet-induced encephalopathy. Mct1 haploinsufficient mice, despite fat accumulation in adipose tissue, were protected from NAFLD and associated cerebral alterations. CONCLUSIONS: This study provides evidence of compromised brain health in obesity and NAFLD, emphasising the importance of the liver-brain axis. The protective effect of Mct1 haploinsufficiency points to this protein as a novel therapeutic target for preventing and/or treating NAFLD and the associated brain dysfunction. IMPACT AND IMPLICATIONS: This study is focused on unravelling the pathophysiological mechanism by which cerebral dysfunction and cognitive decline occurs during NAFLD and exploring the potential of monocarboxylate transporter-1 (MCT1) as a novel preventive or therapeutic target. Our findings point to NAFLD as a serious health risk and its adverse impact on the brain as a potential global health system and economic burden. These results highlight the utility of Mct1 transgenic mice as a model for NAFLD and associated brain dysfunction and call for systematic screening by physicians for early signs of psychological symptoms, and an awareness by individuals at risk of these potential neurological effects. This study is expected to bring attention to the need for early diagnosis and treatment of NAFLD, while having a direct impact on policies worldwide regarding the health risk associated with NAFLD, and its prevention and treatment.

N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial.

BACKGROUND: In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence. OBJECTIVES AND METHODS: An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS). RESULTS: Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points. CONCLUSIONS: Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.

The role of brain inflammation and abnormal brain oxygen homeostasis in the development of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE.

Hericium erinaceus Promotes Anti-Inflammatory Effects and Regulation of Metabolites in an Animal Model of Cerebellar Ataxia.

Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although previous study demonstrated the neuroprotective effects of Hericium erinaceus (H.E.), the mechanisms of H.E. treatment on the neuroinflammatory response, neurotransmission, and related metabolites remain largely unknown. We demonstrated that 3-AP rats treated with 25 mg/kg H.E. extracts had improved motor coordination and balance in the accelerated rotarod and rod tests. We showed that the H.E. treatment upregulated the expression of Tgfb1, Tgfb2, and Smad3 genes to levels comparable to those in the non-3-AP control group. Interestingly, we also observed a significant correlation between Tgfb2 gene expression and rod test performance in the 3-AP saline group, but not in the non-3-AP control or H.E.+3-AP groups, indicating a relationship between Tgfb2 gene expression and motor balance in the 3-AP rat model. Additionally, we also found that the H.E. treatment increased mitochondrial COX-IV protein expression and normalized dopamine-serotonin neurotransmission and metabolite levels in the cerebellum of the H.E.+3-AP group compared to the 3-AP saline group. In conclusion, our findings suggest that the H.E. treatment improved motor function in the 3-AP rat model, which was potentially mediated through neuroprotective mechanisms involving TGFB2-Smad3 signaling via normalization of neurotransmission and metabolic pathways.

Imipramine prevents Porphyromonas gingivalis lipopolysaccharide-induced microglial neurotoxicity.

Porphyromonas gingivalis (P. gingivalis) is a Gram-negative anaerobe involved in the pathogenesis of chronic periodontitis, including local inflammation of the oral cavity. However, periodontal disease has recently been identified as a significant factor in the pathogenesis of neural diseases, including Alzheimer's disease. A virulence factor, P. gingivalis-lipopolysaccharide (LPS-PG), is involved in pro-inflammatory responses, not only in peripheral tissues but also in the brain. In this study, we examined whether P. gingivalis-induced brain inflammation could be ameliorated by pharmacotherapy, using in vivo and in vitro studies. In an animal experiment, peripheral administration of LPS-PG induced inflammation in the hippocampus via microglial activation, which was inhibited by pre-treatment with the antidepressant imipramine. Similarly, LPS-PG-induced inflammation in MG-6 cells, a mouse microglial cell line, was inhibited by pre-treatment with imipramine, which caused imipramine-induced inhibition of NF-κB signaling. Culture media obtained from LPS-PG-treated MG-6 cells induced neuronal cell death in Neuro-2A cells, a mouse neuroblastoma cell line, which was prevented by pre-treatment of MG-6 cells with imipramine. These results indicate that imipramine inhibits LPS-PG-induced inflammatory responses in microglia and ameliorates periodontal disease-related neural damage.

Lung inflammation induced by silica particles triggers hippocampal inflammation, synapse damage and memory impairment in mice.

BACKGROUND: Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO2 (silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory. METHODS: Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO2/kg in mice. Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-ß (Aß) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests. RESULTS: Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aß peptide, and memory impairment in mice. CONCLUSION: The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.

Restoring Oat Nanoparticles Mediated Brain Memory Function of Mice Fed Alcohol by Sorting Inflammatory Dectin-1 Complex Into Microglial Exosomes.

