Microglial gp91phox-mediated neuroinflammation and ferroptosis contributes to learning and memory deficits in rotenone-treated mice.

Apart from dopaminergic neurotoxicity, exposure to rotenone, a commonly used insecticide in agriculture, also adversely affects hippocampal and cortical neurons, resulting in cognitive impairments in mice. We recently established a role of microglia-mediated neuroinflammation in rotenone-elicited deficits of cognition, yet the mechanisms remain elusive. Here, we investigated the involvement of NADPH oxidase 2 (NOX2) catalytic subunit gp91phox in rotenone-induced cognitive deficits and the associated mechanisms. Our study demonstrated that rotenone exposure elevated expression of gp91phox and phosphorylation of the NOX2 cytosolic subunit p47phox, along with NADPH depletion in the hippocampus and cortex of mice, indicating NOX2 activation. Specific knockdown of gp91phox in microglia via adeno-associated virus delivery resulted in reduced microglial activation, proinflammatory gene expression and improved learning and memory capacity in rotenone-intoxicated mice. Genetic deletion of gp91phox also reversed rotenone-elicited cognitive dysfunction in mice. Furthermore, microglial gp91phox knockdown attenuated neuronal damage and synaptic loss in mice. This intervention also suppressed iron accumulation, disruption of iron-metabolism proteins and iron-dependent lipid peroxidation and restored the balance of ferroptosis-related parameters, including GPX4, SLC711, PTGS2, and ACSL4 in rotenone-lesioned mice. Intriguingly, pharmacological inhibition of ferroptosis with liproxstatin-1 conferred protection against rotenone-induced neurodegeneration and cognitive dysfunction in mice. In summary, our findings underscored the contribution of microglial gp91phox-dependent neuroinflammation and ferroptosis to learning and memory dysfunction in rotenone-lesioned mice. These results provided valuable insights into the pathogenesis of cognitive deficits associated with pesticide-induced Parkinsonism, suggesting potential therapeutic avenues for intervention.

Interior decorative volatile organic compounds exposure induces sleep disorders through aberrant branched chain amino acid transaminase 2 mediated glutamatergic signaling resulting from a neuroinflammatory cascade.

Air pollution has been recognized as a contributing factor to sleep disorders (SD), which have been correlated with an elevated susceptibility to a variety of human diseases. Nevertheless, research has not definitively established a connection between SD and interior decorative volatile organic compounds (ID-VOCs), a significant indoor air pollutant. In this study, we employed a mouse model exposed to ID-VOCs to explore the impacts of ID-VOCs exposure on sleep patterns and the potential underlying mechanism. Of the 23 key compositions of ID-VOCs identified, aromatic hydrocarbons were found to be the most prevalent. Exposure to ID-VOCs in mice resulted in SD, characterized by prolonged wake fullness and decreased sleep during the light period. ID-VOCs exposure triggered neuroinflammatory responses in the suprachiasmatic nucleus (SCN), with microglia activation leading to the overproduction of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), ultimately inducing A1 astrocytes. Consequently, the upregulation of branched chain amino acid transaminase 2 (BCAT2) in A1 astrocytes resulted in elevated extracellular glutamate and disruption of the wake-sleep transition mechanism, which might be the toxicological mechanism of SD caused by ID-VOCs.

Hyperglycemia enhances brain susceptibility to lipopolysaccharide-induced neuroinflammation via astrocyte reprogramming.

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.

CCR5 antagonist maraviroc alleviates doxorubicin-induced neuroinflammation and neurobehavioral deficiency by regulating NF-κB/NLRP3 signaling in a breast cancer mouse model.

