Minocycline Abrogates Individual Differences in Nerve Injury-Evoked Affective Disturbances in Male Rats and Prevents Associated Supraspinal Neuroinflammation.

Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.

Auraptene-ameliorating depressive-like behaviors induced by lipopolysaccharide combined with chronic unpredictable mild stress in mice mitigate hippocampal neuroinflammation mediated by microglia.

An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-ß (TGF-ß) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia.

Empagliflozin alleviates neuroinflammation by inhibiting astrocyte activation in the brain and regulating gut microbiota of high-fat diet mice.

A high-fat diet can modify the composition of gut microbiota, resulting in dysbiosis. Changes in gut microbiota composition can lead to increased permeability of the gut barrier, allowing bacterial products like lipopolysaccharides (LPS) to enter circulation. This process can initiate systemic inflammation and contribute to neuroinflammation. Empagliflozin (EF), an SGLT2 inhibitor-type hypoglycemic drug, has been reported to treat neuroinflammation. However, there is a lack of evidence showing that EF regulates the gut microbiota axis to control neuroinflammation in HFD models. In this study, we explored whether EF could improve neuroinflammation caused by an HFD via regulation of the gut microbiota and the mechanism underlying this phenomenon. Our data revealed that EF alleviates pathological brain injury, reduces the reactive proliferation of astrocytes, and increases the expression of synaptophysin. In addition, the levels of inflammatory factors in hippocampal tissue were significantly decreased after EF intervention. Subsequently, the results of 16S rRNA gene sequencing showed that EF could change the microbial community structure of mice, indicating that the abundance of Lactococcus, Ligilactobacillus and other microbial populations decreased dramatically. Therefore, EF alleviates neuroinflammation by inhibiting gut microbiota-mediated astrocyte activation in the brains of high-fat diet-fed mice. Our study focused on the gut-brain axis, and broader research on neuroinflammation can provide a more holistic understanding of the mechanisms driving neurodegenerative diseases and inform the development of effective strategies to mitigate their impact on brain health. The results provide strong evidence supporting the larger clinical application of EF.

A rare olive compound oleacein functions as a TrkB agonist and mitigates neuroinflammation both in vitro and in vivo.

BACKGROUND: Neuroinflammation is widely acknowledged as a characteristic feature of almost all neurological disorders and specifically in depression- and anxiety-like disorders. In recent years, there has been significant attention on natural compounds with potent anti-inflammatory effects due to their potential in mitigating neuroinflammation and neuroplasticity. METHODS: In the present study, we aimed to evaluate the neuroprotective effects of oleacein (OC), a rare secoiridoid derivative found in extra virgin olive oil. Our goal was to explore the BDNF/TrkB neurotrophic activity of OC and subsequently assess its potential for modulating neuroinflammatory response using human neuroblastoma cells (SH-SY5Y cells) and an in vivo model of depression induced by lipopolysaccharide (LPS)-mediated inflammation. RESULTS: In SH-SY5Y cells, OC exhibited a significant dose-dependent increase in BDNF expression. This enhancement was absent when cells were co-treated with inhibitors of BDNF's receptor TrkB, as well as downstream molecules PI3K and MEK. Whole-transcriptomics analysis revealed that OC upregulated cell cycle-related genes under normal conditions, while downregulating inflammation-associated genes in LPS-induced conditions. Furthermore, surface plasmon resonance (SPR) assays demonstrated that OC exhibited a stronger and more stable binding affinity to TrkB compared to the positive control, 7,8-dihydroxyflavone. Importantly, bioluminescence imaging revealed that a single oral dose of OC significantly increased BDNF expression in the brains of Bdnf-IRES-AkaLuc mice. Furthermore, oral administration of OC at a dosage of 10 mg/kg body weight for 10 days significantly reduced immobility time in the tail suspension test compared to the LPS-treated group. RT-qPCR analysis revealed that OC significantly decreased the expression of pro-inflammatory cytokines Tnfα, Il6, and Il1ß, while simultaneously enhancing Bdnf expression, as well as both pro and mature BDNF protein levels in mice hippocampus. These changes were comparable to those induced by the positive control antidepressant drug fluoxetine. Additionally, microarray analysis of mouse brains confirmed that OC could counteract LPS-induced inflammatory biological events. CONCLUSION: Altogether, our study represents the first report on the potential antineuroinflammatory and antidepressant properties of OC via modulation of BDNF/TrkB neurotrophic activity. This finding underscores the potential of OC as a natural therapeutic agent for depression- and anxiety-related disorders.

