Disease Of Central Nervous System Research Articles

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

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

Tackling Neuroinflammation in Cognitive Disorders with Single-Targeted and Multi-Targeted Histamine H3 Receptor Modulators.

Neuroinflammation is a process involved in a variety of central nervous system (CNS) diseases and is being increasingly recognized as a key mediator of cognitive impairments. Neuroinflammatory responses including glial activation, increased production of proinflammatory cytokines, and aberrant neuronal signaling, contribute to cognitive dysfunctions. Histamine is a key peripheral inflammatory mediator, but plays an important role in neuroinflammatory processes as well. The unique localization of histamine H3 receptor (H3R) in the CNS along with the modulation of the release of other neurotransmitters via its action on heteroreceptors on non-histaminergic neurons have led to the development of several H3R ligands for various brain diseases. H3R antagonists/ inverse agonists have revealed potential to treat diverse neuroinflammatory CNS disorders, including neurodegenerative diseases, attention-deficit hyperactivity syndrome and schizophrenia. In this mini review, we provide a brief overview on the crucial involvement of the histaminergic transmission in the neuroinflammatory processes underlying these cognitive disorders, with a special focus on H3R involvement. The anti-neuroinflammatory potential of single-targeted and multi-targeted H3R antagonists/inverse agonists for the treatment of these conditions is discussed here.

Clinicopathologic features of primary central nervous system anaplastic large cell lymphoma: a multicenter study identifies age and ALK status as prognostic factors.

Anaplastic large cell lymphoma with primary presentation in, and disease limited to, the central nervous system (primary CNS ALCL) is a rare and aggressive lymphoma found in a sensitive anatomic site. We report the clinical and pathologic characteristics of 17 primary CNS ALCL cases that are newly reported from six academic medical centers. We are investigating the characteristics of these cases, alongside their commonalities and differences from systemic ALCL arising at conventional anatomic sites. Clinical, pathologic, and outcome data were extracted by medical record review. The median patient age was 32years with a male-to-female ratio of 2.4:1. Cases presented with either localized or multifocal central nervous system (CNS) disease without coinciding systemic disease. Histologically, the common pattern prevailed, and loss of pan-T-cell markers was frequent. There was a similar proportion of anaplastic lymphoma kinase (ALK) positivity in primary CNS ALCL (12/17, 71%) compared to that reported in systemic ALCL (70-80%). Our data indicate a 5-year overall survival (OS) rate of 65% and a 5-year progression-free survival (PFS) rate of 48%. Five patient deaths occurred in this study of which all were in the ALK-negative group, and all were patients over 40years old. ALK-positive patients were significantly younger than ALK-negative patients, and survival analyses showed that both ALK-positive and younger age (≤ 40years) were favorable prognostic factors. This is the largest series of primary CNS ALCL reported to date, which demonstrates a high proportion of ALK-positive cases and favorable outcomes for both younger and ALK-positive patients despite the involvement of a sensitive anatomic site.

Molecular and cellular mechanisms of mitochondria transfer in models of central nervous system disease.

In the central nervous system (CNS), neuronal function and dysfunction are critically dependent on mitochondrial integrity and activity. In damaged or diseased brains, mitochondrial dysfunction reduces adenosine triphosphate (ATP) levels and impairs ATP-dependent neural firing and neurotransmitter dynamics. Restoring mitochondrial capacity to generate ATP may be fundamental in restoring neuronal function. Recent studies in animals and humans have demonstrated that endogenous mitochondria may be released into the extracellular environment and transported or exchanged between cells in the CNS. Under pathological conditions in the CNS, intercellular mitochondria transfer contributes to new classes of signaling and multifunctional cellular activities, thereby triggering deleterious effects or promoting beneficial responses. Therefore, to take full advantage of the beneficial effects of mitochondria, it may be useful to transplant healthy and viable mitochondria into damaged tissues. In this review, we describe recent findings on the mechanisms of mitochondria transfer and provide an overview of experimental methodologies, including tissue sourcing, mitochondrial isolation, storage, and modification, aimed at optimizing mitochondria transplantation therapy for CNS disorders. Additionally, we examine the clinical relevance and potential strategies for the therapeutic application of mitochondria transplantation.

Current state and perspectives of CAR T cell therapy in central nervous system diseases.