The chemotherapeutic agent Doxorubicin (DOX) is known to cause chemotherapy-induced cognitive impairment (CICI). Maraviroc, a potent C-C chemokine receptor 5 (CCR5) antagonist, shows neuroprotective properties, while its role in CICI remains unclear. This study determined the therapeutic potential of maraviroc on CICI. Adult C57BL/6J mice with implanted breast cancer cells received four weekly intraperitoneal injections of saline (Control group), 5 mg/kg DOX (DOX group), 10 mg/kg maraviroc (MVC group), or 5 mg/kg DOX with 10 mg/kg maraviroc (DOX + MVC group). The Morris Water Maze (MWM) was used for neurobehavioural test. Western blot analysis and immunofluorescence were used to evaluate the expressions of inflammatory markers, apoptosis-related proteins, and synaptic-related proteins. The volume and weight of tumor were also evaluated after treatments. DOX treatment significantly increased chemokines (CCL3, CCL4) and inflammatory cytokines (IL-1ß, TNF-α) in tumor-bearing mice hippocampus. While maraviroc administration reduced hippocampal proinflammatory factors compared to the DOX group. Furthermore, it also lowered apoptosis markers, restored synaptic proteins levels, and inhibited the NF-κB/NLRP3 pathway. Accordingly, maraviroc treatment significantly improved DOX-induced neurobehavioural impairments as evidenced by an increased number of platform crossings and percentage of target quadrant time in the MWM test. Additionally, when combined with DOX, maraviroc had additional inhibitory effects on tumor growth. These findings suggest that maraviroc can mitigate DOX-induced CICI by suppressing elevated proinflammatory chemokines and cytokines through the NF-κB/NLRP3 pathway, potentially offering an anti-tumor benefit. This research presents a promising therapeutic approach for DOX-induced CICI, enhancing the safety and efficacy of cancer treatments.

Is Methylglyoxal a Potential Biomarker for the Warburg Effect Induced by the Lipopolysaccharide Neuroinflammation Model?

Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1ß, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses.

Neonatal brain inflammation enhances methamphetamine-induced reinstated behavioral sensitization in adult rats analyzed with explainable machine learning.

Neonatal brain inflammation produced by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) results in long-lasting brain dopaminergic injury and motor disturbances in adult rats. The goal of the present work is to investigate the effect of neonatal systemic LPS exposure (1 or 2 mg/kg, i.p. injection in postnatal day 5, P5, male rats)-induced dopaminergic injury to examine methamphetamine (METH)-induced behavioral sensitization as an indicator of drug addiction. On P70, subjects underwent a treatment schedule of 5 once daily subcutaneous (s.c.) administrations of METH (0.5 mg/kg) (P70-P74) to induce behavioral sensitization. Ninety-six hours following the 5th treatment of METH (P78), the rats received one dose of 0.5 mg/kg METH (s.c.) to reintroduce behavioral sensitization. Hyperlocomotion is a critical index caused by drug abuse, and METH administration has been shown to produce remarkable locomotor-enhancing effects. Therefore, a random forest model was used as the detector to extract the feature interaction patterns among the collected high-dimensional locomotor data. Our approaches identified neonatal systemic LPS exposure dose and METH-treated dates as features significantly associated with METH-induced behavioral sensitization, reinstated behavioral sensitization, and perinatal inflammation in this experimental model of drug addiction. Overall, the analysis suggests that the implementation of machine learning strategies is sensitive enough to detect interaction patterns in locomotor activity. Neonatal LPS exposure also enhanced METH-induced reduction of dopamine transporter expression and [3H]dopamine uptake, reduced mitochondrial complex I activity, and elevated interleukin-1ß and cyclooxygenase-2 concentrations in the P78 rat striatum. These results indicate that neonatal systemic LPS exposure produces a persistent dopaminergic lesion leading to a long-lasting change in the brain reward system as indicated by the enhanced METH-induced behavioral sensitization and reinstated behavioral sensitization later in life. These findings indicate that early-life brain inflammation may enhance susceptibility to drug addiction development later in life, which provides new insights for developing potential therapeutic treatments for drug addiction.

Atractylodin ameliorates lipopolysaccharide-induced depressive-like behaviors in mice through reducing neuroinflammation and neuronal damage.

Depression is a psychiatric disorder associated with multiple factors including microglia-mediated neuroinflammation. Although atractylodin exerted a variety of biological activities, however the effect of atractylodin on neuroinflammation-related depression was still unclear. In this study, the lipopolysaccharide (LPS)-induced mouse model was used to explore the antidepressant effects and molecular mechanisms of atractylodin. The results showed that atractylodin increased sugar preference, also reduced immobility time in FST and TST. Further study showed atractylodin reduced the oxidative stress and the activation of microglia in mouse hippocampus, also inhibited the level of cytokine release, especially IL-1ß. The results of western blotting showed that atractylodin significantly inhibited the expression of NLRP3 and pro-IL1ß via inhibition of NF-κB pathway. Our studies showed that atractylodin upregulated BDNF/Akt pathway in mouse hippocampus. Therefore, this study firstly indicated that atractylodin can ameliorate lipopolysaccharide-induced depressive-like behaviors in mice through reducing neuroinflammation and neuronal damage, and its molecular mechanism may be associated with the decrease of the expression of NLRP3 inflammasome and upregulation of BDNF/Akt pathway.