A helping HAND: therapeutic potential of MAGL inhibition against HIV-1-associated neuroinflammation.

Background: Human immunodeficiency virus (HIV) affects nearly 40 million people globally, with roughly 80% of all people living with HIV receiving antiretroviral therapy. Antiretroviral treatment suppresses viral load in peripheral tissues but does not effectively penetrate the blood-brain barrier. Thus, viral reservoirs persist in the central nervous system and continue to produce low levels of inflammatory factors and early viral proteins, including the transactivator of transcription (Tat). HIV Tat is known to contribute to chronic neuroinflammation and synaptodendritic damage, which is associated with the development of cognitive, motor, and/or mood problems, collectively known as HIV-associated neurocognitive disorders (HAND). Cannabinoid anti-inflammatory effects are well documented, but therapeutic utility of cannabis remains limited due to its psychotropic effects, including alterations within brain regions encoding reward processing and motivation, such as the nucleus accumbens. Alternatively, inhibiting monoacylglycerol lipase (MAGL) has demonstrated therapeutic potential through interactions with the endocannabinoid system. Methods: The present study utilized a reward-related operant behavioral task to quantify motivated behavior in female Tat transgenic mice treated with vehicle or MAGL inhibitor MJN110 (1 mg/kg). Brain tissue was collected to assess dendritic injury and neuroinflammatory profiles, including dendritic microtubule-associated protein (MAP2ab) intensity, microglia density, microglia morphology, astrocyte density, astrocytic interleukin-1ß (IL-1ß) colocalization, and various lipid mediators. Results: No significant behavioral differences were observed; however, MJN110 protected against Tat-induced dendritic injury by significantly upregulating MAP2ab intensity in the nucleus accumbens and in the infralimbic cortex of Tat(+) mice. No or only minor effects were noted for Iba-1+ microglia density and/or microglia morphology. Further, Tat increased GFAP+ astrocyte density in the infralimbic cortex and GFAP+ astrocytic IL-1ß colocalization in the nucleus accumbens, with MJN110 significantly reducing these measures in Tat(+) subjects. Lastly, selected HETE-related inflammatory lipid mediators in the striatum were downregulated by chronic MJN110 treatment. Conclusions: These findings demonstrate anti-inflammatory and neuroprotective properties of MJN110 without cannabimimetic behavioral effects and suggest a promising alternative to cannabis for managing neuroinflammation.

NADPH and NAC synergistically inhibits chronic ocular hypertension-induced neurodegeneration and neuroinflammation through regulating p38/MAPK pathway and peroxidation.

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.

Inhibition of Amyloid-ß (Aß)-Induced Cognitive Impairment and Neuroinflammation in CHI3L1 Knockout Mice through Downregulation of ERK-PTX3 Pathway.

Several clinical studies reported that the elevated expression of Chitinase-3-like 1 (CHI3L1) was observed in patients suffering from a wide range of diseases: cancer, metabolic, and neurological diseases. However, the role of CHI3L1 in AD is still unclear. Our previous study demonstrated that 2-({3-[2-(1-Cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}culfanyl)-N-(4-ethylphenyl)butanamide, a CHI3L1 inhibiting compound, alleviates memory and cognitive impairment and inhibits neuroinflammation in AD mouse models. In this study, we studied the detailed correlation of CHI3L1 and AD using serum from AD patients and using CHI3L1 knockout (KO) mice with Aß infusion (300 pmol/day, 14 days). Serum levels of CHI3L1 were significantly elevated in patients with AD compared to normal subjects, and receiver operating characteristic (ROC) analysis data based on serum analysis suggested that CHI3L1 could be a significant diagnostic reference for AD. To reveal the role of CHI3L1 in AD, we investigated the CHI3L1 deficiency effect on memory impairment in Aß-infused mice and microglial BV-2 cells. In CHI3L1 KO mice, Aß infusion resulted in lower levels of memory dysfunction and neuroinflammation compared to that of WT mice. CHI3L1 deficiency selectively inhibited phosphorylation of ERK and IκB as well as inhibition of neuroinflammation-related factors in vivo and in vitro. On the other hand, treatment with recombinant CHI3L1 increased neuroinflammation-related factors and promoted phosphorylation of IκB except for ERK in vitro. Web-based gene network analysis and our results showed that CHI3L1 is closely correlated with PTX3. Moreover, in AD patients, we found that serum levels of PTX3 were correlated with serum levels of CHI3L1 by Spearman correlation analysis. These results suggest that CHI3L1 deficiency could inhibit AD development by blocking the ERK-dependent PTX3 pathway.

