Astrocyte-mediated Neuroinflammation Research Articles

Sodium Butyrate Ameliorates Postoperative Delirium by Regulating Gut Microbiota Dysbiosis to Inhibit Astrocyte Activation in Aged Mice.

Postoperative delirium (POD) is a common complication in elderly surgical patients, with limited targeted interventions due to incomplete understanding of its pathophysiological mechanisms. Central nervous system (CNS) inflammation, involving glial cell activation, particularly astrocytes, is considered crucial in POD development. Butyrate, a four-carbon fatty acid, has shown protective effects in CNS diseases, but its potential in mitigating POD remains unclear. This study aimed to investigate the impact of sodium butyrate on POD in aged mice. Behavioral tests, including open field, Y maze, and food burying tests, demonstrated that sodium butyrate preconditioning ameliorated laparotomy-induced delirium in aged mice. Pre-treatment with sodium butyrate inhibited astrocyte activation in the hippocampus, reduced interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) expression levels, and protected hippocampal neurons. Furthermore, the study revealed a connection between gut microbiota regulation and central neuroprotective effects mediated by astrocyte activation inhibition. Sodium butyrate improved the intestinal morphological barrier by rebalancing gut microbiota, inhibiting Proteobacteria and Actinobacteria, reducing Allobaculum and Bacteroides abundance, and increasing Oscillospira abundance. This regulation decreased gut permeability, limiting the entry of toxic substances into the bloodstream, thereby reducing inflammation spread and astrocyte overactivation, leading to central anti-inflammatory effects. In conclusion, sodium butyrate may ameliorate POD by inhibiting astrocyte-mediated neuroinflammation through gut microbiota rebalancing.

Inhibition of HMOX1 by MAFG potentiates the development of depression‑like behavior in mice associated with astrocyte-mediated neuroinflammation

MAF bZIP transcription factor G (MAFG)-driven astrocytes have been reported to promote inflammation in the CNS. However, its function in depression, the primary cause of disability worldwide, has not been well characterized. This study investigated the possible perturbation of heme oxygenase 1 (HMOX1, also known as HO1) by the transcription factor MAFG as an underlying mechanism of the development of depression. The GSE98793 dataset was included for gene expression analysis of whole blood from donors with major depressive disorder and controls, and the target of MAFG was predicted by multiple database mining. Mouse and cellular models of depression were established by chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS) treatment of astrocytes, which were treated with MAFG and HMOX1 knockdown plasmids. MAFG was highly expressed in the hippocampal tissues of CUMS-challenged mice and LPS-induced astrocytes. MAFG knockdown alleviated depression-like behaviors in mice. MAFG bound to the HMOX1 promoter and repressed its transcription. Knockdown of HMOX1 exacerbated neuroinflammation in astrocytes and accelerated depression-like behavior in mice. In conclusion, MAFG knockdown attenuated CUMS-stimulated depression-like behaviors in mice by astrocyte-mediated neuroinflammation via restoration of HMOX1.

CYR61 is Involved in Neonatal Hypoxic-ischemic Brain Damage Via Modulating Astrocyte-mediated Neuroinflammation

The activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in astrocytes has been found in the hypoxic-ischemic brain damage (HIBD) model. Cysteine rich angiogenic inducer 61 (CYR61) is secreted by reactive astrocytes. However, the effects of CYR61 on HIBD and its related mechanisms remain unclear. This study sought to explore the role of CYR61 in the activation of astrocytes and the NLRP3 inflammasome in neonatal HIBD. HIBD models were established in 7-day Sprague-Dawley rat pups. Neurobehavioral evaluation and 2,3,5-triphenyl-tetrazolium chloride staining were performed. In addition, rat primary astrocytes were used to establish the cell model of HIBD in vitro by oxygen-glucose deprivation/reperfusion (OGD/R). Then, CYR61-overexpression and sh-CYR61 viruses mediated by lentivirus were transduced into ODG/R-treated primary astrocytes. The expressions of related genes were evaluated using real-time quantitative PCR, western blot, immunofluorescence staining, and Enzyme-linked immunosorbent assay. The results showed that hypoxia–ischemia induced short-term neurological deficits, neuronal damage, and cerebral infarction in neonatal rats. In vivo, the expressions of CYR61, NLRP3, and glial fibrillary acidic protein (GFAP) were up-regulated in the HIBD model. In vitro, CYR61 exhibited high expression. CYR61 overexpression increased the expressions of GFAP and C3, whereas decreased S100A10 expression. CYR61 overexpression increased the expression of NLRP3, ASC, caspase-1 p20 and IL-1β. CYR61 overexpression activated NF-κB by promoting the phosphorylation of IκBα and p65. Thus, CYR61 is involved in neonatal HIBD progress, which may be related to the activation of astrocytes, the NLRP3 inflammasome, and the NF-κB signaling pathway.

Edaravone Dexborneol mitigates pathology in animal and cell culture models of Alzheimer’s disease by inhibiting neuroinflammation and neuronal necroptosis

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease with limited disease-modifying treatments. Drug repositioning strategy has now emerged as a promising approach for anti-AD drug discovery. Using 5×FAD mice and Aβ-treated neurons in culture, we tested the efficacy of Y-2, a compounded drug containing the antioxidant Edaravone (Eda), a pyrazolone and (+)-Borneol, an anti-inflammatory diterpenoid from cinnamon, approved for use in amyotrophic lateral sclerosis patients.ResultsWe examined effects of Y-2 versus Eda alone by i.p. administered in 8-week-old 5×FAD mice (females) for 4 months by comparing cognitive function, Aβ pathologies, neuronal necroptosis and neuroinflammation. Using primary neurons and astrocytes, as well as neuronal and astrocytic cell lines, we elucidated the molecular mechanisms of Y-2 by examining neuronal injury, astrocyte-mediated inflammation and necroptosis. Here, we find that Y-2 improves cognitive function in AD mice. Histopathological data show that Y-2, better than Eda alone, markedly ameliorates Aβ pathologies including Aβ burden, astrogliosis/microgliosis, and Tau phosphorylation. In addition, Y-2 reduces Aβ-induced neuronal injury including neurite damage, mitochondrial impairment, reactive oxygen species production and NAD+ depletion. Notably, Y-2 inhibits astrocyte-mediated neuroinflammation and attenuates TNF-α-triggered neuronal necroptosis in cell cultures and AD mice. RNA-seq further demonstrates that Y-2, compared to Eda, indeed upregulates anti-inflammation pathways in astrocytes.ConclusionsOur findings infer that Y-2, better than Eda alone, mitigates AD pathology and may provide a potential drug candidate for AD treatment.

Matrilin-3 supports neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation

In the brain, the role of matrilin-3, an extracellular matrix component in cartilage, is unknown. Here, we identify that matrilin-3 decreased in reactive astrocytes but was unchanged in neurons after ischemic stroke in animals. Importantly, it declined in serum of patients with acute ischemic stroke. Genetic or pharmacological inhibition or supplementation of matrilin-3 aggravates or reduces brain injury, astrocytic cell death, and glial scar, respectively, but has no direct effect on neuronal cell death. RNA sequencing demonstrates that Matn3-/- mice display an increased inflammatory response profile in the ischemic brain, including the nuclear factor κB (NF-κB) signaling pathway. Both endogenous and exogenous matrilin-3 reduce inflammatory mediators. Mechanistically, extracellular matrilin-3 enters astrocytes via caveolin-1-mediated endocytosis. Cytoplasmic matrilin-3 translocates into the nucleus by binding to NF-κB p65, suppressing inflammatory cytokine transcription. Extracellular matrilin-3 binds to BMP-2, blocking the BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection, at least partially, by suppressing astrocyte-mediated neuroinflammation.

Amelioration of Astrocyte-Mediated Neuroinflammation by EI-16004 Confers Neuroprotection in an MPTP-induced Parkinson's Disease Model.

