Model Of Neuroinflammation Research Articles

A 3D bioprinted neuroinflammatory co-culture model for in vitro study of parkinson's disease pathology

This study developed a 3D bioprinted neuroinflammatory co-culture model to simulate key pathological features of Parkinson’s disease (PD) in vitro. PD, a common neurodegenerative disorder, is characterized by dopaminergic (DA) neuron apoptosis, mitochondrial dysfunction, and aggregation of α-synuclein (α-syn). Traditional 2D cell culture models fail to accurately replicate the complex microenvironment of PD, leading to the development of this 3D bioprinted model. Utilizing a polyethylene glycol-hyaluronic acid methacryloyl (PEG-HAMA) hydrogel matrix, this model supports the co-culture of DA  neurons and microglia, allowing a more accurate representation of PD pathology. Experimental results demonstrated that, under 6-hydroxydopamine (6-OHDA) induction, the 3D model successfully mimicked neuroinflammatory responses associated with PD, including M1 polarization of microglia and increased secretion of pro-inflammatory factors. Compared to traditional 2D models, DA  neurons in the 3D model exhibited greater resistance to oxidative stress and neurotoxic challenges, with significantly slower rates of apoptosis. Additionally, the 3D model displayed key PD-specific pathological features, such as altered mitochondrial membrane potential, elevated reactive oxygen species (ROS) levels, and overexpression of α-syn. This 3D bioprinted PD model provides a closer-to-physiological platform for investigating the pathogenesis of PD and holds potential for use in drug screening. However, further optimization is required to enhance the model’s complexity and long-term stability, including incorporating peripheral immune cells to better simulate the progression of chronic neuroinflammation.

Effective Nose-to-Brain Delivery of Blood-Brain Barrier Impermeant Anti-IL-1β Antibody via the Minimally Invasive Nasal Depot (MIND) Technique.

Treatment of neuroinflammation and neurodegenerative diseases using biologic therapies is limited due to the blood-brain barrier (BBB). This study explores a clinically validated approach to bypass the BBB for the purposes of direct central nervous system (CNS) delivery of antibodies using the Minimally Invasive Nasal Depot (MIND) technique. Using a lipopolysaccharide (LPS)-induced mouse model of neuroinflammation, we evaluated the efficacy of MIND in delivering a BBB impermeant full-length anti-IL-1β antibody. The results demonstrated that MIND delivery resulted in a significant reduction in IL-1β levels and microglial activation in relevant brain regions, notably outperforming conventional intravenous (IV) administration. These results underscore the ability of the MIND approach to transform the treatment landscape for a range of neurodegenerative diseases by enabling the targeted delivery of otherwise BBB impermeant therapeutics.

Programming tissue-sensing T cells that deliver therapies to the brain.

To engineer cells that can specifically target the central nervous system (CNS), we identified extracellular CNS-specific antigens, including components of the CNS extracellular matrix and surface molecules expressed on neurons or glial cells. Synthetic Notch receptors engineered to detect these antigens were used to program T cells to induce the expression of diverse payloads only in the brain. CNS-targeted T cells that induced chimeric antigen receptor expression efficiently cleared primary and secondary brain tumors without harming cross-reactive cells outside of the brain. Conversely, CNS-targeted cells that locally delivered the immunosuppressive cytokine interleukin-10 ameliorated symptoms in a mouse model of neuroinflammation. Tissue-sensing cells represent a strategy for addressing diverse disorders in an anatomically targeted manner.

Therapeutic effect of cyclosporine A-loading TPGS micelles on a mouse model of LPS-induced neuroinflammation

Therapeutic effect of cyclosporine A-loading TPGS micelles on a mouse model of LPS-induced neuroinflammation

A Novel Compound Ligusticum Cycloprolactam Alleviates Neuroinflammation After Ischemic Stroke via the FPR1/NLRP3 Signaling Axis.