Blockade of the ADAM8-Fra-1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury.

BACKGROUND: Mechanical spinal cord injury (SCI) is a deteriorative neurological disorder, causing secondary neuroinflammation and neuropathy. ADAM8 is thought to be an extracellular metalloproteinase, which regulates proteolysis and cell adherence, but whether its intracellular region is involved in regulating neuroinflammation in microglia after SCI is unclear. METHODS: Using animal tissue RNA-Seq and clinical blood sample examinations, we found that a specific up-regulation of ADAM8 in microglia was associated with inflammation after SCI. In vitro, microglia stimulated by HMGB1, the tail region of ADAM8, promoted microglial inflammation, migration and proliferation by directly interacting with ERKs and Fra-1 to promote activation, then further activated Map3k4/JNKs/p38. Using SCI mice, we used BK-1361, a specific inhibitor of ADAM8, to treat these mice. RESULTS: The results showed that administration of BK-1361 attenuated the level of neuroinflammation and reduced microglial activation and recruitment by inhibiting the ADAM8/Fra-1 axis. Furthermore, treatment with BK-1361 alleviated glial scar formation, and also preserved myelin and axonal structures. The locomotor recovery of SCI mice treated with BK-1361 was therefore better than those without treatment. CONCLUSIONS: Taken together, the results showed that ADAM8 was a critical molecule, which positively regulated neuroinflammatory development and secondary pathogenesis by promoting microglial activation and migration. Mechanically, ADAM8 formed a complex with ERK and Fra-1 to further activate the Map3k4/JNK/p38 axis in microglia. Inhibition of ADAM8 by treatment with BK-1361 decreased the levels of neuroinflammation, glial formation, and neurohistological loss, leading to favorable improvement in locomotor functional recovery in SCI mice.

Inhibition of Microglial Activation Ameliorates Inflammation, Reduced Neurogenesis in the hippocampus, and Impaired Brain Function in a Rat Model of Bilirubin Encephalopathy.

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1ß, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies.

Crocin ameliorates neuroinflammation and cognitive impairment in mice with Alzheimer's disease by activating PI3K/AKT pathway.

BACKGROUND: Crocin has a good prospect in the treatment of Alzheimer's disease (AD), but the mechanisms underlying its neuroprotective effects remain elusive. This study aimed to investigate the neuroprotective effects of Crocin and its underlying mechanisms in AD. METHODS: AD mice were set up by injecting Aß25-35 solution into the hippocampus. Then, the AD mice were injected intraperitoneally with 40 mg/kg/day of Crocin for 14 days. Following the completion of Crocin treatment, an open-field test, Y-maze test and Morris water maze test were conducted to evaluate the impact of Crocin on spatial learning and memory deficiency in mice. The effects of Crocin on hippocampal neuron injury, proinflammatory cytokine expressions (IL-1ß, IL-6, and TNF-α), and PI3K/AKT signaling-related protein expressions were measured using hematoxylin and eosin staining, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, respectively. RESULTS: Crocin attenuated Aß25-35-induced spatial learning and memory deficiency and hippocampal neuron injury. Furthermore, the Western blot and qRT-PCR results showed that Crocin effectively suppressed inflammation and activated the PI3K/AKT pathway in Aß25-35-induced mice. CONCLUSION: Crocin restrained neuroinflammation via the activation of the PI3K/AKT pathway, thereby ameliorating the cognitive dysfunction of AD mice.

Danshen injection mitigated the cerebral ischemia/reperfusion injury by suppressing neuroinflammation via the HIF-1α/CXCR4/NF-κB signaling pathway.

Danshen injection (DI) is effective in treating cardiovascular and cerebrovascular diseases, including ischemic stroke (IS), including IS, but its mechanism is unclear. A middle cerebral artery occlusion model was used to simulate ischemia/reperfusion (I/R) injury in SD rats. Overexpression of hypoxia-inducible factor 1α (HIF-1α) was achieved by AAV-HIF-1α. Rats were treated with DI or saline. Neurological scores and infarction rates were assessed. I/R damage was examined by HE, 2,3,5-triphenyltetrazolium and Nissl stainings. Expression levels of relative proteins [TNF-α, IL-6, IL-1ß, SOD, MDA, ROS, HIF-1α, CXC chemokine receptor 4 (CXCR4) and NF-κB] were measured. DI treatment improved neurological scores and reduced infarction rates, suggesting that it inhibits inflammation and oxidative stress. The expression levels of HIF-1α, CXCR4 and NF-κB were decreased. However, the effectiveness of DI on inflammation inhibition was lost after HIF-1α overexpression. DI may directly target HIF-1α to suppress neuroinflammation and reduce I/R injury by suppressing the HIF-1α/CXCR4/NF-κB signaling pathway.