Parkinson's disease (PD) is a neurodegenerative disorder that results in motor impairment due to dopaminergic neuronal loss. The pathology of PD is closely associated with neuroinflammation, which can be characterized by astrocyte activation. Thus, targeting the inflammatory response in astrocytes might provide a novel therapeutic approach. We conducted a luciferase assay on an in-house chemical library to identify compounds with anti-inflammatory effects capable of reducing MPP+-induced NF-κB activity in astrocytes. Among the compounds identified, EI-16004, a novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides, exhibited a significant anti-inflammatory effect by significantly reducing MPP+-induced astrocyte activation. Biochemical analysis and docking simulation indicated that EI-16004 inhibited the MPP+-induced phosphorylation of p65 by attenuating ERK phosphorylation, and EI-16004 reduced pro-inflammatory cytokine and chemokine levels in astrocytes. In vivo studies on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in male C57BL/6 mice showed that EI-16004 ameliorated motor impairment and protected against dopaminergic neuronal loss, and EI-16004 effectively mitigated the MPTP-induced astrocyte activation in striatum (STR) and substantia nigra (SN). These results indicate EI-16004 is a potential neuroprotective agent for the prevention and treatment of astrocyte-mediated neuroinflammatory conditions in PD.

Desloratadine alleviates ALS-like pathology in hSOD1G93A mice via targeting 5HTR2A on activated spinal astrocytes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1G93A (hSOD1G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1G93A mice were administered DLT (20 mg·kg-1·d-1, i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1G93A mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease. DLT as a 5HTR2A antagonist effectively promoted autophagy to reduce mutant hSOD1 level through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocytic neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice.

MUSCLE MITOCHONDRIAL FUNCTION PREDICTS COGNITIVE IMPAIRMENT AND IS ASSOCIATED WITH PET AND BLOOD BIOMARKERS OF AD

Abstract Mitochondrial dysfunction is a hallmark of aging. Whether mitochondrial dysfunction is related to future cognitive impairment and biomarkers of Alzheimer’s disease (AD) is unknown. In the Baltimore Longitudinal Study of Aging, we used Cox regression to examine the association of skeletal muscle mitochondrial function (post-exercise recovery rate of phosphocreatine, kPCr) via MR spectroscopy with future MCI or dementia over an average follow-up of 3.3 years among 460 initially cognitively normal participants (mean age=76.8±11.0 years, 56.7% women, 22.4% Black). We also examined associations with PiB-distribution volume ratio (DVR) for β-amyloid (Aβ)(n=115), Flortaucipir (FTP)-standardized uptake value ratio (SUVR) for tau(n=70), and blood biomarkers of AD pathology (Aβ42/Aβ40 ratio,n=299; pTau181,n=505), neuronal injury (NfL)(n=299), and astrocyte-mediated neuroinflammation (GFAP)(n=299) using linear regression. After adjustment for age, sex, and race, each SD higher kPCr (i.e. 0.005) was associated with 45% lower hazards of developing cognitive impairment (19 MCI, 4 dementia) (p=0.04). In the PET sample, each SD higher kPCr was associated with 51% lower odds of being PiB positive(p=0.003). Higher kPCr was specifically associated with lower DVR in precentral and postcentral gyri, superior parietal lobe, and pallidum (FDR-adjusted p<0.05). In samples with blood biomarkers, higher kPCr was associated with lower GFAP(p=0.01) and showed a trend toward significance with lower pTau181(p=0.08). Preserved skeletal muscle mitochondrial function is associated with reduced risk of cognitive impairment and PET and blood biomarkers of AD. Future studies are needed to investigate the role of mitochondrial function of the central nervous system in dementia risk and the progression of AD pathologic change.