Microglia/macrophages, as pivotal immune cells in the central nervous system (CNS), play a critical role in neuroinflammation associated with ischemic brain injury. Targeting their activation through pharmacological interventions represents a promising strategy to alleviate neurological deficits, thereby harboring significant implications for the prevention and treatment of ischemic stroke. Ligusticum cycloprolactam (LIGc), a novel monomeric derivative of traditional Chinese medicine, has shown potential as a therapeutic agent; however, its specific role in cerebral ischemic injury remains unclear. In vitro experiments utilized lipopolysaccharide (LPS)-induced inflammation models of RAW264.7 cells and primary mouse microglia. Invivo studies employed LPS-induced neuroinflammation models in mice and a transient middle cerebral artery occlusion (tMCAO) mouse model to evaluate the impact of LIGc on neuroinflammation and microglia/macrophage phenotypic alterations. Further elucidation of the molecular mechanisms underlying these effects was achieved through RNA-Seq analyses. LIGc exhibited the capacity to attenuate LPS-induced production of pro-inflammatory markers in macrophages and microglia, facilitating their transition to an anti-inflammatory phenotype. In models of LPS-induced neuroinflammation and tMCAO, LIGc ameliorated pathological behaviors and neurological deficits while mitigating brain inflammation. RNA-seq analyses revealed formyl peptide receptor 1 (FPR1) as a critical mediator of LIGc's effects. Specifically, FPR1 enhances the pro-inflammatory phenotype of microglia/macrophages and inhibits their anti-inflammatory response by upregulating NLR family pyrin domain protein 3 (NLRP3) inflammasomes, thus aggravating inflammatory processes. Conversely, LIGc exerts anti-inflammatory effects by downregulating the FPR1/NLRP3 signaling axis. Furthermore, FPR1 overexpression or NLRP3 agonists reversed the effects of LIGc observed in this study. Our findings suggest that LIGc holds promise in improving ischemic brain injury and neuroinflammation through modulation of microglia/macrophage polarization. Mechanistically, LIGc attenuates the pro-inflammatory phenotype and promotes the anti-inflammatory phenotype by targeting the FPR1/NLRP3 signaling pathway, ultimately reducing inflammatory responses and mitigating neurological damage.

IL1R2 Acts as a Negative Regulator of Monocyte Recruitment During Inflammation.

IL1-β plays a central role in inflammation but its biological action needs to be tightly controlled. Such negative regulation can be exerted by the decoy receptor IL1R2. However, IL1R2 biology in immune cells remains poorly characterized, in particular in monocytes. Using conditional deficient mice, we show that Il1r2 deficiency in monocytes does not affect their steady-state life cycle but dysregulates their trafficking to inflamed tissues in models of peritonitis and neuro-inflammation. Mechanistically, we found that Il1r2 deficiency in monocytes increases CCL2 secretion in the inflamed peritoneum, thereby amplifying monocyte recruitment from blood. In autoimmune neuro-inflammation, Il1r2 deficiency in monocytes exacerbates disease severity. Our findings suggest that the specific action of IL1R2 in monocytes contributes to a feedback mechanism for fine-tuning the numbers of recruited monocytes during inflammation.

Discovery of NP3-253, a Potent Brain Penetrant Inhibitor of the NLRP3 Inflammasome.

Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results in the production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked to many acute and chronic conditions ranging from atherosclerosis to Alzheimer's disease and cancer, and based on the clinical success of IL-1-targeting therapies, NLRP3 has emerged as an attractive therapeutic target. Herein we describe our discovery, characterization, and structure-based optimization of a pyridazine-based series of NLRP3 inhibitors initiating from an high-throughput screening campaign. The scaffold, exemplified by lead molecule NP3-253, has excellent potency and physicochemical and pharmacokinetic properties, including good brain penetration. The establishment of pharmacokinetic/pharmacodynamic relationships in the periphery and central nervous system in mechanistic models facilitates the use of NP3-253 as a tool to further interrogate the biology of NLRP3 in peripheral and neuroinflammatory models.