B cell-directed CAR T cell therapy has fundamentally changed the treatment of hematological malignancies and its scope of application is rapidly expanding to include other diseases such as solid tumors or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include limited access of current therapies to the CNS, as well as enormous inter- and intraindividual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option to overcome this problem and to tackle pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has lately revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further perspective, pre-clinical data reveal potential benefits of CAR T cell therapy also in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as the extension to target different antigens or the variation of the modified T cell subtype, new and promising fields of application for CAR T cells are rapidly opening up. These innovations offer the potencial to address the complex pathophysiological properties of CNS diseases. To optimally utilize CAR T cell therapy for CNS diseases in the future while minimizing therapy risks, there is a need for further mechanistic research as well as prospective controlled trials to seriously assess the disease and patient-specific risk-benefit ratio.

Nanotechnological approaches for efficient N2B delivery: from small-molecule drugs to biopharmaceuticals

Central nervous system diseases negatively affect patients and society. Providing successful noninvasive treatments for these diseases is challenging because of the presence of the blood–brain barrier. While protecting the brain’s homeostasis, the barrier limits the passage of almost all large-molecule drugs and most small-molecule drugs. A noninvasive method, nose-to-brain delivery (N2B delivery) has been proposed to overcome this challenge. By exploiting the direct anatomical interaction between the nose and the brain, the drugs can reach the target, the brain. Moreover, the drugs can be encapsulated into various drug delivery systems to enhance physicochemical characteristics and targeting success. Many preclinical data show that this strategy can effectively deliver biopharmaceuticals to the brain. Therefore, this review focuses on N2B delivery while giving examples of different drug delivery systems suitable for the applications. In addition, we emphasize the importance of the effective delivery of monoclonal antibodies and RNA and stress the recent literature tackling this challenge. While giving examples of nanotechnological approaches for the effective delivery of small or large molecules from the current literature, we highlight the preclinical studies and their results to prove the strategies’ success and limitations.

Formyl peptide receptors in the microglial activation: New perspectives and therapeutic potential for neuroinflammation.

Secondary neurological impairment mediated by neuroinflammation is recognized as a crucial pathological factor in central nervous system (CNS) diseases. Currently, there exists a lack of specific therapies targeting neuroinflammation. Given that microglia constitute the primary immune cells involved in the neuroinflammatory response, a thorough comprehension of their role in CNS diseases is imperative for the development of efficacious treatments. Recent investigations have unveiled the significance of formyl peptide receptors (FPRs) in various neuroinflammatory diseases associated with microglial overactivation. Consequently, FPRs emerge as promising targets for modulating the neuroinflammatory response. This review aims to comprehensively explore the therapeutic potential of targeting FPRs in the management of microglia-mediated neuroinflammation. It delineates the molecular characteristics and functions of FPRs, elucidates their involvement in the inflammatory response linked to microglial overactivation, and synthesizes therapeutic strategies for regulating microglia-mediated neuroinflammation via FPR modulation, thereby charting a novel course for the treatment of neuroinflammatory diseases.

Regulation of ROS metabolism in macrophage via xanthine oxidase is associated with disease progression in pulmonary tuberculosis.

Pulmonary tuberculosis (PTB) exacerbation can lead to respiratory failure, multi-organ failure, and symptoms related to central nervous system diseases. The purpose of this study is to screen biomarkers and metabolic pathways that can predict the progression of PTB, and to verify the role of the metabolic enzyme xanthine oxidase (XO) in the progression of PTB. To explore the biomarkers and mechanisms underlying the progression of PTB, plasma metabolomics sequencing was conducted on patients with severe PTB, non-severe PTB, and healthy individuals. Screening differential metabolites and metabolic pathways that can predict the progression of PTB, and verifying the function and mechanism of action of XO through experiments. The purine metabolism, sphingolipid metabolism, and amino acid metabolism between the three groups differ. In patients with severe PTB, the levels of xanthosine and hypoxanthine are increased, while the levels of D-tryptophan, dihydroceramide and uric acid are decreased. Inhibition of XO activity has been observed to reduce the levels of tumor necrosis factor (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), as well as to suppress the production of reactive oxygen species (ROS) and the activation of the NF-κB pathway, while also promoting the growth of MTB within cells. D-tryptophan, xanthosine, and dihydroceramide can be utilized as biomarkers for progression of PTB, assisting in the evaluation of disease progression, and XO stands out as a potential therapeutic target for impeding the progression of PTB.