Dl-3-n-butylphthalide promotes microglial phagocytosis and inhibits microglial inflammation via regulating AGE-RAGE pathway in APP/PS1 mice.

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative condition worldwide, and its correlation with microglial function is notably significant. Dl-3-n-butylphthalide (NBP), derived from the seeds of Apium graveolens L. (Chinese celery), has demonstrated the capacity to diminish Aß levels in the brain tissue of Alzheimer's transgenic mice. Despite this, its connection to neuroinflammation and microglial phagocytosis, along with the specific molecular mechanism involved, remains undefined. In this study, NBP treatment exhibited a substantial improvement in learning deficits observed in AD transgenic mice (APP/PS1 transgenic mice). Furthermore, NBP treatment significantly mitigated the total cerebral Aß plaque deposition. This effect was attributed to the heightened presence of activated microglia surrounding Aß plaques and an increase in microglial phagocytosis of Aß plaques. Transcriptome sequencing analysis unveiled the potential involvement of the AGE (advanced glycation end products) -RAGE (receptor for AGE) signaling pathway in NBP's impact on APP/PS1 mice. Subsequent investigation disclosed a reduction in the secretion of AGEs, RAGE, and proinflammatory factors within the hippocampus and cortex of NBP-treated APP/PS1 mice. In summary, NBP alleviates cognitive impairment by augmenting the number of activated microglia around Aß plaques and ameliorating AGE-RAGE-mediated neuroinflammation. These findings underscore the related mechanism of the crucial neuroprotective roles of microglial phagocytosis and anti-inflammation in NBP treatment for AD, offering a potential therapeutic target for the disease.

Jingfang granules protects against intracerebral hemorrhage by inhibiting neuroinflammation and protecting blood-brain barrier damage.

Intracerebral hemorrhage (ICH) can induce intensive oxidative stress, neuroinflammation, and brain cell apoptosis. However, conventional methods for ICH treatment have many disadvantages. There is an urgent need for alternative, effective therapies with minimal side effects. Pharmacodynamics experiment, molecular docking, network pharmacology, and metabolomics were adopted to investigate the treatment and its mechanism of Jingfang Granules (JFG) in ICH. In this study, we investigated the therapeutic effects of JFG on ICH using behavioral, brain water content and Magnetic resonance imaging experiments. However, the key active component and targets of JFG remain unknown. Here we verified that JFG was beneficial to improve brain injury after ICH. A network pharmacology analysis revealed that the anti-inflammatory effect of JFG is predominantly mediated by its activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway through Luteolin, (+)-Anomalin and Phaseol and their targeting of AKT1, tumor necrosis factorα (TNF-α), and interleukin-1ß (IL-1ß). Molecular docking analyses revealed an average affinity of -8.633 kcal/mol, indicating a binding strength of less than -5 kcal/mol. Metabolomic analysis showed that JFG exerted its therapeutic effect on ICH by regulating metabolic pathways, such as the metabolism of taurine and hypotaurine, biosynthesis of valine, leucine, and isoleucine. In conclusion, we demonstrated that JFG attenuated neuroinflammation and BBB injury subsequent to ICH by activating the PI3K/Akt signaling pathway.

Nobiletin regulates intracellular Ca2+ levels via IP3R and ameliorates neuroinflammation in Aß42-induced astrocytes.