Structural optimization of naturally derived Ar-turmerone, as novel neuroinflammation suppressors effective in an Alzheimer mouse model

Microglia-mediated neuroinflammation plays a pivotal role in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. The modulation of chronic and sustained inflammatory processes in the brain with small molecules presents a promising therapeutic strategy for these devastating conditions. Aromatic turmerone (ar-turmerone, ART), an active constituent of turmeric essential oil derived from the edible plant Curcuma longa, has shown substantial potential in mitigating neuroinflammatory responses and associated cognitive deficits. Building on our previous work, we sought to discover more potent neuroinflammation suppressors by designing and synthesizing a series of ar-turmerone derivatives to investigate their structure–activity relationships. Microglia-based cellular evaluations revealed that naphthyl-substituted (7c) and N-substituted amides (7a) demonstrated the most pronounced inhibitory effects against NO, TNF-α, and IL-1β release in vitro. Furthermore, in a lipopolysaccharide (LPS)-induced neuroinflammation model of Alzheimer’s disease in mice, these two compounds significantly reduced proinflammatory cytokine release, protected neurons from damage, and ameliorated memory impairments and cognitive deficits in Morris water maze tests. This structural optimization of ar-turmerone yielded highly potent anti-neuroinflammatory compounds, which may serve as promising agents for the treatment of neuroinflammation-related neurodegenerative disorders.

Maresin-1 Ameliorates Sepsis-Induced Microglial Activation Through Modulation of the P38 MAPK Pathway.

Sepsis is a life-threatening disease characterized by a dysregulated immune response to infection, often leading to neuroinflammation. As a known immunomodulator, Maresin-1 (MaR1) may have potential applications in the treatment of sepsis-induced neuroinflammation, but its effects in this context are unknown. We used a mouse cecum ligation and puncture (CLP)-induced sepsis model and an in vitro lipopolysaccharide (LPS)-induced neuroinflammatory model of BV2 microglia. Expression of microglial cell markers (IBA1, CD11B, CD68, CD86 and CD206) and pro-inflammatory markers (iNOS and COX2) was assessed. The role of MaR1 in regulating the P38 MAPK pathway was explored using the P38 MAPK inhibitor SB203580. In the CLP model, an increased proportion of M1-type microglia was observed, and MaR1 was able to reverse it. However, the combination of SB203580 and MaR1 did not enhance the therapeutic effect compared to SB20580 alone. In vitro experiments, MaR1 inhibited LPS-induced P38 MAPK nuclear translocation and decreased the expression of pro-inflammatory markers such as iNOS and COX2. As with the animal results, no stacking effect could be obtained with the co-administration of SB203580 and MaR1. Our findings suggest that MaR1 attenuates sepsis-induced neuroinflammation mainly by inhibiting phosphorylation of P38 MAPK in microglial cells. This suggests that MaR1 may have a potential therapeutic role in the treatment of sepsis neuroinflammation.

Darbepoetin alpha has an anxiolytic and anti-neuroinflammatory effect in male rats

AimsWe aimed to investigate the anxiolytic effect of darbepoetin alpha (DEPO), an erythropoietin derivative, in a neuroinflammation model regarding different behaviors and biological pathways.MethodsForty adult male Wistar albino rats were divided into four groups (control, LPS, DEPO, and DEPO + LPS). The rats were treated with 5 µg /kg DEPO once a week for four weeks, after which neuroinflammation was induced with 2 mg/kg lipopolysaccharide (LPS). The elevated plus maze, open-field, and light‒dark box tests were conducted to assess anxiety levels. Harderian gland secretions were scored via observation. Tumor necrosis factor alpha (TNF-α), Interleukin-1-beta (IL-1β), brain-derived growth factor (BDNF), serotonin, cortisol, total antioxidant/oxidant (TAS/TOS), and total/free thiol levels were measured in the prefrontal cortex, striatum, and serum.ResultsDEPO had a potent anxiolytic effect on both DEPO and DEPO + LPS groups. Compared to the control group, DEPO administration caused an increase in serotonin and BDNF levels and decreased basal cortisol and TNF-α levels in naive rats. IL-1β did not alter after DEPO administration in naive rats. Prophylactic DEPO treatment remarkably downregulated cortisol, IL-1β, and TNF-α in the DEPO + LPS group. In addition, prophylactic DEPO administration significantly attenuated the decrease in serotonin and BDNF levels in the DEPO + LPS group. Furthermore, DEPO ameliorated excessive harderian gland secretion in the DEPO + LPS group. Compared with those in the control group, the free thiol content in the serum increased after DEPO administration. No similar effect was seen in the DEPO + LPS group receiving prophylactic DEPO. TAS showed no difference among all experimental groups. DEPO administration increased TOS and OSI in the serum and prefrontal cortex but not in the striatum. This effect was not seen in the DEPO + LPS group.ConclusionDarbepoetin alpha had an anxiolytic effect on many physiological mechanisms in a neuroinflammation model and naive rats.