Alzheimer's Disease-Derived Outer Membrane Vesicles Exacerbate Cognitive Dysfunction, Modulate the Gut Microbiome, and Increase Neuroinflammation and Amyloid-β Production.

Although our understanding of the molecular biology of Alzheimer's disease (AD) continues to improve, the etiology of the disease, particularly the involvement of gut microbiota disturbances, remains a challenge. Outer membrane vesicles (OMVs) play a key role in central nervous system diseases, but the impact of OMVs on AD progression remains unclear. In this study, we hypothesized that AD-derived OMVs (OMVsAD) were a risk factor in AD pathology. To test our hypothesis, young APP/PS1 mice (AD mice) were given OMVsAD by gavage. Young AD mice were euthanized 120days after gavage to assess the intestinal barrier, gut microbiota diversity, mediators of neuroinflammation, glial markers, amyloid burden, and short-chain fatty acid (SCFA) levels. Our results showed that OMVsAD accelerated cognitive dysfunction after 120days of intragastric administration. Morris water maze experiment and new object recognition test showed that OMVsAD caused significantly poorer spatial ability learning and memory of the AD mice. We observed the OMVsAD-treated APP/PS1 mice display OMVs disrupting the intestinal barrier compared with controls of normal human-derived OMVs. Compared with the OMVsHC group, claudin-5 and ZO-1 related to the intestinal barrier were significantly downregulated in the OMVsAD group. The OMVsAD activate microglia in the cerebral cortex and hippocampus of AD mice, and the levels of IL-1β, IL-6, TNF-α, and NF-Κb were upregulated. We also found that OMVsAD increased Aβ production. 16S rRNA sequencing showed that OMVsAD negatively regulated the α- and β-diversity index of intestinal flora and reduced the levels of SCFA. OMVsAD may change the intestinal flora of young AD, damage the intestinal mucosa and blood-brain barrier, and accelerate AD neuropathological damage.

An In Vitro Platform for Pharmacokinetic Quantification and Optimization of Cerebrospinal Fluid Filtration and Drug Circulation

Abstract Modification of cerebrospinal fluid (CSF) transport dynamics is an expanding method for treating central nervous system injury and diseases. One application of this route is to modify the distribution of solutes in the CSF; however, few tools currently exist for this purpose. The present study describes the use of a subject-specific in vitro CSF phantom to perform a parametric evaluation of the Neurapheresis™ CSF Management System (NP) for both CSF filtration and intrathecal drug circulation. An in vitro CSF phantom was constructed which included realistic anatomy for the complete subarachnoid space (SAS). This platform was configured to test multiple parametric modifications of a dual-lumen catheter and filtration system. Calibrated mapping of tracer distribution and area under the curve (AUC) measurements were used to compare filtration and intrathecal-circulation schemes using the NP device versus the clinical standards of care. The NP device showed potential advantages over lumbar drain (LD) for clearance of simulated subarachnoid hemorrhage (SAH), especially in the spinal canal. Use of the NP device in combination with simulated intracerebroventricular (ICV) drug infusion resulted in an increased extent and uniformity of tracer spread compared to ICV alone. NP improved clearance of simulated subarachnoid hemorrhage compared to LD and increased uniformity of tracer concentration via simulated ICV, providing support for NP use in these scenarios. The in vitro CSF phantom system presented here quantitatively described the effects of parametric boundary modification on solute distribution in the intrathecal space.

PECULIARITIES OF FATAL CASES IN HIV-INFECTED PATIENTS WITH CENTRAL NERVOUS SYSTEM LESIONS IN TUBERCULOSIS INPATIENT SETTINGS FOR 2014-2023

Aim of the work is to study the peculiarities of fatal cases of CNS lesions in patients with tuberculosis against the background of HIV infection.Materials and methods. A retrospective analysis of 68 medical histories of tuberculosis patients with HIV infection who died in the CNE "Zaporizhia Regional Phthisiopulmonology Clinical Treatment and Diagnostic Center" for the years 2014-2023 was carried out. An analysis of the anamnesis, clinical and radiological data, laboratory indicators, final clinical and pathological diagnoses was carried out.Results. The mortality rate among HIV-infected people in TB hospitals has a steady downward trend. In 2014-2023, 1234 patients with HIV infection were treated at the CNE "Zaporizhia Regional Phthisiopulmonology Clinical Treatment and Diagnostic Center", 214 (17.3%) died. In 2014, 33 (24.6%) out of 134 HIV-positive patients died, and in 2023, 3 (6.8%) out of 44 HIV-positive patients died. Central nervous system (CNS) lesions among the dead were noted in 68 (31.8%) patients. The study of medical records found that among those who died with CNS lesions, men prevailed - 55 (80.9%), women - 13 (19.1%), young patients - 53 (77.9%), and 15 (22.1%) patients over 45 years of age. In the structure of central nervous system lesions in patients with active tuberculosis, tuberculous meningoencephalitis prevails in fatal cases - 35 (51.5%), a significant share of cryptococcal meningoencephalitis - 18 (26.5%) and progressive multifocal leukoencephalopathy - 9 (13.2%). The main reason that leads to fatal consequences is the late diagnosis of HIV infection - in 26 (38.2%) the number of CD4<50 cl./μl, 36 (52.9%) patients did not receive antiretroviral therapy (ART), 18 (26 .5%) of patients had been taking ART for a year. Improvement of tuberculosis microbiological diagnosis due to the introduction of the Xpert MTB/RIF® (Ultra) test at all levels of the laboratory network, the introduction of a mandatory test for cryptococci, free CT, MRI examination for the diagnosis in HIV-infected patients, improvement of drug-resistant tuberculosis treatment regimens contributed to the reduction of mortality in case of HIV and tuberculosis combination, which was 24.6% in 2014, and 6.8% in 2023.Conclusions. Diagnosis and treatment of CNS diseases in patients with active tuberculosis against the background of HIV infection requires a comprehensive approach: early diagnosis of HIV infection, tuberculosis and lesions of the CNS, improvement of treatment.

Neuroimaging Applications for the Delivery and Monitoring of Gene Therapy for Central Nervous System Diseases.

Neurological disease due to single-gene defects represents a targetable entity for adeno-associated virus (AAV)-mediated gene therapy. The delivery of AAV-mediated gene therapy to the brain is challenging, owing to the presence of the blood-brain barrier. Techniques in gene transfer, such as convection-enhanced intraparenchymal delivery and image-guided delivery to the cerebrospinal fluid spaces of the brain, have led the field into highly accurate delivery techniques, which provide correction of genetic defects in specific brain regions or more broadly. These techniques commonly use magnetic resonance imaging (MRI), computed tomography, and fluoroscopic guidance. Even more, the neuroimaging changes evaluated by MRI, MR spectroscopy, diffusion tensor imaging, and functional MRI can serve as important biomarkers of therapy effect and overall disease progression. Here, we discuss the role of neuroimaging in delivering AAV vectors and monitoring the effect of gene therapy.

Development and validation of the prediction score for augmented renal clearance in critically Ill Japanese adults.

Augmented renal clearance (ARC) decreases the therapeutic concentration of drugs excreted by the kidneys in critically ill patients. Several ARC prediction models have been developed and validated; however, their usefulness in Japan has not been comprehensively investigated. Thus, we developed a unique ARC prediction model for a Japanese mixed intensive care unit (ICU) population and compared it with existing models. This retrospective study enrolled a mixed ICU population in Japan from January 2019 and June 2022. The primary outcome was the development and validation of a model to predict ARC onset based on baseline information at ICU admission. Patients admitted until May 2021 were included in the training set, and external validation was performed on patients admitted thereafter. A multivariate logistic regression model was used to develop an integer-based predictive scoring system for ARC. The new model (the JPNARC score) was externally validated along with the ARC and Augmented Renal Clearance in Trauma Intensive Care (ARCTIC) scores. A total of 2,592 critically ill patients were enrolled initially, with 651 patients finally included after excluding 1,941 patients. The training and validation datasets comprised 456 and 195 patients, respectively. Multivariate analysis was performed to develop the JPNARC score, which incorporated age, sex, serum creatinine, and diagnosis upon ICU admission (trauma or central nervous system disease). The JPNARC score had a larger area under the receiver operating characteristic curve than the ARC and ARCTIC scores in the validation dataset (0.832, 0.633, and 0.740, respectively). An integer-based scoring system was developed to predict ARC onset in a critically ill Japanese population and showed high predictive performance. New models designed to predict the often-unrecognized ARC phenomenon may aid in the decision-making process for upward drug dosage modifications, especially in resource- and labor-limited settings.

The Yin and Yang of Microglia-Derived Extracellular Vesicles in CNS Injury and Diseases

Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining neural homeostasis but can also contribute to disease and injury when this state is disrupted or conversely play a pivotal role in neurorepair. One way that microglia exert their effects is through the secretion of small vesicles, microglia-derived exosomes (MGEVs). Exosomes facilitate intercellular communication through transported cargoes of proteins, lipids, RNA, and other bioactive molecules that can alter the behavior of the cells that internalize them. Under normal physiological conditions, MGEVs are essential to homeostasis, whereas the dysregulation of their production and/or alterations in their cargoes have been implicated in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), spinal cord injury (SCI), and traumatic brain injury (TBI). In contrast, MGEVs may also offer therapeutic potential by reversing inflammation or being amenable to engineering for the delivery of beneficial biologics or drugs. The effects of MGEVs are determined by the phenotypic state of the parent microglia. Exosomes from anti-inflammatory or pro-regenerative microglia support neurorepair and cell survival by delivering neurotrophic factors, anti-inflammatory mediators, and molecular chaperones. Further, MGEVs can also deliver components like mitochondrial DNA (mtDNA) and proteins to damaged neurons to enhance cellular metabolism and resilience. MGEVs derived from pro-inflammatory microglia can have detrimental effects on neural health. Their cargo often contains pro-inflammatory cytokines, molecules involved in oxidative stress, and neurotoxic proteins, which can exacerbate neuroinflammation, contribute to neuronal damage, and impair synaptic function, hindering neurorepair processes. The role of MGEVs in neurodegeneration and injury—whether beneficial or harmful—largely depends on how they modulate inflammation through the pro- and anti-inflammatory factors in their cargo, including cytokines and microRNAs. In addition, through the propagation of pathological proteins, such as amyloid-beta and alpha-synuclein, MGEVs can also contribute to disease progression in disorders such as AD and PD, or by the transfer of apoptotic or necrotic factors, they can induce neuron toxicity or trigger glial scarring during neurological injury. In this review, we have provided a comprehensive and up-to-date understanding of the molecular mechanisms underlying the multifaceted role of MGEVs in neurological injury and disease. In particular, the role that specific exosome cargoes play in various pathological conditions, either in disease progression or recovery, will be discussed. The therapeutic potential of MGEVs has been highlighted including potential engineering methodologies that have been employed to alter their cargoes or cell-selective targeting. Understanding the factors that influence the balance between beneficial and detrimental exosome signaling in the CNS is crucial for developing new therapeutic strategies for neurodegenerative diseases and neurotrauma.

A Narrative Review of Congenital Syphilis in the United States: Innovative Perspectives on a Complex Public Health and Medical Disease.

Over the past two decades, congenital syphilis cases have risen 11-fold in the United States. While disparities across geography, race, and ethnicity exist, lack of timely screening or treatment is identified in 88% of cases nationally. Congenital syphilis is a public health and medical problem rooted in systematic and societal structural determinants of health and healthcare limitations. Early syphilis in pregnancy leads to congenital syphilis if untreated in 50 - 70% of cases, with risk for fetal demise, and among survivors, congenital anomalies, organ damage, and central nervous system disease. Prevention of congenital syphilis lies in early detection and treatment in pregnant persons. In this narrative review, we describe the evolving epidemiology of syphilis and congenital syphilis, highlighting unique aspects among women. We explore the role of novel screening and treatment strategies, public health policy, and medical considerations in terms of congenital syphilis prevention. Readers of this review will understand CS as a complex public health and medical disease that can be prevented through innovative and coordinated strategies in public health policy, expanded screening and research opportunities.

Neddylation of protein, a new strategy of protein post-translational modification for targeted treatment of central nervous system diseases

Neddylation, a type of protein post-translational modification that links the ubiquitin-like protein NEDD8 to substrate proteins, can be involved in various significant cellular processes and generate multiple biological effects. Currently, the best-characterized substrates of neddylation are the Cullin protein family, which is the core subunit of the Cullin-RING E3 ubiquitin ligase complex and controls many important biological processes by promoting ubiquitination and subsequent degradation of various key regulatory proteins. The normal or abnormal process of protein neddylation in the central nervous system can lead to a series of occurrences of normal functions and the development of diseases, providing an attractive, reasonable, and effective targeted therapeutic strategy. Therefore, this study reviews the phenomenon of neddylation in the central nervous system and summarizes the corresponding substrates. Finally, we provide a detailed description of neddylation involved in CNS diseases and treatment methods that may be used to regulate neddylation for the treatment of related diseases.

Discovery of 18F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

The histamine subtype 3 (H3) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H3 receptor. In this study, we synthesized and evaluated the binding effects of [18F]H3-2404 and [18F]H3-2405 by modifying the structure of AZD5213, a selective H3 antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [18F]H3-2404 and [18F]H3-2405 are unsuitable as PET tracers for brain imaging of the H3 receptor, this study provides a valuable attempt for optimizing 18F labeled radiotracers based on AZD5213.

Unveiling the potential of intranasal delivery of renin-angiotensin system drugs: Insights on the pharmacokinetics of irbesartan

The therapeutic interest of renin-angiotensin system (RAS) drugs for the treatment of neuroinflammation has been recently acknowledged. Nevertheless, most RAS drugs display limited passage across the blood–brain barrier (BBB). Therefore, this study investigated the potential of intranasal (IN) delivery of six RAS drugs to circumvent the BBB and attain the brain, envisioning its future use in central nervous system (CNS) neuroinflammatory diseases, such as Alzheimer’s disease (AD).Captopril, enalaprilat, irbesartan, lisinopril, losartan and valsartan were firstly screened based on their impact on the viability of nasal, lung, and neuronal cell lines and their apparent permeability (Papp) across porcine olfactory mucosa. Irbesartan, identified as the one with the best safety and permeability balance, was selected for pharmacokinetic characterization following single and multidose IN administration to CD-1 mice. The results were compared to those obtained by intravenous (IV) injection to assess direct nose-to-brain drug delivery. Olfactory toxicity and anxiety were also evaluated after multidose IN treatment.Irbesartan IN administration significantly enhanced brain targeting, with a 3-fold increase in the maximum concentration (Cmax) and a 2.5-fold increase in the area under the curve (AUCt) in the brain compared to IV route. The drug exhibited a tmax of 15 min post-IN administration and achieved a brain targeting efficiency of 239.56%, with a significant direct transport percentage of 58.26%. Multidose administration indicated no systemic or tissue accumulation, with accumulation ratio (Rac) values below 1.0, and no significant olfactory toxicity.Overall, the study highlights the potential of IN delivery of irbesartan as a promising strategy to improve brain targeting and therapeutic outcomes in CNS diseases such as AD, providing an effective approach to bypass BBB limitations.

FGF21 Alleviates Hypoxic-Ischemic White Matter Injury in Neonatal Mice by Mediating Inflammation and Oxidative Stress Through PPAR-γ Signaling Pathway.

White matter injury (WMI), the most common type of brain damage in infants born preterm, is characterized by failure in oligodendrocyte progenitor cell maturation and myelination, thereby contributing to long-term neurological impairments. Regrettably, effective therapies for promoting remyelination and improving function are currently lacking for this growing population affected by WMI. Recombinant human fibroblast growth factor (rhFGF) 21 modulated microglial activation and then ameliorated brain damage and improved neurological deficits in several central nervous system diseases. However, the effects of rhFGF21 treatment on WMI in preterm infants remain uncertain. In this study, we established an in vivo mouse model of cerebral hypoxia-ischemia (HI)-induced brain WMI and an in vitro model using oxygen-glucose deprivation (OGD)-treated HMC3 cells to investigate the neuroprotective effects of rhFGF21 against WMI and elucidated the potential mechanism. Our findings demonstrated that administration of rhFGF21 significantly ameliorated the retardation of oligodendrocyte differentiation, promoted myelination, and mitigated axonal deficits, synaptic loss, and GFAP scarring, thereby improving lifelong cognitive and neurobehavioral dysfunction associated with WMI. Moreover, rhFGF21 modulated microglial polarization, promoted a shift from the M1 to the M2 microglial phenotype, and suppressed microglial activation, thus ameliorating inflammatory response and oxidative stress. Additionally, rhFGF21 treatment significantly inhibited the HMGB1/NF-κB pathway linked to inflammation, and activated the NRF2 pathway associated with oxidative stress through the upregulation of PPAR-γ. Importantly, the beneficial effects of rhFGF21 on HI-induced WMI and microglial activation were dramatically inhibited by PPAR-γ antagonist and its siRNA. Our findings provide compelling evidence that rhFGF21 treatment mitigated the inflammatory response and oxidative stress through the modulation of microglial polarization via the PPAR-γ-mediated HMGB1/NF-κB pathway and the NRF2 pathway, respectively, contributes to neuroprotection and the amelioration of WMI in neonatal mice. Thus, rhFGF21 represents a promising therapeutic agent for the treatment of neonatal WMI.