Participation of the spleen in the neuroinflammation after pilocarpine-induced status epilepticus: implications for epileptogenesis and epilepsy.

Epilepsy, a chronic neurological disorder characterized by recurrent seizures, affects millions of individuals worldwide. Despite extensive research, the underlying mechanisms leading to epileptogenesis, the process by which a normal brain develops epilepsy, remain elusive. We, here, explored the immune system and spleen responses triggered by pilocarpine-induced status epilepticus (SE) focusing on their role in the epileptogenesis that follows SE. Initial examination of spleen histopathology revealed transient disorganization of white pulp, in animals subjected to SE. This disorganization, attributed to immune activation, peaked at 1-day post-SE (1DPSE) but returned to control levels at 3DPSE. Alterations in peripheral blood lymphocyte populations, demonstrated a decrease following SE, accompanied by a reduction in CD3+ T-lymphocytes. Further investigations uncovered an increased abundance of T-lymphocytes in the piriform cortex and choroid plexus at 3DPSE, suggesting a specific mobilization toward the Central Nervous System. Notably, splenectomy mitigated brain reactive astrogliosis, neuroinflammation, and macrophage infiltration post-SE, particularly in the hippocampus and piriform cortex. Additionally, splenectomized animals exhibited reduced lymphatic follicle size in the deep cervical lymph nodes. Most significantly, splenectomy correlated with improved neuronal survival, substantiated by decreased neuronal loss and reduced degenerating neurons in the piriform cortex and hippocampal CA2-3 post-SE. Overall, these findings underscore the pivotal role of the spleen in orchestrating immune responses and neuroinflammation following pilocarpine-induced SE, implicating the peripheral immune system as a potential therapeutic target for mitigating neuronal degeneration in epilepsy.

Itaconate inhibits corticosterone-induced necroptosis and neuroinflammation via up-regulating menin in HT22 cells.

Corticosterone (CORT) damages hippocampal neurons as well as induces neuroinflammation. The tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis is a form of programmed cell death, also known as inflammatory cell death. Menin is a multifunctional scaffold protein, which deficiency aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation as well as necroptosis and further investigated the mediatory role of Menin in this protective effect of itaconate by using an exposure of CORT to HT22 cells (a hippocampal neuronal cell line). The viability of HT22 cells was examined by the cell counting kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) were evaluated by western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay (ELISA) kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1ß, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL-4, IL-10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/RIP1, p-RIP3/RIP3, and p-MLKL/MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis in HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.

Curcumin abrogates cobalt-induced neuroinflammation by suppressing proinflammatory cytokines release, inhibiting microgliosis and modulation of ERK/MAPK signaling pathway.

Curcumin, a bioactive polyphenol derived from turmeric, has been reported to have anti-inflammatory properties. The current study investigated the anti-inflammatory effect of curcumin in the hippocampal subfields (CA1 and CA3) after exposure to cobalt (Co) and the impact of ERK protein. Twenty-eight albino Wistar rats were divided into four groups, each with seven randomly selected rats as follows: Control (distilled water), Cobalt (Co) only (40 mg/kg), 120 mg/kg or 240 mg/kg curcumin + Co (40 mg/kg). Treatment was via oral gavage for 28 days. We performed a biochemical investigation to determine the levels of proinflammatory cytokines (TNFα and IL-1ß). Furthermore, we conducted an immunohistochemical evaluation to assess the expression of IBA1 by microglial cells and the immunoexpression of ERK protein in the hippocampus. Results revealed a significant (p<0.05) elevation in the tissue level of TNFα and IL-1ß, an increase in the number of IBA1-positive microglia, and upregulation of ERK protein in the hippocampal subfields of the rats after exposure to cobalt-only. Nevertheless, pretreatment with curcumin restored these parameters to levels comparable to control. In conclusion, our results showed that curcumin abrogated the Co-induced neuroinflammation by suppressing the release of proinflammatory biomarkers, reducing microgliosis, and modulating the ERK/MAPK pathway.