Targeting glycolysis for neuroprotection in early LPS-induced neuroinflammation

Neuroinflammation is a pathophysiological feature of numerous neurological and psychiatric disorders. The immune response in the central nervous system, driven by microglia and astrocytes, leads to metabolic reprogramming towards aerobic glycolysis, a phenomenon known as the Warburg effect. The control of metabolic reprogramming via immunomodulation may represent a potential therapeutic target for providing protection against neuroinflammation, which contributes to neuronal dysfunction and death in several neurological disorders. For this purpose, we investigated putative neuroprotective effects of the downregulation of aerobic glycolysis using the 3PO inhibitor, and the downregulation of neuroinflammation using MCC950, in the early LPS-induced neuroinflammation model. The LPS-induced shift towards glycolysis, inflammatory and glial changes (IL-1β, NF-κB, COX2, Iba1, GFAP) were reversed by 3PO, which improved animal behavior. Additionally, MCC950 (an NLRP3 inhibitor) downregulated TLR4/Akt/p38 MAPK/NF-κB/STAT3 signaling, expressions of COX2 and IL-1β, and the astrocyte reactivity (decreasing GFAP) induced by early neuroinflammation, resulting in low glucose uptake. Our data support the occurrence of the Warburg effect during early neuroinflammation and suggest potential new approaches for the treatment of brain injury, given the role of neuroinflammation in such events.

Immunomodulatory effect of lithium treatment on in vitro model of neuroinflammation

Bipolar disorder (BD) is psychiatric disorder of not fully acknowledged pathophysiology. Studies show the involvement of innate-immune system activation and inflammation in BD course and treatment efficiency. Microglia are crucial players in the inflammatory response possibly responsible for BD innate-immune activity. Lithium is a mood stabilizer used in treatment for 75 years. Immunomodulation was previously described as one of the potential modes of its action. We hypothesized that lithium might modulate the microglia response to innate-immune-associated cytokines (10 ng/mL TNF-α, 50 ng/mL IL-1β, 20 ng/mL IFN-γ). We aimed to investigate whether lithium treatment and pretreatment of microglia modify the expression of genes associated with NLRP3 inflammasome. We also aimed to verify lithium treatment effect on caspase activity and extracellular IL-1β concentration. For the first time, our study used human microglial cell line - HMC3, the cytokine stimuli and lithium in concentration corresponding to that in the brains of patients. To analyze lithium mode of action, we analyzed the short- and long-term treatment and pretreatment. To assess the influence on microglia responding to innate-immune cytokines, we analyzed the expression of genes involved in innate-immune and inflammasome (TSPO, TLR4, NFKB1, CASP1, CASP4, NLRP3, IL-1β, IL-6), caspase activity, extracellular IL-1β concentration, phospho-GSK-3β(Ser9) expression and lactate concentration. We found that lithium treatment significantly reduced NLRP3 inflammasome-related genes expression. We observed that lithium treatment reduces inflammasome activity, which may attenuate the inflammatory state. Interestingly, the lithium pretreatment resulted in significantly elevated inflammasome activity, suggesting that lithium does not impair the immune response to additional stimuli.

Inhibition of Glycolysis Alleviates Chronic Unpredictable Mild Stress Induced Neuroinflammation and Depression-like Behavior.

Growing evidence suggests that glucose metabolism plays a crucial role in activated immune cells, significantly contributing to the occurrence and development of neuroinflammation and depression-like behaviors. Chronic stress has been reported to induce microglia activation and disturbances in glucose metabolism in the hippocampus. This study aims to investigate how chronic stress-mediated glycolysis promotes neuroinflammation and to assess the therapeutic potential of the glycolysis inhibitor, 2-deoxy-D-glucose (2-DG), in a model of chronic stress-induced neuroinflammation and depression-like behavior. In in vitro studies, we first explored the effects of 2-DG on the inflammatory response of microglia cells. The results showed that corticosterone (Cort) induced reactive oxygen species (ROS) production, increased glycolysis, and promoted the release of inflammatory mediators. However, these effects were reversed by intervention with 2-DG. Subsequently, we examined changes in depression-like behavior and hippocampal glycolysis in mice during chronic stress. The results indicated that chronic stress led to prolonged escape latency in the Morris water maze, increased platform-crossing frequency, reduced sucrose preference index, and extended immobility time in the forced swim test, all of which are indicative of depression-like behavior in mice. Additionally, we found that the expression of the key glycolytic enzyme hexokinase 2 (HK2) was upregulated in the hippocampus of stressed mice, along with an increased release of inflammatory factors. Further in vivo experiments investigated the effects of 2-DG on glycolysis and pro-inflammatory mediator production, as well as the therapeutic effects of 2-DG on chronic stress-induced depression-like behavior in mice. The results showed that 2-DG alleviated chronic stress-induced depression-like behaviors, such as improving escape latency and platform-crossing frequency in the Morris water maze, and increasing the time spent in the center of the open field. Additionally, 2-DG intervention reduced the level of glycolysis in the hippocampus and decreased the release of pro-inflammatory mediators. These findings suggest that 2-DG can mitigate neuroinflammation and depressive behaviors by inhibiting glycolysis and inflammatory responses. Overall, our results highlight the potential of 2-DG as a therapeutic agent for alleviating chronic stress-induced neuroinflammation through the regulation of glycolysis.

Monitoring Glutathione Content of the Endoplasmic Reticulum under Scrap Leather-Induced Endoplasmic Reticulum Stress via an Endoplasmic Reticulum-Targeted Two-Photon Fluorescent Probe.

Maintaining tissue homeostasis necessitates the coordinated efforts of various cell types to regulate inflammation. Endoplasmic reticulum (ER) stress, a hallmark of inflammation, exacerbates tissue pathology in various human diseases. Glutathione (GSH), a pivotal regulator of cellular redox balance, controls disulfide bond formation in the ER, thereby shielding cells from oxidative stress. In this study, we developed a two-photon fluorescent probe, ER-GSH, with specific ER targeting and demonstrated its high sensitivity and rapid response to GSH. Experiments conducted on BV2 cells and a mice model of neuroinflammation induced by scrap leather revealed that inflammatory reactions led to ER stress and a substantial reduction in GSH levels. Notably, the anti-inflammatory drug NS-398 effectively inhibited cell inflammation and ER stress by maintaining GSH levels. These findings underscore the potential therapeutic significance of modulating GSH levels to alleviate the impact of neuroinflammation.

Delayed effects of antibiotic therapy in endotoxinemia

BACKGROUND: Nowadays, due to the increasing number of infectious and inflammatory diseases, the problem of the use of antibacterial drugs becomes especially important. As a result of the action of toxins, inflammatory processes can affect the central nervous system with the subsequent development of neuroinflammation. Activation of neuroinflammation leads to dysregulation of many physiological functions. These negative appearances can be observed even after a long period. It is known that doxycycline is a tetracycline-type antibiotic, which is able to penetrate the blood-brain barrier and has anti-inflammatory activity. AIM: The aim of this study was to investigate the nature of delayed physiological changes in rats against the background of administration of the antibacterial drug doxycycline in the LPS-induced model of neuroinflammation. MATERIALS AND METHODS: Four groups of Wistar rats, 10 males in each group, were used in the experiment. The first group was injected once intraperitoneally with physiological solution, the second group — with lipopolysaccharide (1 mg/kg). Animals of the third and fourth groups received intragastrically doxycycline solution (25 mg/kg) daily for two weeks. On the 15th day of the experiment, rats from the fourth group were injected with lipopolysaccharide (1 mg/kg). Body weight of animals, mass coefficients of immunocompetent organs, as well as behaviour and motor activity of rats in the “Open Field” test were evaluated at several time points. RESULTS: It was shown that systemic injection of lipopolysaccharide led to an increase in the mass coefficients of spleen, kidneys and adrenal glands compared to the group of animals receiving doxycycline beforehand. These changes were noted 48 h and 2 months after the injection of endotoxin. In the “Open Field” test, animals that were injected with doxycycline and lipopolysaccharide showed no violations of motor activity and research behavior, unlike the group that received only lipopolysaccharide. CONCLUSIONS: It can be assumed that the physiological effects of doxycycline in the lipopolysaccharide-induced model of neuroinflammation revealed at early and late terms are not limited to the antibacterial effect of the drug and are mediated by anti-inflammatory and potential neuroprotective effects on the central nervous system.

Application of an in vitro neuroinflammation model to evaluate the efficacy of magnesium-lithium alloys.

Mg-Li alloys can be promising candidates as bioresorbable Li-releasing implants for bipolar disorder and other neurodegenerative disorders. In order to compare the therapeutic efficacy of conventional Li salts and Li delivered through Mg-Li alloy extracts, we tested an in vitro model based on the neuroinflammation hypothesis of mood disorders (peripheral inflammation inducing neuroinflammation) wherein, a coculture of microglia and astrocytes was treated with conditioned medium from pro-inflammatory macrophages. Two alloys, Mg-1.6Li and Mg-9.5Li, were tested in the form of material extracts and well-known outcomes of Li treatment such as GSK3β phosphorylation (indirect flow cytometry) and influence on inflammation-related gene expression (qPCR) were compared against Li salts. This is the first study demonstrating that Li can increase the phosphorylation of GSK3β in glial cells in the presence of excess Mg. Furthermore, Mg-Li alloys were more effective than Li salts in downregulating IL6 and upregulating the neurotrophin GDNF. Mg had no antagonistic effects toward Li-driven downregulation of astrogliosis markers. Overall, the results provide evidence to support further studies employing Mg-Li alloys for neurological applications.

Antidepressant-like Effects of Cannabis sativa L. Extract in an Lipopolysaccharide Model: Modulation of Mast Cell Activation in Deep Cervical Lymph Nodes and Dura Mater.

Lipopolysaccharide (LPS)-induced neuroinflammation is a well-established model for studying depression-like behavior, driven by pro-inflammatory cytokines such as TNF-α and IL-1β. Mast cells (MCs) contribute to neuroinflammation by releasing mediators that exacerbate depressive-like symptoms. This study evaluates the antidepressant-like and anti-inflammatory effects of Cannabis sativa L. inflorescence extract (CSL) in an LPS-induced neuroinflammation model. Male C57BL/6 mice were intraperitoneally injected with CSL at doses of 10, 20, and 30 mg/kg, 30 min prior to LPS (0.83 mg/kg) administration. Depressive behaviors were assessed using the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). The neutrophil-to-lymphocyte ratio (NLR) was measured to assess systemic inflammation. Cytokine levels in the prefrontal cortex (PFC) were measured, and mast cell degranulation in the lymph nodes and dura mater was analyzed histologically (approval number: WKU24-64). CSL significantly improved depressive-like behaviors and decreased the NLR, indicating reduced systemic inflammation. CSL also significantly reduced TNF-α and IL-1β levels in the PFC. Furthermore, CSL inhibited MC degranulation in the deep cervical lymph nodes and dura mater, with the strongest effects observed at 30 mg/kg. CSL demonstrated antidepressant-like and anti-inflammatory effects in an LPS-induced neuroinflammation model, likely through the modulation of cytokine expression and mast cell activity. These results suggest the potential of CSL as a therapeutic option for treating inflammation-related depression.

Exploring chitosan nanoparticles for enhanced therapy in neurological disorders: a comprehensive review.

Chitosan nanoparticles have emerged as a promising therapeutic platform for treating neurological disorders due to their biocompatibility, biodegradability, and ease of functionalization. One of the significant challenges in treating neurological conditions is overcoming the blood-brain barrier (BBB), which restricts the effective delivery of therapeutic agents to the brain. Addressing this barrier is crucial for the successful treatment of various neurological diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, migraine, psychotic disorders, and brain tumors. Chitosan nanoparticles offer several advantages: they enhance drug absorption, protect drugs from degradation, and enable targeted delivery. These properties open new possibilities for non-invasive therapies for neurological conditions. Numerous studies have highlighted the neuroprotective potential of chitosan nanoparticles, demonstrating improved outcomes in animal models of neurodegeneration and neuroinflammation. Additionally, surface modifications of these nanoparticles allow for the attachment of specific ligands or molecules, enhancing the precision of drug delivery to neuronal cells. Despite these advancements, several challenges persist in the clinical translation of chitosan nanoparticles. Issues such as large-scale production, regulatory hurdles, and the need for further research into long-term safety must be addressed. This review explores recent advancements in the use of chitosan nanoparticles for managing neurological disorders and outlines potential future directions in this rapidly evolving field of research.

Locomotor and gait changes in the LPS model of neuroinflammation are correlated with inflammatory cytokines in blood and brain.

Lipopolysaccharide (LPS) challenge in mice has been used to identify the mechanisms and therapeutics for neuroinflammation. In this study, we aimed to comprehensively evaluate the behavioral changes including locomotion, exploration, and memory, correlating them with a panel of thirteen inflammatory cytokines in both blood and brain.We found that acute LPS administration (0.83 mg/Kg i.p.) reduced body weight, food intake, and glucose levels compared to the saline-injected mice, concomitant with decreased activity in home cage monitoring. Locomotion was significantly reduced in Open Field, Introduced Object, and Y-Maze tests. Decreased exploratory behavior in the Y-Maze and Introduced Object tests was noticed, by measuring the number of arms explored and object interaction time, respectively. Additionally, in rotarod, LPS administration led to a significant decrease in the distance achieved, while in the MouseWalker, LPS led to a reduction in average velocity.LPS induced a decrease in microglia ramification index in the motor cortex and the striatum, while surprisingly a reduction in microglia number was observed in the motor cortex.The concentrations of thirteen cytokines in the blood were significantly altered, while only CXCL1, CCL22, CCL17, G-CSF, and IL-12p40 were changed in the brain. Correlations between cytokine levels in blood and brain were found, most notably for CCL17 and CCL22. TGFβ was the only one with negative correlations to other cytokines. Correlations between cytokines and behavior changes were also disclosed, especially for CCL17, CCL22, G-CSF, and IL-6 and negatively for TGFβ and IL-10.In summary, our study employing acute LPS challenge in mice has revealed a comprehensive profile of behavioral alterations alongside significant changes in inflammatory cytokine levels, both in peripheral blood and brain tissue. These findings contribute to a deeper understanding of the interplay between inflammation and behavior, with possible implications for identifying prognostics and therapeutic targets for neuroinflammatory conditions.

25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and, in response to different inflammatory stimuli, overexpress a proinflammatory signature of genes. Among these, Ch25h is a gene overexpressed in brain tissue from Alzheimer’s disease as well as various mouse models of neuroinflammation. Ch25h encodes cholesterol 25-hydroxylase, an enzyme upregulated in activated microglia under conditions of neuroinflammation, that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC can be further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant of leukocytes. We have previously shown that 25HC increases the production and secretion of the proinflammatory cytokine, IL-1β, by primary mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) and Ch25h-knockout (KO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treated WT mice, Ch25h expression and 25HC levels increased in the brain relative to vehicle-treated WT mice. Among LPS-treated WT mice, females produced significantly higher levels of 25HC and showed transcriptomic changes reflecting higher levels of cytokine production and leukocyte migration than WT male mice. However, females were similar to males among LPS-treated KO mice. Ch25h-deficiency coincided with decreased microglial activation in response to systemic LPS. Proinflammatory cytokine production and intra-parenchymal infiltration of leukocytes were significantly lower in KO compared to WT mice. Amounts of IL-1β and IL-6 in the brain strongly correlated with 25HC levels. Our results suggest a proinflammatory role for 25HC in the brain following peripheral administration of LPS.