The Neuroprotective Mechanisms of PPAR-γ: Inhibition of Microglia-Mediated Neuroinflammation and Oxidative Stress in a Neonatal Mouse Model of Hypoxic-Ischemic White Matter Injury.

Neuroinflammation and oxidative stress, mediated by microglial activation, hinder the development of oligodendrocytes (OLs) and delay myelination in preterm infants, leading to white matter injury (WMI) and long-term neurodevelopmental sequelae. Peroxisome proliferator-activated receptor gamma (PPAR-γ) has been reported to inhibit inflammation and oxidative stress via modulating microglial polarization in various central nervous system diseases. However, the relationship between PPAR-γ and microglial polarization in neonatal WMI is not well understood. Therefore, this study aimed to elucidate the role and mechanisms of PPAR-γ in preterm infants affected by WMI. In this study, an invivo hypoxia-ischemia (HI) induced brain WMI neonatal mouse model was established. The mice were administered intraperitoneally with either RSGI or GW9662 to activate or inhibit PPAR-γ, respectively. Additionally, an invitro oxygen-glucose deprivation (OGD) cell model was established and pretreated with pcDNA 3.1-PPAR-γ or si-PPAR-γ to overexpress or silence PPAR-γ, respectively. The neuroprotective effects of PPAR-γ were investigated invivo. Firstly, open field test, novel object recognization test, and beam-walking test were employed to assess the effects of PPAR-γ on neurobehavioral recovery. Furthermore, assessment of OLs loss and OL-maturation disorder, the number of myelinated axons, myelin thickness, synaptic deficit, activation of microglia and astrocyte, and blood-brain barrier (BBB) were used to evaluate the effects of PPAR-γ on pathological repair. The mechanisms of PPAR-γ were explored both invivo and invitro. Assessment of microglia polarization, inflammatory mediators, reactive oxygen species (ROS), MDA, and antioxidant enzymes was used to evaluate the anti-inflammatory and antioxidative effects of PPAR-γ activation. An assessment of HMGB1/NF-κB and NRF2/KEAP1 signaling pathway was conducted to clarify the mechanisms by which PPAR-γ influences HI-induced WMI in neonatal mice. Activation of PPAR-γ using RSGI significantly mitigated BBB disruption, promoted M2 polarization of microglia, inhibited activation of microglia and astrocytes, promoted OLs development, and enhanced myelination in HI-induced WMI. Conversely, inhibition of PPAR-γ using GW9662 further exacerbated the pathologic hallmark of WMI. Neurobehavioral tests revealed that neurological deficits were ameliorated by RSGI, while further aggravated by GW91662. In addition, activation of PPAR-γ significantly alleviated neuroinflammation and oxidative stress by suppressing HMGB1/NF-κB signaling pathway and activating NRF2 signaling pathway both invivo and invitro. Conversely, inhibition of PPAR-γ further exacerbated HI or OGD-induced neuroinflammation, oxidative stress via modulation of the same signaling pathway. Our findings suggest that PPAR-γ regulates microglial activation/polarization as well as subsequent neuroinflammation/oxidative stress via the HMGB1/NF-κB and NRF2/KEAP1 signaling pathway, thereby contributing to neuroprotection and amelioration of HI-induced WMI in neonatal mice.