Adora2A downregulation promotes caffeine neuroprotective effect against LPS-induced neuroinflammation in the hippocampus.

Caffeine has been extensively studied in the context of CNS pathologies as many researchers have shown that consuming it reduces pro-inflammatory biomarkers, potentially delaying the progression of neurodegenerative pathologies. Several lines of evidence suggest that adenosine receptors, especially A1 and A2A receptors, are the main targets of its neuroprotective action. We found that caffeine pretreatment 15 min before LPS administration reduced the expression of Il1b in the hippocampus and striatum. The harmful modulation of caffeine-induced inflammatory response involved the downregulation of the expression of A2A receptors, especially in the hippocampus. Caffeine treatment alone promoted the downregulation of the adenosinergic receptor Adora2A; however, this promotion effect was reversed by LPS. Although administering caffeine increased the expression of the enzymes DNA methyltransferases 1 and 3A and decreased the expression of the demethylase enzyme Tet1, this effect was reversed by LPS in the hippocampus of mice that were administered Caffeine + LPS, relative to the basal condition; no significant differences were observed in the methylation status of the promoter regions of adenosine receptors. Finally, the bioinformatics analysis of the expanded network demonstrated the following results: the Adora2B gene connects the extended networks of the adenosine receptors Adora1 and Adora2A; the Mapk3 and Esr1 genes connect the extended Adora1 network; the Mapk4 and Arrb2 genes connect the extended Adora2A network with the extended network of the proinflammatory cytokine Il1ß. These results indicated that the anti-inflammatory effects of acute caffeine administration in the hippocampus may be mediated by a complex network of interdependencies between the Adora2B and Adora2A genes.

MoS2 2D materials induce spinal cord neuroinflammation and neurotoxicity affecting locomotor performance in zebrafish.

MoS2 nanosheets belong to an emerging family of nanomaterials named bidimensional transition metal dichalcogenides (2D TMDCs). The use of such promising materials, featuring outstanding chemical and physical properties, is expected to increase in several fields of science and technology, with an enhanced risk of environmental dispersion and associated wildlife and human exposures. In this framework, the assessment of MoS2 nanosheets toxicity is instrumental to safe industrial developments. Currently, the impact of the nanomaterial on the nervous tissue is unexplored. In this work, we use as in vivo experimental model the early-stage zebrafish, to investigate whether mechano-chemically exfoliated MoS2 nanosheets reach and affect, when added in the behavioral ambient, the nervous system. By high throughput screening of zebrafish larvae locomotor behavioral changes upon exposure to MoS2 nanosheets and whole organism live imaging of spinal neuronal and glial cell calcium activity, we report that sub-acute and prolonged ambient exposures to MoS2 nanosheets elicit locomotor abnormalities, dependent on dose and observation time. While 25 µg mL-1 concentration treatments exerted transient effects, 50 µg mL-1 ones induced long-lasting changes, correlated to neuroinflammation-driven alterations in the spinal cord, such as astrogliosis, glial intracellular calcium dysregulation, neuronal hyperactivity and motor axons retraction. By combining integrated technological approaches to zebrafish, we described that MoS2 2D nanomaterials can reach, upon water (i.e. ambient) exposure, the nervous system of larvae, resulting in a direct neurological damage.

Stimulation of Formyl Peptide Receptor-2 by the New Agonist CMC23 Protects against Endotoxin-Induced Neuroinflammatory Response: A Study in Organotypic Hippocampal Cultures.