Astrocytes are the major glial cells in the human brain and provide crucial metabolic and trophic support to neurons. The amyloid-ß peptide (Aß) alter the morphological and functional properties of astrocytes and induce inflammation and calcium dysregulation, contributing to Alzheimer's disease (AD) pathology. Recent studies highlight the role of Toll-like receptor (TLR) 4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in inflammation. Reactive oxygen species (ROS) generated due to Aß, induce apoptosis in the brain cells worsening AD progression. Astrocytic cell surface receptors, such as purinergic receptors (P2Y1 and P2Y2), metabotropic glutamate receptor (mGLUR)5, α7 nicotinic acetylcholine receptor (α7nAChR), and N-methyl-d-aspartate receptors (NMDARs), have been suggested to interact with inositol trisphosphate receptor (IP3R) on the endoplasmic reticulum (ER) to induce Ca2+ movement from ER to cytoplasm, causing Ca2+ dysregulation. We found that the citrus flavonoid nobiletin (NOB) protected primary astrocytes from Aß42-induced cytotoxicity and inhibited TLR4/NF-κB signaling in Aß42-induced primary rat astrocytes. NOB was found to regulate Aß42-induced ROS levels through Keap1-Nrf2 pathway. The receptors P2Y1, P2Y2, mGLUR5, α7nAChR, and NMDARs induced intracellular Ca2+ levels by activating IP3R and NOB regulated them, thereby regulating intracellular Ca2+ levels. Molecular docking analysis revealed a possible interaction between NOB and IP3R in IP3R regulation. Furthermore, RNA sequencing revealed various NOB-mediated biological signaling pathways, such as the AD-presenilin, AD-amyloid secretase, and Wnt signaling pathway, suggesting possible neuroprotective roles of NOB. To conclude, NOB is a promising therapeutic agent for AD and works by modulating AD pathology at various levels in Aß42-induced primary rat astrocytes.

SOCS modulates JAK-STAT pathway as a novel target to mediate the occurrence of neuroinflammation: Molecular details and treatment options.

SOCS (Suppressor of Cytokine Signalling) proteins are intracellular negative regulators that primarily modulate and inhibit cytokine-mediated signal transduction, playing a crucial role in immune homeostasis and related inflammatory diseases. SOCS act as inhibitors by regulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, thereby intervening in the pathogenesis of inflammation and autoimmune diseases. Recent studies have also demonstrated their involvement in central immunity and neuroinflammation, showing a dual functionality. However, the specific mechanisms of SOCS in the central nervous system remain unclear. This review thoroughly elucidates the specific mechanisms linking the SOCS-JAK-STAT pathway with the inflammatory manifestations of neurodegenerative diseases. Based on this, it proposes the theory that SOCS proteins can regulate the JAK-STAT pathway and inhibit the occurrence of neuroinflammation. Additionally, this review explores in detail the current therapeutic landscape and potential of targeting SOCS in the brain via the JAK-STAT pathway for neuroinflammation, offering insights into potential targets for the treatment of neurodegenerative diseases.

JR14a: A novel antagonist of C3aR attenuates neuroinflammation in cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion injury (CIRI), a prevalent stroke-related complication, can lead to severe brain damage. Inflammation is a crucial factor in CIRI pathogenesis, and the complement component 3a receptor (C3aR) could be a key mediator in the post-CIRI inflammatory cascade. In this study, the role of C3aR in CIRI was investigated utilizing a middle cerebral artery occlusion (MCAO) model in C3aR knockout (KO) mice. Magnetic resonance imaging (MRI) and neurofunctional assessments revealed that C3aR KO mice exhibited significantly diminished cerebral infarction and improved neurological impairments. Consequently, the focus shifted to searching for a small molecule antagonist of C3aR. JR14a, a new potent thiophene antagonist of C3aR, was injected intraperitoneally into mice 1-h post-MCAO model implementation. The mass spectrometry (MS) results indicated the ability of JR14a to penetrate the blood-brain barrier. Subsequent TTC staining and neurofunctional assessments revealed the efficacy of JR14a in reducing cerebral infarct volume and neurological impairment following MCAO. In addition, immunofluorescence (IF) and immunohistochemistry (IHC) demonstrated attenuated microglial activation, neutrophil infiltration, and blood-brain barrier disruption by JR14a in the MCAO model. Furthermore, enzyme-linked immunosorbent assay (ELISA) and Western blotting supported the role of JR14a in downregulating the expression levels of C3aR, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), as well as the phosphorylation of p65. In conclusion, the findings suggested that C3aR could be a potential therapeutic target for CIRI, and JR14a emerged as a promising treatment candidate.

Acorus tatarinowii oils exert protective effects on microglia-mediated inflammatory injury via restoring gut microbiota composition in experimental stroke rats.