Inhibition of spinal Rac1 attenuates chronic inflammatory pain by regulating the activation of astrocytes

BackgroundSpinal astrocyte-mediated neuroinflammation is an important mechanism for the maintenance of chronic inflammatory pain. Previous studies have investigated that Ras-related C3 botulinum toxin substrate 1 (Rac1) is closely related to astrocyte activation after central nervous system injury. However, the role of Rac1 in astrocyte activation in chronic inflammatory pain has not been reported. MethodsComplete Freund's adjuvant (CFA)-induced chronic inflammatory pain model and LPS-stimulated astrocytes were used to investigate the role of Rac1 in astrocyte activation and the underlying mechanism. Rac1-interfering adeno-associated virus (AAV) targeting astrocytes was delivered to spinal astrocytes by intrathecal administration and a Rac1 specific inhibitor, NSC23766, was used to block cultured astrocytes. The glial fibrillary acidic protein (GFAP), proinflammatory cytokines, p-NF-κB, and nod-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome were detected by RT-qPCR, Western blotting, and immunofluorescence to investigate the activation of astrocytes. ResultsCFA induced spinal astrocyte activation and increased the expression of active Rac1 in spinal astrocytes. Knockdown of astrocyte Rac1 alleviated chronic inflammatory pain and inhibited astrocyte activation. Inhibition of Rac1 activation in cultured astrocytes decreased the expression of GFAP and proinflammatory cytokines. Knockdown of Rac1 inhibited the increase of expression of NLRP3 inflammasome and phosphorylation of NF-κB in the spinal lumbar enlargement after CFA injection. Similarly, the inhibition of Rac1 suppressed the increase of NLRP3 inflammasome and p-NF-κB protein level after LPS stimulation. ConclusionKnockdown of astrocyte Rac1 attenuated CFA-induced hyperalgesia and astrocyte activation possibly by blocking the expression of NLRP3 inflammasome and phosphorylation of NF-κB.

Bear bile powder alleviates Parkinson's disease-like behavior in mice by inhibiting astrocyte-mediated neuroinflammation.

Parkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. In particular, increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD. As a precious traditional Chinese medicine, bear bile powder (BBP) has a long history of use in clinical practice. It has numerous activities, such as clearing heat, calming the liver wind and anti-inflammation, and also exhibits good therapeutic effect on convulsive epilepsy. However, whether BBP can prevent the development of PD has not been elucidated. Hence, this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD. PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg·kg-1) for five days, followed by BBP (50, 100, and 200 mg·kg-1) treatment daily for ten days. LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation. THe results indicated that BBP treatment significantly ameliorated dyskinesia, increased the levels of tyrosine hydroxylase (TH) and inhibited astrocyte hyperactivation in the substantia nigra (SN) of PD mice. Furthermore, BBP decreased the protein levels of glial fibrillary acidic protein (GFAP), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS), and up-regulated the protein levels of takeda G protein-coupled receptor 5 (TGR5) in the SN. Moreover, BBP significantly activated TGR5 in a dose-dependent manner, and decreased the protein levels of GFAP, iNOS and COX2, as well as the mRNA levels of GFAP, iNOS, COX2, interleukin (IL) -1β, IL-6 and tumor necrosis factor-α (TNF-α) in LPS-stimulated C6 cells. Notably, BBP suppressed the phosphorylation of protein kinase B (AKT), inhibitor of NF-κB (IκBα) and nuclear factor-κB (NF-κB) proteins in vivo and in vitro. We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells. Taken together, BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.

AVE 0991 Suppresses Astrocyte-Mediated Neuroinflammation of Alzheimer's Disease by Enhancing Autophagy.

Our previous study has shown that AVE 0991, a nonpeptide analogue of Ang-(1-7), ameliorates cognitive decline and inhibits NLRP3 inflammasome of astrocytes in Alzheimer's disease model mice. Additionally, several studies have suggested that activation of autophagy appears to effectively inhibit the progression of neuroinflammation. However, it is unclear whether AVE 0991 can modulate astrocyte autophagy to suppress neuroinflammation in Alzheimer's disease. APP/PS1 mice and Aβ-treated primary astrocytes were used as the research objects in vivo and in vitro, respectively. Water maze test was used to evaluate cognitive function of mice, Nissl staining and immunofluorescence staining was used to assess neuronal damage. ELISA kits were used to detect the levels of Ang-(1-7) and Aβ in the cortex, and qRT-PCR was used to detect the expression of cortical inflammation-related mediators. The expression of autophagy-related proteins in cortex were detected by Western blot. The upstream molecular responses involved in inflammation inhibition by AVE 0991 were validated by means of using the Mas1 antagonist and autophagy inhibitor. We found that 30 days of intraperitoneal administration of AVE 0991 improved. Aβ deposition, neuronal death, and cognitive deficits in APP/PS1 Alzheimer's disease model mice. Moreover, AVE 0991 treatment greatly suppressed astrocyte-mediated inflammation and up-regulated the expression of autophagy. Furthermore, the inhibitory effect of AVE 0991 on the expression of inflammatory factors was reversed by 3-MA, an autophagy inhibitor. These findings suggest that regulation of autophagy is critical for inhibiting astrocyte neuroinflammatory responses and demonstrate a potential neuroprotective mechanism by which AVE 0991 could suppress neuroinflammatory responses by enhancing autophagy.

Microglia and Astrocytes in Alzheimer's Disease: Significance and Summary of Recent Advances.

Alzheimer's disease, one of the most common forms of dementia, is characterized by a slow progression of cognitive impairment and neuronal loss. Currently, approved treatments for AD are hindered by various side effects and limited efficacy. Despite considerable research, practical treatments for AD have not been developed. Increasing evidence shows that glial cells, especially microglia and astrocytes, are essential in the initiation and progression of AD. During AD progression, activated resident microglia increases the ability of resting astrocytes to transform into reactive astrocytes, promoting neurodegeneration. Extensive clinical and molecular studies show the involvement of microglia and astrocyte-mediated neuroinflammation in AD pathology, indicating that microglia and astrocytes may be potential therapeutic targets for AD. This review will summarize the significant and recent advances of microglia and astrocytes in the pathogenesis of AD in three parts. First, we will review the typical pathological changes of AD and discuss microglia and astrocytes in terms of function and phenotypic changes. Second, we will describe microglia and astrocytes' physiological and pathological role in AD. These roles include the inflammatory response, "eat me" and "don't eat me" signals, Aβ seeding, propagation, clearance, synapse loss, synaptic pruning, remyelination, and demyelination. Last, we will review the pharmacological and non-pharmacological therapies targeting microglia and astrocytes in AD. We conclude that microglia and astrocytes are essential in the initiation and development of AD. Therefore, understanding the new role of microglia and astrocytes in AD progression is critical for future AD studies and clinical trials. Moreover, pharmacological, and non-pharmacological therapies targeting microglia and astrocytes, with specific studies investigating microglia and astrocyte-mediated neuronal damage and repair, may be a promising research direction for future studies regarding AD treatment and prevention.

Hydrogen Sulfide Attenuates Lipopolysaccharide-Induced Inflammation via the P-glycoprotein and NF-κB Pathway in Astrocytes

Astrocyte activation is key in neurodegenerative diseases. Hydrogen sulfide (H2S) exhibits neuroprotective effects on astrocytes, although the underlying molecular mechanism remains unclear. Here, we explored the effects of H2S on lipopolysaccharide (LPS)-induced astrocyte activation and astrocyte-mediated neuroinflammation. After inducing primary astrocytes via LPS exposure, H2S levels were altered. The generation and secretion of inflammatory mediators by astrocytes and their interrelation with P-glycoprotein (P-gp), an important transporter belonging to the ABC transporter family, were assessed. Activated astrocytes showed upregulated glial fibrillary acidic protein (GFAP) mRNA expression, and significantly increased proinflammatory factor mRNA/protein expression and release. The secretory capacity of astrocytes was reduced, with significantly decreased proinflammatory factor levels in culture supernatant after P-gp inhibitor verapamil pretreatment. The increase in the intracellular H2S level inhibited LPS-induced GFAP expression and P65 nuclear entry in astrocytes. mRNA expression and release of proinflammatory factors were reduced significantly, with no significant changes in cytoplasmic protein expression. S-sulfhydration levels increased significantly with the increased concentration of sodium hydrosulfide or S-adenosyl-l-methionine addition, with only moderate changes in astrocyte P-gp expression. H2S regulates NF-κB activation, leads to S-sulfhydration of P-gp, and inhibits the biosynthesis and secretion of proinflammatory factors by astrocytes. The regulatory effects of H2S on astrocytes may have clinical value for exploring new therapeutic strategies against neurodegenerative diseases.

Effect of benzo(a)pyrene on oxidative stress and inflammatory mediators in astrocytes and HIV-infected macrophages.

BackgroundBenzo(a)pyrene (BaP), an important polycyclic aromatic hydrocarbons (PAH) component of cigarette/tobacco smoking, is known to cause adverse health effects and is responsible for various life-threatening conditions including cancer. However, it is not yet clear whether BaP contributes to the macrophage- and astrocyte-mediated inflammatory response.MethodsWe examined the acute (up to 72 h) effects of BaP on the expression of antioxidant enzymes (AOEs), cytokines/chemokines, and cytochromes P450 (CYP) enzymes in astrocytic cell lines, SVGA, and chronically HIV-infected U1 macrophage. The treated cells were examined for mRNA, protein levels of CYPs, AOEs superoxide dismutase-1 (SOD1) and catalase (CAT), cytokines/chemokines, using Western blot, multiplex ELISA, and reactive oxygen species (ROS) by flow cytometry analysis.ResultsUpon acute exposure, BaP (1 μM) showed a significant increase in the mRNA levels of CYPs (CYP1A1 and CYP1B1), and pro-inflammatory cytokine IL-1β in SVGA cells following BaP for 24, 48, and 72h. In addition, we observed a significant increase in the mRNA levels of SOD1 and CAT at 24h of BaP treatment. In contrast, BaP did not exert any change in the protein expression of AOEs and CYP enzymes. In U1 cells, however, we noticed an interesting increase in the levels of MCP-1 as well as a modest increase in TNFα, IL-8 and IL-1β levels observed at 72 h of BaP treatment but could not reach to statistically significant level.ConclusionsOverall, these results suggest that BaP contributes in part to macrophage and astrocyte-mediated neuroinflammation by mainly inducing IL-1β and MCP-1 production, which is likely to occur with the involvement of CYP and/or oxidative stress pathways.

Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders.

Sinomenine is a natural compound extracted from the medicinal plant Sinomenium acutum. Its supplementation has been shown to present benefits in a variety of animal models of central nervous system (CNS) disorders, such as cerebral ischemia, intracerebral hemorrhage, traumatic brain injury (TBI), Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, depression, multiple sclerosis, morphine tolerance, and glioma. Therefore, sinomenine is now considered a potential agent for the prevention and/or treatment of CNS disorders. Mechanistic studies have shown that inhibition of oxidative stress, microglia- or astrocyte-mediated neuroinflammation, and neuronal apoptosis are common mechanisms for the neuroprotective effects of sinomenine. Other mechanisms, including activation of nuclear factor E2-related factor 2 (Nrf2), induction of autophagy in response to inhibition of protein kinase B (Akt)-mammalian target of rapamycin (mTOR), and activation of cyclic adenosine monophosphate-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), may also mediate the anti-glioma and neuroprotective effects of sinomenine. Sinomenine treatment has also been shown to enhance dopamine receptor D2 (DRD2)-mediated nuclear translocation of αB-crystallin (CRYAB) in astrocytes, thereby suppressing neuroinflammation via inhibition of Signal Transducer and Activator of Transcription 3 (STAT3). In addition, sinomenine supplementation can suppress N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx and induce γ-aminobutyric acid type A (GABAA) receptor-mediated Cl− influx, each of which contributes to the improvement of morphine dependence and sleep disturbance. In this review, we outline the pharmacological effects and possible mechanisms of sinomenine in CNS disorders to advance the development of sinomenine as a new drug for the treatment of CNS disorders.

Transfer of neuron-derived α-synuclein to astrocytes induces neuroinflammation and blood–brain barrier damage after methamphetamine exposure: Involving the regulation of nuclear receptor-associated protein 1

The α-synuclein (α-syn) is involved in methamphetamine (METH)-induced neurotoxicity. Neurons can transfer excessive α-syn to neighboring neurons and glial cells. The effects of α-syn aggregation in astrocytes after METH exposure on the blood–brain barrier (BBB) remains unclear. Our previous study demonstrated that nuclear receptor-related protein 1 (Nurr1), a member of the nuclear receptor family widely expressed in the brain, was involved in the process of METH-induced α-syn accumulated in astrocytes to activate neuroinflammation. The role Nurr1 plays in astrocyte-mediated neuroinflammation, which results in BBB injury induced by METH, remains uncertain. This study found that METH up-regulated α-syn expression in neurons extended to astrocytes, thereby eliciting astrocyte activation, increasing and decreasing IL-1β, IL-6, TNF-α, and GDNF levels by down-regulating Nurr1 expression, and ultimately damaging the BBB. Specifically, the permeability of BBB to Evans blue and sodium fluorescein (NaF) increased; IgG deposits in the brain parenchyma increased; the Claudin5, Occludin, and PDGFRβ levels decreased. Several ultrastructural pathological changes occurred in the BBB, such as abnormal cerebral microvascular diameter, astrocyte end-foot swelling, decreased pericyte coverage, and loss of tight junctions. However, knockout or inhibition of α-syn or astrocyte-specific overexpression of Nurr1 partially alleviated these symptoms and BBB injury. Moreover, the in vitro experiments confirmed that METH increased α-syn level in the primary cultured neurons, which could be further transferred to primary cultured astrocytes, resulting in decreased Nurr1 levels. The decreased Nurr1 levels mediated the increase of IL-1β, IL-6, and TNF-α, and the decrease of GDNF, thereby changing the permeability to NaF, transendothelial electrical resistance, and Claudin5 and Occludin levels of primary cultured brain microvascular endothelial cells. Based on our findings, we proposed a new mechanism to elucidate METH-induced BBB injury and presented α-syn and Nurr1 as promising drug intervention targets to reduce BBB injury and resulting neurotoxicity in METH abusers.

Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain

The molecular determinants of tissue composition of the human brain remain largely unknown. Recent genome-wide association studies (GWAS) on this topic have had limited success due to methodological constraints. Here, we apply advanced whole-brain analyses on multi-shell diffusion imaging data and multivariate GWAS to two large scale imaging genetic datasets (UK Biobank and the Adolescent Brain Cognitive Development study) to identify and validate genetic association signals. We discover 503 unique genetic loci that have impact on multiple regions of human brain. Among them, more than 79% are validated in either of two large-scale independent imaging datasets. Key molecular pathways involved in axonal growth, astrocyte-mediated neuroinflammation, and synaptogenesis during development are found to significantly impact the measured variations in tissue-specific imaging features. Our results shed new light on the biological determinants of brain tissue composition and their potential overlap with the genetic basis of neuropsychiatric disorders.

Japanese encephalitis viral infection modulates proinflammatory cyto/chemokine profile in primary astrocyte and cell line of astrocytic origin