A substantial body of evidence demonstrates an association between a malfunction in the resolution of acute inflammation and the development of chronic inflammation. Recently, in this context, the importance of formyl peptide receptor 2 (FPR2) has been underlined. FPR2 activity is modulated by a wide range of endogenous ligands, including specialized pro-resolving mediators (SPMs) (e.g., LXA4 and AT-LXA4) and synthetic ligands. Since SPMs have unfavorable pharmacokinetic properties, we aimed to evaluate the protective and pro-resolving effects of a new potent FPR2 agonist, compound CMC23, in organotypic hippocampal cultures (OHCs) stimulated with lipopolysaccharide (LPS). The protective activity of CMC23 limited the lactate dehydrogenase release in LPS-stimulated cultures. This activity was mediated by the interaction with FPR2 as pretreatment with the FPR2 selective antagonist WRW4 abolished CMC23-induced protection. Furthermore, decreased levels of pro-inflammatory IL-1ß and IL-6 were observed after CMC23 administration in LPS-treated OHCs. CMC23 also diminished the LPS-induced increase in IL-17A and both IL-23 subunits p19 and p40 in OHCs. Finally, we demonstrated that CMC23 exerts its beneficial impact via the STAT3/SOCS3 signaling pathway since it attenuated the level of phospho-STAT3 and maintained the LPS-induced SOCS3 levels in OHCs. Collectively, our research implies that the new FPR2 agonist CMC23 has beneficial protective and anti-inflammatory properties in nanomolar doses and FPR2 represents a promising target for the enhancement of inflammation resolution.

Effect and mechanism of chlorogenic acid on cognitive dysfunction in mice by lipopolysaccharide-induced neuroinflammation.

Background: Neuroinflammation is an important factor causing numerous neurodegenerative pathologies. Inflammation can lead to abnormal neuronal structure and function and even death, followed by cognitive dysfunction. There is growing evidence that chlorogenic acid has anti-inflammatory effects and immunomodulatory activity. Purpose: The aim of this study was to elucidate the potential targets and molecular mechanisms of chlorogenic acid in the treatment of neuroinflammation. Methods: We used the lipopolysaccharide-induced neuroinflammation mouse model and the lipopolysaccharide-stimulated BV-2 cells in vitro model. Behavioral scores and experiments were used to assess cognitive dysfunction in mice. HE staining and immunohistochemistry were used to assess neuronal damage in the mouse brain. Immunofluorescence detected microglia polarization in mouse brain. Western blot and flow cytometry detected the polarization of BV-2 cells. The migration of BV-2 cells was detected by wound healing assay and transwell assay. Potential targets for chlorogenic acid to exert protective effects were predicted by network pharmacology. These targets were then validated using molecular docking and experiments. Results: The results of in vivo experiments showed that chlorogenic acid had an obvious ameliorating effect on neuroinflammation-induced cognitive dysfunction. We found that chlorogenic acid was able to inhibit BV-2 cells M1 polarization and promote BV-2 cells M2 polarization in vitro while also inhibiting the abnormal migration of BV-2 cells. Based on the network pharmacology results, we identified the TNF signaling pathway as a key signaling pathway in which chlorogenic acid exerts anti-neuroinflammatory effects. Among them, Akt1, TNF, MMP9, PTGS2, MAPK1, MAPK14, and RELA are the core targets for chlorogenic acid to function. Conclusion: Chlorogenic acid can inhibit microglial polarization toward the M1 phenotype and improve neuroinflammation-induced cognitive dysfunction in mice by modulating these key targets in the TNF signaling pathway.

Chronic alcohol induced mechanical allodynia by promoting neuroinflammation: A mouse model of alcohol-evoked neuropathic pain.

BACKGROUND AND PURPOSE: Chronic pain is considered a key factor contributing to alcohol use disorder (AUD). The mechanisms responsible for chronic pain associated with chronic alcohol consumption are unknown. We evaluated the development of chronic pain in a mouse model of alcohol dependence and investigate the role of neuroinflammation. EXPERIMENTAL APPROACH: The chronic-intermittent ethanol two-bottle choice CIE-2BC paradigm generates three groups: alcohol-dependent with escalating alcohol intake, nondependent (moderate drinking) and alcohol-naïve control male and female mice. We measured mechanical allodynia during withdrawal and after the last voluntary drinking. Immunoblotting was used to evaluate the protein levels of IBA-1, CSFR, IL-6, p38 and ERK2/1 in spinal cord tissue of dependent and non-dependent animals. KEY RESULTS: We found significant escalation of drinking in the dependent group in male and female compared with the non-dependent group. The dependent group developed mechanical allodynia during 72 h of withdrawal, which was completely reversed after voluntary drinking. We observed an increased pain hypersensitivity compared with the naïve in 50% of non-dependent group. Increased IBA-1 and CSFR expression was observed in spinal cord tissue of both hypersensitivity-abstinence related and neuropathy-alcohol mice, and increased IL-6 expression and ERK1/2 activation in mice with hypersensitivity-related to abstinence, but not in mice with alcohol-evoked neuropathic pain. CONCLUSIONS AND IMPLICATIONS: The CIE-2BC model induces two distinct pain conditions specific to the type of ethanol exposure: abstinence-related hypersensitivity in dependent mice and alcohol-evoked neuropathic pain in about a half of the non-dependent mice.