Microglia modulate pro-inflammatory and neurotoxic activities. Edible plant-derived factors improve brain function. Current knowledge of the molecular interactions between edible plant-derived factors and the microglial cell is limited. Here an alcohol-induced chronic brain inflammation model is used to identify that the microglial cell is the novel target of oat nanoparticles (oatN). Oral administration of oatN inhibits brain inflammation and improves brain memory function of mice that are fed alcohol. Mechanistically, ethanol activates dectin-1 mediated inflammatory pathway. OatN is taken up by microglial cells via ß-glucan mediated binding to microglial hippocalcin (HPCA) whereas oatN digalactosyldiacylglycerol (DGDG) prevents assess of oatN ß-glucan to dectin-1. Subsequently endocytosed ß-glucan/HPCA is recruited in an endosomal recycling compartment (ERC) via interaction with Rab11a. This complex then sequesters the dectin-1 in the ERC in an oatN ß-glucan dependent manner and alters the location of dectin-1 from Golgi to early endosomes and lysosomes and increases exportation of dectin-1 into exosomes in an Rab11a dependent manner. Collectively, these cascading actions lead to preventing the activation of the alcoholic induced brain inflammation signing pathway(s). This coordinated assembling of the HPCA/Rab11a/dectin-1 complex by oral administration of oatN may contribute to the prevention of brain inflammation.

Introduction to the Special Issue "The Brain-Gut Axis".

This special Issue presents comprehensive and state-of-the-art advances in supporting the crucial role of the bidirectional interactions between the Brain-Gut Axis in health and diseases with an emphasis on the microbiome-gut-brain axis and its implications in variety of neurological disorders. There are intimate connections between the brain and the digestive system. Gut microbiota dysbiosis activates the intestinal immune system, enhances intestinal permeability and bacterial translocation, leading to neuroinflammation, epigenetic changes, cerebrovascular alterations, amyloid ß formation and α-synuclein protein aggregates. These alterations may participate in the development of hypertension, Alzheimer, Parkinson, stroke, epilepsy and autism. Brainstem nuclei such as the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) regulate gastric motor function by way of bidirectional inputs through the vagus nerve.

Autoimmune encephalitis and CSF anti-AMPA GluR3 antibodies in childhood: a case report and literature review.

Acute autoimmune encephalitis is a severe neurological disorder presenting with altered level of consciousness, confusion, irritability, headache, vomiting, and in some cases seizures. An infective event precedes by 1-2 weeks the onset of the symptoms. Cognitive impairment is considered the cardinal symptom. The autoimmune encephalitis comprises an increasingly group of inflammatory brain disorder caused by an underlying abnormal immune response to the CNS to the infective agent. In children, several antibodies have been recorded as causative agent. Among these, GAD65, MOG, and NMDAR antibodies are more commonly reported and with less frequency, the Dopamine-2 receptor, GABA A receptor, GABA B receptor, and Glycinereceptorandm-GluR5. We report here a 10-year-old male with acute autoimmune encephalitis with altered status of consciousness and severe cerebral involvement at the brain-MRI. Serum and cerebrospinal fluid disclosed the presence of anti-AMPA-GluR3 antibodies suggesting a possible pathogenetic correlation with the disorder presented by the proband. Precocious treatment with intravenous methylprednisolone and immunoglobulin resulted in progressive but constant improvement. At 3-month follow-up, the clinical condition of the child and the neuro-radiological brain anomalies returned to the normal. At the 2-year follow-up, no recurrence or other disturbances were reported.

Liver Steatosis and Steatohepatitis Alter Bile Acid Receptors in Brain and Induce Neuroinflammation: A Contribution of Circulating Bile Acids and Blood-Brain Barrier.

A tight relationship between gut-liver diseases and brain functions has recently emerged. Bile acid (BA) receptors, bacterial-derived molecules and the blood-brain barrier (BBB) play key roles in this association. This study was aimed to evaluate how non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) impact the BA receptors Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) expression in the brain and to correlate these effects with circulating BAs composition, BBB integrity and neuroinflammation. A mouse model of NAFLD was set up by a high-fat and sugar diet, and NASH was induced with the supplementation of dextran-sulfate-sodium (DSS) in drinking water. FXR, TGR5 and ionized calcium-binding adaptor molecule 1 (Iba-1) expression in the brain was detected by immunohistochemistry, while Zonula occludens (ZO)-1, Occludin and Plasmalemmal Vesicle Associated Protein-1 (PV-1) were analyzed by immunofluorescence. Biochemical analyses investigated serum BA composition, lipopolysaccharide-binding protein (LBP) and S100ß protein (S100ß) levels. Results showed a down-regulation of FXR in NASH and an up-regulation of TGR5 and Iba-1 in the cortex and hippocampus in both treated groups as compared to the control group. The BA composition was altered in the serum of both treated groups, and LBP and S100ß were significantly augmented in NASH. ZO-1 and Occludin were attenuated in the brain capillary endothelial cells of both treated groups versus the control group. We demonstrated that NAFLD and NASH provoke different grades of brain dysfunction, which are characterized by the altered expression of BA receptors, FXR and TGR5, and activation of microglia. These effects are somewhat promoted by a modification of circulating BAs composition and by an increase in LBP that concur to damage BBB, thus favoring neuroinflammation.

Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases.

The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain and displays a critical role in neuroprotection and inflammation by activating the GLP-1 receptor signaling pathways. Several studies in vivo and in vitro using preclinical models of neurodegenerative diseases show that GLP-1R activation has anti-inflammatory properties. This review explores the molecular mechanistic action of GLP-1 RAS in relation to inflammation in the brain. These findings update our knowledge of the potential benefits of GLP-1RAS actions in reducing the inflammatory response. These molecules emerge as a potential therapeutic tool in treating neurodegenerative diseases and neuroinflammatory pathologies.

Inflammatory Disorders of the Central Nervous System Vessels: Narrative Review.

Inflammatory disorders of the central nervous system (CNS) vessels, also called CNS vasculitides, can cause substantial disability or even be fatal. Inflammation of the CNS vessels can be caused by primary angiitis of the CNS (PACNS), inflammatory cerebral amyloid angiopathy, or systemic inflammatory disorders. Clinical symptoms of these disorders are often non-specific, such as encephalopathy, cognitive and affective abnormalities, headache and focal neurological symptoms. Diagnostic workup includes a thorough neuropsychiatric examination, blood and cerebrospinal fluid analysis and magnetic resonance imaging (MRI) of the brain and its vessels. Biopsy of the brain remains the gold standard diagnostic test. Timely diagnosis and treatment initiation is of high importance, as it might prevent severe complications, such as ischemic and hemorrhagic stroke. In this review, we describe the specific characteristics of primary and secondary non-infectious CNS vasculitides which help to establish the diagnosis, discuss the peculiarities of the diagnostic workup and present current treatment recommendations.

Adult hippocampal neurogenesis in the context of lipopolysaccharide-induced neuroinflammation: A molecular, cellular and behavioral review.

The continuous generation of new neurons occurs in at least two well-defined niches in the adult rodent brain. One of these areas is the subgranular zone of the dentate gyrus (DG) in the hippocampus. While the DG is associated with contextual and spatial learning and memory, hippocampal neurogenesis is necessary for pattern separation. Hippocampal neurogenesis begins with the activation of neural stem cells and culminates with the maturation and functional integration of a portion of the newly generated glutamatergic neurons into the hippocampal circuits. The neurogenic process is continuously modulated by intrinsic factors, one of which is neuroinflammation. The administration of lipopolysaccharide (LPS) has been widely used as a model of neuroinflammation and has yielded a body of evidence for unveiling the detrimental impact of inflammation upon the neurogenic process. This work aims to provide a comprehensive overview of the current knowledge on the effects of the systemic and central administration of LPS upon the different stages of neurogenesis and discuss their effects at the molecular, cellular, and behavioral levels.

Inhibitory effect of panaxytriol on BV-2 microglial cell activation.

Activated microglia induce brain inflammation and neuronal death. Panaxytriol, ((3R,9R,10R)-Heptadec-1-en-4,6-diyne-3,9,10-triol), is a component of Panax ginseng C. A. Meyer extracts and activates the Nrf2-ARE signaling pathway. However, little is known about its effects on activated microglia in the brain. In this study, we investigated the effect of panaxytriol on lipopolysaccharide (LPS)-induced activated microglia in BV-2 cells. Panaxytriol suppressed LPS-induced NO production and inhibited the increase in iNOS protein expression in BV-2 cells. Besides, panaxytriol inhibited the mRNA expression of proinflammatory cytokines such as TNF-α, IL-1ß, and IL-6. The inhibitory effect of panaxytriol on microglia activation did not affect the Nrf2-ARE pathway and the MAPK pathway. However, panaxytriol suppressed LPS-induced NF-κB nuclear translocation. These results suggest that panaxytriol inhibits the LPS-induced activation of microglia via the inhibition of NF-κB signaling pathway.

Panaxytriol Inhibits Lipopolysaccharide-Induced Microglia Activation in Brain Inflammation in Vivo.

Brain inflammation is a pathological characteristic of neurodegenerative diseases. In this condition, excessively activated microglia elevate proinflammatory mediator levels. We previously reported that panaxytriol inhibited lipopolysaccharide (LPS)-induced microglia activation in vitro. However, the effects of panaxytriol on microglia activation in vivo require confirmation. In the present study, we found that panaxytriol suppressed both microglia and astrocyte activation by injected LPS intracerebrally to mice with LPS-induced brain inflammation. Panaxytriol was more effective on microglia than astrocytes. Moreover, panaxytriol tended to reduce LPS-induced spontaneous motor activity dysfunction. These results suggested that panaxytriol could improve brain health by suppressing microglia activation in neurodegenerative diseases.