Growing evidence has demonstrated that gut microbiota could be developed as a therapeutic target due to its contribution to microglia activation in the pathological process of ischemic stroke. Acorus tatarinowii oils (AT oils), which is considered as the active fraction of a traditional Chinese herbal medicine Acorus tatarinowii, exerts various bioactivities and prebiotic effects. However, it remains unclear that the effect of AT oils on inflammatory response after ischemic stroke and whether its underlying mechanism is associated to gut microbiota and the intestinal barrier. In the current study, we aim to investigate the anti-microglial neuroinflammation mechanism of AT oils in a middle cerebral artery occlusion model of ischemic stroke. The compositions of AT oils were identified by GC-MS. Our results demonstrated that AT oils could effectively relieve cerebral infarction, inhibit neuronal apoptosis, degrade the release of pro-inflammatory factors (TNF-α, IL-17, IL-6 and IFN-γ), and mediate the polarization of microglia. Moreover, AT oils restored the composition and the balance of gut microbiota in stroke rats, and reduced abundance of opportunistic genera including Verrucomicrobia, Akkermansia and Tenericutes, as well as increased beneficial bacteria abundance such as Tenericutes and Prevotella_copri. To investigate the role of gut microbiota on AT oils against ischemic stroke, we conducted the fecal microbiota transplantation (FMT) experiments with gut microbiota consumption, which suggested that the depletion of gut microbiota took away the protective effect of AT oils, confirming the importance of gut microbiota in the protective effect of AT oils on ischemic stroke. FMT experiments have demonstrated that AT oils preserved the gut permeability and blood-brain barrier, as well as mediated the microglial phenotype under the intervention of gut microbiota. In summary, AT oils could efficaciously moderate neuronal damage and intervene microglial phenotype by reversing gut microbiota disorder in ischemic stroke rats.

Mitigation of CXCL10 secretion by metabolic disorder drugs in microglial-mediated neuroinflammation.

Metabolic disorders are associated with several neurodegenerative diseases. We previously identified C-X-C motif chemokine ligand 10 (CXCL10), also known as interferon gamma-induced protein 10 (IP-10), as a major contributor to the type I interferon response in microglial-mediated neuroinflammation. Therefore, we hypothesized FDA-approved metabolic disorder drugs that attenuate CXCL10 secretion may be repurposed as a treatment for neurodegenerative diseases. Screening, dose curves, and cytotoxicity assays in LPS-stimulated microglia yielded treprostinil (hypertension), pitavastatin (hyperlipidemia), and eplerenone (hypertension) as candidates that significantly reduced CXCL10 secretion (in addition to other pro-inflammatory mediators) without impacting cell viability. Altogether, these data suggest metabolic disorder drugs that attenuate CXCL10 as potential treatments for neurodegenerative disease through mitigating microglial-mediated neuroinflammation.

Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target?

Neurological diseases with a neurodegenerative component have been associated with alterations in the cerebrovasculature. At the anatomical level, these are centred around changes in cerebral blood flow and vessel organisation. At the molecular level, there is extensive expression of cellular adhesion molecules and increased release of pro-inflammatory mediators. Together, these has been found to negatively impact blood-brain barrier integrity. Systemic inflammation has been found to accelerate and exacerbate endothelial dysfunction, neuroinflammation and degeneration. Here, we review the role of cerebrovasculature dysfunction in neurodegenerative disease and discuss the potential contribution of intermittent pro-inflammatory systemic disease in causing endothelial pathology, highlighting a possible mechanism that may allow broad-spectrum therapeutic targeting in the future.

Intervention of CXCL5 attenuated neuroinflammation and promoted neurological recovery after traumatic brain injury.

Neuroinflammation after traumatic brain injury (TBI) exhibits a strong correlation with neurological impairment, which is a crucial target for improving the prognosis of TBI patients. The involvement of CXCL5/CXCR2 signaling in the regulation of neuroinflammation in brain injury models has been documented. Therefore, the effects of CXCL5 on post-TBI neuroinflammation and its potential mechanisms need to be explored. Following TBI, C57BL/6 mice were administered intraperitoneal injections of a CXCL5 neutralizing antibody (Nab-CXCL5) (5 mg/kg, 2 times/day). Subsequently, the effects on neuroinflammation, nerve injury, and neurological function were assessed. Nab-CXCL5 significantly reduced the release of inflammatory factors, inhibited the formation of inflammatory microglia and astrocytes, and reduced the infiltration of peripheral immune cells in TBI mice. Additionally, this intervention led to a reduction in neuronal impairment and facilitated the restoration of sensorimotor abilities, as well as improvements in learning and memory functions. Peripheral administration of the Nab-CXCL5 to TBI mice could suppress neuroinflammation, reduce neurological damage, and improve neurological function. Our data suggest that neutralizing antibodies against CXCL5 (Nab-CXCL5) may be a promising agent for treating TBI.