Japanese Encephalitis Virus (JEV) is a neurotropic virus that invades Central Nervous System (CNS) and causes severe neuroinflammation. Given the abundance and the position of astrocytes in the CNS, we speculate that they might play a critical role in the process of neuroinflammation. Unfortunately, the role of astrocytes in JEV-mediated neuroinflammation has long been understated. In this study, we have attempted to assess the role of astrocyte-mediated neuroinflammation upon JEV infection. Mouse model of JEV infection, generated by intraperitoneal injection, showed severe reactive astrogliosis. To further address our hypothesis, we employed immortalized astrocytic cell line (in vitro) and primary astrocyte-enriched culture (ex vivo) as experimental models. JEV infection in the astrocytes induces proinflammatory cytokines like MCP1/CCL2 and IL6 in both ex vivo and in vitro cultures as observed from the cytometric bead array analysis. A significantly altered cytokine profile was observed using PCR analysis in in vitro and ex vivo models upon infection, with respect to control, validating our previous results. We also show that there exists a major inconsistency in the viral replication kinetics, wherein the cell line showed a robust rate of replication whereas the primary astrocyte-enriched culture showed negligibly low number of plaques, underlining the importance of the selection of appropriate experimental model system. In conclusion, we claim that astrocytes significantly contribute to JEV-mediated neuroinflammation, despite not being a CNS immune cell.

Astilbin ameliorates depressive-like behavior caused by postnatal immune activation through Menin-regulated astrocyte inflammation

Postnatal immune activation (PIA) can affect normal brain development and increase the risk of behavioral abnormalities in later life, including depressive-like behavior. Therefore, there is an urgent need to find safe and effective clinical medications for PIA. Recently, the protective effect of astilbin (ASB) in nervous system diseases has attracted much attention. However, the effect of ASB on neurodevelopmental diseases remains unclear. In this study, we used a lipopolysaccharide (LPS)-induced PIA mouse model and found that ASB specifically improved PIA-induced depressive-like behavior but not anxiety-like behavior in adult mice. Astrocytes play an essential role in regulating neuroinflammation, and are the most abundant cell type in the brain. In the PIA model, we found that ASB selectively inhibited astrocyte activation but not microglial activation in the cortex and hippocampus. Moreover, our results showed that ASB specifically upregulated the expression of menin protein in astrocytes and blocked the entry of P65 protein into the nucleus, thus inhibiting the secretion of IL-1β and TNF-α by astrocytes. Taken together, ASB reduced the occurrence of astrocyte-mediated neuroinflammation by targeting menin, thereby attenuating the PIA-induced depressive-like behavior. Our results reveal that ASB may be an attractive antidepressant drug and exert an antidepressant effect in PIA. In terms of drug selection, ASB may be a specific drug for patients with depressive symptoms.

Ponesimod inhibits astrocyte-mediated neuroinflammation and protects against cingulum demyelination via S1P1 -selective modulation.

Ponesimod is a sphingosine 1‐phosphate (S1P) receptor (S1PR) modulator that was recently approved for treating relapsing forms of multiple sclerosis (MS). Three other FDA‐approved S1PR modulators for MS—fingolimod, siponimod, and ozanimod—share peripheral immunological effects via common S1P1 interactions, yet ponesimod may access distinct central nervous system (CNS) mechanisms through its selectivity for the S1P1 receptor. Here, ponesimod was examined for S1PR internalization and binding, human astrocyte signaling and single‐cell RNA‐seq (scRNA‐seq) gene expression, and in vivo using murine cuprizone‐mediated demyelination. Studies confirmed ponesimod’s selectivity for S1P1 without comparable engagement to the other S1PR subtypes (S1P2,3,4,5). Ponesimod showed pharmacological properties of acute agonism followed by chronic functional antagonism of S1P1. A major locus of S1P1 expression in the CNS is on astrocytes, and scRNA‐seq of primary human astrocytes exposed to ponesimod identified a gene ontology relationship of reduced neuroinflammation and reduction in known astrocyte disease‐related genes including those of immediate early astrocytes that have been strongly associated with disease progression in MS animal models. Remarkably, ponesimod prevented cuprizone‐induced demyelination selectively in the cingulum, but not in the corpus callosum. These data support the CNS activities of ponesimod through S1P1, including protective, and likely selective, effects against demyelination in a major connection pathway of the brain, the limbic fibers of the cingulum, lesions of which have been associated with several neurologic impairments including MS fatigue.