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

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

Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors.

BACKGROUND: Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. METHODS: Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. RESULTS: This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the "Eat Me" complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted. CONCLUSIONS: These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.

Aluminum induces neuroinflammation via P2X7 receptor activating NLRP3 inflammasome pathway.

INTRODUCTION: Aluminum is everywhere in nature and is a recognized neurotoxicant closely associated with various neurodegenerative diseases. Neuroinflammation occurs in the early stage of neurodegenerative diseases, but the underlying mechanism by which aluminum induces neuroinflammation remains unclear. MATERIAL AND METHODS: A 3-month subchronic aluminum exposure mouse model was established by drinking water containing aluminum chloride (AlCl3). Microglia BV2 cells and hippocampal neuron HT22 cells were treated with AlCl3 in vitro. BBG and YC-1 were used as intervention agents. RESULTS: Aluminum could activate microglia and increase the level of extracellular ATP, stimulate P2X7 receptor, HIF-1α, activate NLRP3 inflammasome and CASP-1, release more cytokine IL-1ß, and induce an inflammatory response in nerve cells. There was a mutual regulatory relationship between P2X7 and HIF-1α at mRNA and protein levels. The co-culture system of BV2-HT22 cells observed that conditioned medium from microglia treated with aluminum could aggravate neuronal morphological damage, inflammatory response and death. While BBG and YC-1 intervention could rescue these injuries to some extent. CONCLUSION: The P2X7-NLRP3 pathway was involved in aluminum-induced neuroinflammation and injury. P2X7 and HIF-1α might mutually regulate and promote the progression of neuroinflammation, both BBG and YC-1 could relieve it.

Neuropharmacological effects of honey in lipopolysaccharide-induced neuroinflammation, cognitive impairment, anxiety and motor impairment.

Objectives: Honey contains phenolic acids and flavonoids, which are significant in developing drugs against neuroinflammation. The study was designed to evaluate the ameliorative potential of honey in lipopolysaccharides-induced neuroinflammation.Methods: Thirty male Wistar rats were divided into six groups, namely: the control group (10 mL/kg vehicle), the LPS only group (250 µg/kg), the honey (0.26, 0.31 and 0.36 g/kg) and the ibuprofen (100 mg/kg). LPS (250 µg/kg i.p) was administered for 7days followed by the treatment with honey and Ibuprofen for another 7days. Animals were assessed for memory impairment and anxiety levels using a Novel object recognition test (NORT), elevated plus maze (EPM), and open field test (OFT). Brain levels of pro-inflammatory cytokine level, acetylcholinesterase activity, and oxidative stress were determined. The neuronal alteration was assessed histologically using cresyl fast violet staining of the hippocampus, prefrontal cortex, and striatum.Results: Honey (0.31 and 0.36 g/kg) significantly ameliorated LPS-induced memory impairment on NORT and increased time spent in the open arm and increased the locomotor activity in the OFT. Honey significantly (p < 0.05) reduced LPS-induced elevation of tumor necrosis factor (TNF-α) and interleukin-6 (IL-6). It significantly reduced malondialdehyde and nitrite levels in mice brains and reversed depletion of reduced glutathione levels. Honey attenuated LPS-induced elevation of acetylcholinesterase activity in rat brains. Cresyl violet staining showed the restoration of neuronal organization and Nissl body distribution in the hippocampus, prefrontal cortex and striatum compared to the LPS only group.Discussion: Honey effectively ameliorated LPS-induced poor cognitive performance, anxiety, motor coordination responses to neuroinflammation, and oxidative stress.

Blockage of KHSRP-NLRP3 by MCC950 Can Reverse the Effect of Manganese-Induced Neuroinflammation in N2a Cells and Rat Brain.

Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl2 to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1ß) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl2 exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl2-exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory.