Treatment Of Central Nervous System Diseases Research Articles

Emerging functions and therapeutic targets of IL-38 in central nervous system diseases.

Interleukin (IL)-38 is a newly discovered cytokine of the IL-1 family, which binds various receptors (i.e., IL-36R, IL-1 receptor accessory protein-like 1, and IL-1R1) in the central nervous system (CNS). The hallmark physiological function of IL-38 is competitive binding to IL-36R, as does the IL-36R antagonist. Emerging research has shown that IL-38 is abnormally expressed in the serum and brain tissue of patients with ischemic stroke (IS) and autism spectrum disorder (ASD), suggesting that IL-38 may play an important role in neurological diseases. Important advances include that IL-38 alleviates neuromyelitis optica disorder (NMOD) by inhibiting Th17 expression, improves IS by protecting against atherosclerosis via regulating immune cells and inflammation, and reduces IL-1β and CXCL8 release through inhibiting human microglial activity post-ASD. In contrast, IL-38 mRNA is markedly increased and is mainly expressed in phagocytes in spinal cord injury (SCI). IL-38 ablation attenuated SCI by reducing immune cell infiltration. However, the effect and underlying mechanism of IL-38 in CNS diseases remain inadequately characterized. In this review, we summarize the biological characteristics, pathophysiological role, and potential mechanisms of IL-38 in CNS diseases (e.g., NMOD, Alzheimer's disease, ASD, IS, TBI, and SCI), aiming to explore the therapeutic potential of IL-38 in the prevention and treatment of CNS diseases.

Potential Roles of Nr4a3-Mediated Inflammation in Immunological and Neurological Diseases.

As a protein of the orphan nuclear receptor Nr4a family, Nr4a3 has no identified natural ligands. However, its biological activity can be mediated by inducing conformational changes through interactions with specific certain small molecules and receptors. Nr4a3 is activated as an early stress factor under various pathological conditions and plays a regulatory role in various tissues and cells, participating in processes such as cell differentiation, apoptosis, metabolism, and homeostasis. At present, research on the role of Nr4a3 in the pathophysiology of inflammation is considerably limited, especially with respect to its role in the central nervous system (CNS). In this review, we discuss the role of Nr4a3 in multiple sclerosis, Alzheimer's disease, retinopathy, Parkinson's disease, and other CNS diseases. This review shows that Nr4a3 has considerable potential as a therapeutic target in the treatment of CNS diseases. We provide a theoretical basis for the targeted therapy of CNS diseases and neuroinflammation, among other conditions.

Pharmacological Effects of Traditional Chinese Medicine on Central Nervous System: A Narrow Update

Abstract: Central nervous system (CNS) diseases seriously affect human life and health, currently, drugs used to treat CNS diseases mainly include receptor modulators and neurotransmitter inhibitors, which possess considerable side effects; accordingly, there is a need for efficacious drugs for clinical therapy. Traditional Chinese Medicines (TCMs) have a wide range of pharmacological effects on the CNS, especially as anti-CNS diseases. TCMs can enhance both non-specific and specific immune functions. Some TCMs can improve the adaptability of the body, enhance the body's resistance to various harmful stimuli, regulate pathological processes, and reverse the disordered function. TCMs and their active ingredients exhibit diverse pharmacological effects, including anti-neuritis, anti-oxidative stress regulation, and inhibition of cell apoptosis, with mechanisms possibly related to the regulation of the CNS function and restoring cell metabolism disorders. Based on literature from recent years, we summarize the neuroprotective effects of TCMs from the perspective of core pathological changes in the CNS and clinical applications. In addition, we integrated the progress of experimental research with regard to the pharmacological effects of TCMs on CNS. Current pharmacological investigations examining TCMs on CNS diseases, including Parkinson's disease (PD) and Alzheimer's disease (AD), were reviewed to provide a reference and new concepts for further developing TCMs.

Multifunctional Nanotheranostics for Overcoming the Blood–Brain Barrier

AbstractThe blood–brain barrier (BBB) is a tailored system of capillary endothelial cells intermixed with tight junctions and adherent junctions that regulates the transport of various materials and substances between the blood vasculature and the central nervous system (CNS). However, in cases of brain diseases, BBB's protective and regulatory effects hamper therapeutics from reaching affected sites in sufficient quantities. This has so far been a leading challenge in treating CNS diseases and disorders. For this problem to be overcome, recent research has sought to develop novel modalities to achieve efficient therapy and alleviate associated symptoms. Therefore, numerous strategies have operated in recent years to address the limitations of traditional and invasive methods, including poor brain penetration and serious side effects. As a desperately in‐demand technology, nanotheranostics has particularly shown promising results. Herein, this review reports recent advancements in CNS nanotheranostics and novel techniques and nanotechnology‐based strategies developed for treating neurodegenerative disorders. The study provides comprehensive data on the subject to be used for future studies for the therapy and management of CNS disorders and diseases.

Optical Coherence Tomography Angiography: Revolutionizing Clinical Diagnostics and Treatment in Central Nervous System Disease.

Optical coherence tomography angiography (OCTA), as a new generation of non-invasive and efficient fundus imaging technology, can provide non-invasive assessment of vascular lesions in the retina and choroid. In terms of anatomy and development, the retina is referred to as an extension of the central nervous system (CNS). CNS diseases are closely related to changes in fundus structure and blood vessels, and direct visualization of fundus structure and blood vessels provides an effective "window" for CNS research. This has important practical significance for identifying the characteristic changes of various CNS diseases on OCTA in the future, and plays a key role in promoting early screening, diagnosis, and monitoring of disease progression in CNS diseases. This article reviews relevant fundus studies by comparing and summarizing the unique advantages and existing limitations of OCTA in various CNS disease patients, in order to demonstrate the clinical significance of OCTA in the diagnosis and treatment of CNS diseases.

Optical Modulation of the Blood-Brain Barrier for Glioblastoma Treatment.

The blood-brain barrier (BBB) is a major obstacle to the diagnostics and treatment of many central nervous system (CNS) diseases. A prime example of this challenge is seen in glioblastoma (GBM), the most aggressive and malignant primary brain tumor. The BBB in brain tumors, or the blood-brain-tumor barrier (BBTB), prevents the efficient delivery of most therapeutics to brain tumors. Current strategies to overcome the BBB for therapeutic delivery, such as using hyperosmotic agents (mannitol), have impeded progress in clinical translation limited by the lack of spatial resolution, high incidences of complications, and potential for toxicity. Focused ultrasound combined with intravenously administered microbubbles enables the transient disruption of the BBB and has progressed to early-phase clinical trials. However, the poor survival with currently approved treatments for GBM highlights the compelling need to develop and validate treatment strategies as well as the screening for more potent anticancer drugs. In this protocol, we introduce an optical method to open the BBTB (OptoBBTB) for therapeutic delivery via ultrashort pulse laser stimulation of vascular targeting plasmonic gold nanoparticles (AuNPs). Specifically, the protocol includes the synthesis and characterization of vascular-targeting AuNPs and a detailed procedure of optoBBTB. We also report the downstream characterization of the drug delivery and tumor treatment efficacy after BBB modulation. Compared with other barrier modulation methods, our optical approach has advantages in high spatial resolution and minimally invasive access to tissues. Overall, optoBBTB allows for the delivery of a variety of therapeutics into the brain and will accelerate drug delivery and screening for CNS disease treatment. Key features • Pulsed laser excitation of vascular-targeting gold nanoparticles non-invasively and reversibly modulates the blood-brain barrier permeability. • OptoBBTB enhances drug delivery in clinically relevant glioblastoma models. • OptoBBTB has the potential for drug screening and evaluation for superficial brain tumor treatment.

Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies.

Food-derived peptides, as dietary supplements, have significant effects on promoting brain health and relieving central nervous system (CNS) diseases. However, the blood-brain barrier (BBB) greatly limits their in-brain bioavailability. Thus, overcoming the BBB to target the CNS is a major challenge for bioactive peptides in the prevention and treatment of CNS diseases. This review discusses improvement in the neuroprotective function of food-derived active peptides in CNS diseases, as well as the source of BBB penetrating peptides (BBB-shuttles) and the mechanism of transmembrane transport. Notably, this review also discusses various peptide modification methods to overcome the low permeability and stability of the BBB. Lipification, glycosylation, introduction of disulfide bonds, and cyclization are effective strategies for improving the penetration efficiency of peptides through the BBB. This review provides a new prospective for improving their neuroprotective function and developing treatments to delay or even prevent CNS diseases.

Nanocarrier-mediated curcumin delivery: An adjuvant strategy for CNS disease treatment.

Neurological disorders are a major global challenge, which counts for a substantial slice of disease burden around the globe. In these, the challenging landscape of central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and neuro-AIDS, demands innovative and novel therapeutic approaches. Curcumin, a versatile natural compound with antioxidant and anti-inflammatory properties, shows great potential as a CNS adjuvant therapy. However, its limited bioavailability and suboptimal permeability to the blood-brain barrier (BBB) hamper the therapeutic efficacy of curcumin. This review explores how nanocarrier facilitates curcumin delivery, which has shown therapeutic efficacy for various non-CNS diseases, for example, cancers, and can also revolutionize the treatment outcomes in patients with CNS diseases. Toward this, intranasal administration of curcumin as a non-invasive CNS drug delivery route can also aid its therapeutic outcomes as an adjuvant therapy for CNS diseases. Intranasal delivery of nanocarriers with curcumin improves the bioavailability of curcumin and its BBB permeability, which is instrumental in promoting its therapeutic potential. Furthermore, curcumin's inhibitory effect on efflux transporters will help to enhance the BBB and cellular permeability of various CNS drugs. The therapeutic potential of curcumin as an adjuvant has the potential to yield synergistic effects with CNS drugs and will help to reduce CNS drug doses and improve their safety profile. Taken together, this approach holds a promise for reshaping CNS disease management by maximizing curcumin's and other drugs' therapeutic benefits.

Drug Delivery to the Brain: Recent Advances and Unmet Challenges.

Brain cancers and neurodegenerative diseases are on the rise, treatments for central nervous system (CNS) diseases remain limited. Despite the significant advancement in drug development technology with emerging biopharmaceuticals like gene therapy or recombinant protein, the clinical translational rate of such biopharmaceuticals to treat CNS disease is extremely poor. The blood-brain barrier (BBB), which separates the brain from blood and protects the CNS microenvironment to maintain essential neuronal functions, poses the greatest challenge for CNS drug delivery. Many strategies have been developed over the years which include local disruption of BBB via physical and chemical methods, and drug transport across BBB via transcytosis by targeting some endogenous proteins expressed on brain-capillary. Drug delivery to brain is an ever-evolving topic, although there were multiple review articles in literature, an update is warranted due to continued growth and new innovations of research on this topic. Thus, this review is an attempt to highlight the recent strategies employed to overcome challenges of CNS drug delivery while emphasizing the necessity of investing more efforts in CNS drug delivery technologies parallel to drug development.

Cell type-targeting nanoparticles in treating central nervous system diseases: Challenges and hopes

Abstract Effective and safe pharmacotherapies for central nervous system (CNS) disorders remain a major obstacle to human health worldwide. Nanotechnology offers promise in addressing this challenge by enabling the transport of large molecules across the blood–brain barrier (BBB) and the delivery of multiple drugs. Numerous studies have demonstrated the efficacy of nanodrugs in animal models of various CNS disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, lysosomal storage disease, and gliomas. Nanoparticles (NPs), tailor-made to enhance drug enrichment locally and promote extended drug release, can prevent neuronal death, decrease neurotoxicity, and inhibit tumor growth. In addition to drug delivery, gene therapy using nanotechnology has emerged as a potentially curative option for neurodegenerative diseases. In this review, we summarize how NPs have successfully crossed the BBB and specifically targeted different cells in various CNS disease models over the past decade. Although nanotechnology holds great promise, several drawbacks and challenges must be addressed before its effective implementation in the treatment of CNS diseases.

Treatment of Central Nervous System Tumors on Combination MR-Linear Accelerators: Review of Current Practice and Future Directions.

Magnetic resonance imaging (MRI) provides excellent visualization of central nervous system (CNS) tumors due to its superior soft tissue contrast. Magnetic resonance-guided radiotherapy (MRgRT) has historically been limited to use in the initial treatment planning stage due to cost and feasibility. MRI-guided linear accelerators (MRLs) allow clinicians to visualize tumors and organs at risk (OARs) directly before and during treatment, a process known as online MRgRT. This novel system permits adaptive treatment planning based on anatomical changes to ensure accurate dose delivery to the tumor while minimizing unnecessary toxicity to healthy tissue. These advancements are critical to treatment adaptation in the brain and spinal cord, where both preliminary MRI and daily CT guidance have typically had limited benefit. In this narrative review, we investigate the application of online MRgRT in the treatment of various CNS malignancies and any relevant ongoing clinical trials. Imaging of glioblastoma patients has shown significant changes in the gross tumor volume over a standard course of chemoradiotherapy. The use of adaptive online MRgRT in these patients demonstrated reduced target volumes with cavity shrinkage and a resulting reduction in radiation dose to uninvolved tissue. Dosimetric feasibility studies have shown MRL-guided stereotactic radiotherapy (SRT) for intracranial and spine tumors to have potential dosimetric advantages and reduced morbidity compared with conventional linear accelerators. Similarly, dosimetric feasibility studies have shown promise in hippocampal avoidance whole brain radiotherapy (HA-WBRT). Next, we explore the potential of MRL-based multiparametric MRI (mpMRI) and genomically informed radiotherapy to treat CNS disease with cutting-edge precision. Lastly, we explore the challenges of treating CNS malignancies and special limitations MRL systems face.

Injectable nanogel systems for brain drug delivery

<img src=” https://s3.amazonaws.com/production.scholastica/article/88217/large/prnano_912023ga.jpg?1695507286”> The central nervous system (CNS) controls many critical functions, such as intelligence, emotion, sense, and memory, and modulates many other functions of the entire human body. Diseases affecting the CNS are challenging to treat because of the CNS’s sensitive functional and structural features and limited accessibility. The brain is secured from the systemic circulation by a unique biological fence, the blood-brain barrier (BBB), that limits molecular exchange between the peripheral and CNS systems. Most drugs used for treating CNS diseases fail to reach the brain in effective therapeutic concentrations due to the presence of BBB. During the last decade, specifically engineered drug delivery systems (DDS) have offered the opportunity to overcome systemic barriers in brain drug delivery. However, even with the best-engineered nano-carriers, delivering sufficient drug doses into the brain through systemic circulation remains challenging. Here, we review various systems for ‘direct’ drug delivery to the brain using im-plantable or injectable intracranial nano-drug delivery systems (nDDS), which can ensure 100% release of drug to the brain in a sustained or controlled fashion for prolonged periods, bypassing the BBB, thereby radically improving the therapeutic efficacy while minimizing systemic toxicity. Brain injectable nanogels or nanoparticle systems can be considered superior compared to other local drug-delivery systems because they possess better diffusivity of drugs. The nanogels can be injected through minimally invasive procedures, precisely delivering drugs to specific target sites. This review covers a detailed discussion about locally injectable DDS and various nanogel-based drugs, oligonucleotide, and theragnostic delivery systems used for treating brain malignancies, infections, and neurodegenerative diseases.

Role and regulatory mechanism of microRNA mediated neuroinflammation in neuronal system diseases.

MicroRNAs (miRNAs) are small non-coding RNAs with the unique ability to degrade or block specific RNAs and regulate many cellular processes. Neuroinflammation plays the pivotal role in the occurrence and development of multiple central nervous system (CNS) diseases. The ability of miRNAs to enhance or restrict neuroinflammatory signaling pathways in CNS diseases is an emerging and important research area, including neurodegenerative diseases, stroke, and traumatic brain injury (TBI). In this review, we summarize the roles and regulatory mechanisms of recently identified miRNAs involved in neuroinflammation-mediated CNS diseases, aiming to explore and provide a better understanding and direction for the treatment of CNS diseases.

Global Research Trends of Exosomes in the Central Nervous System: A Bibliometric and Visualized Analysis.

Exosomes in the central nervous system (CNS) have become an attractive area of research with great value. However, few bibliometric analysis has been conducted. The study aimed to visualize the scientific trends and research hotspots of exosomes in the CNS by bibliometric analysis. All potential articles and reviews on exosomes in the CNS published in English from 2001 to 2021 were extracted from the Web of Science Core Collection. The visualization knowledge maps of critical indicators, including countries/regions, institutions, authors, journals, references, and keywords, were generated by CiteSpace and VOSviewer software. Besides, each domain's quantitative and qualitative analysis was also considered. A total of 2,629 papers were included. The number of exosomes-related publications and citations regarding CNS increased yearly. These publications came from 2,813 institutions in 77 countries/regions, led by the United States and China. Harvard University was the most influential institution, while the National Institutes of Health was the most critical funding source. We identified 14,468 authors, among which Kapogiannis D had the most significant number of articles and the highest H-index, while Théry C was the most frequently co-cited. The cluster analysis of keywords generated 13 clusters. In summary, the topic of biogenesis, biomarker, and drug delivery will serve as hotspots in future research. Exosomes-related CNS research has gained considerable attention in the past 20 years. The sources and biological functions of exosomes and their promising role in diagnosing and treating CNS diseases are considered hotspots in this field. The clinical translation of the results from exosomes-related CNS research will be of great importance in the future.

Structural genomics of the human dopamine receptor system.

The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson's Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.

Voiding Dysfunction Due to Urethral Sphincter Dysfunction Might Be an Early Neurological Presentation of Central Nervous System Disorders in Aged Patients.

To investigate the incidence of central nervous system (CNS) diseases in adult patients with voiding dysfunction and videourodynamics (VUDS) proven urethral sphincter dysfunction. This retrospective analysis reviewed the medical charts of patients aged > 60 years who underwent VUDS for non-prostatic voiding dysfunction from 2006 to 2021. A chart review was performed to search for the occurrence and treatment of CNS diseases after the VUDS examination up to 2022. The diagnosis of CNS disease, such as cerebrovascular accidents (CVA), Parkinson's disease (PD), and dementia, by neurologists was also retrieved from the charts. Based on the VUDS findings, patients were divided into the following subgroups: dysfunctional voiding (DV), poor relaxation of the external sphincter (PRES), and hypersensitive bladder (HSB) and coordinated sphincter subgroups. The incidence of CVA, PD, and dementia in each subgroup was recorded and compared among them using one-way analysis of variance (ANOVA). A total of 306 patients were included. VUDS examinations revealed DV in 87 patients, PRES in 108, and HSB in 111. Among them, 36 (11.8%) patients had CNS disease, including CVA in 23 (7.5%), PD in 4 (1.3%), and dementia in 9 (2.9%). Among the three subgroups, the DV group had the highest incidence rate of CNS disease (n = 16, 18.4%), followed by PRES (n = 12, 11.1%) and HSB (n = 8, 7.2%). However, no significant difference was noted in the incidence of CNS disease across the three subgroups. Nevertheless, the incidence of CNS disease was higher in patients with DV and PRES than that in the general population. The incidence of CNS diseases was high in patients aged > 60 years with voiding dysfunction due to urethral sphincter dysfunction. Patients with VUDS-confirmed DV had the highest incidence of CNS disease among the three subgroups.

Novel Developments to Enable Treatment of CNS Diseases with Targeted Drug Delivery.

The blood-brain barrier (BBB) is a major hurdle for the development of systemically delivered drugs against diseases of the central nervous system (CNS). Because of this barrier there is still a huge unmet need for the treatment of these diseases, despite years of research efforts across the pharmaceutical industry. Novel therapeutic entities, such as gene therapy and degradomers, have become increasingly popular in recent years, but have not been the focus for CNS indications so far. To unfold their full potential for the treatment of CNS diseases, these therapeutic entities will most likely have to rely on innovative delivery technologies. Here we will describe and assess approaches, both invasive and non-invasive, that can enable, or at least increase, the probability of a successful drug development of such novel therapeutics for CNS indications.

Tripartite Motif Protein Family in Central Nervous System Diseases.

Tripartite motif (TRIM) protein superfamily is a group of E3 ubiquitin ligases characterized by the conserved RING domain, the B-box domain, and the coiled-coil domain (RBCC). It is widely involved in various physiological and pathological processes, such as intracellular signal transduction, cell cycle regulation, oncogenesis, and innate immune response. Central nervous system (CNS) diseases are composed of encephalopathy and spinal cord diseases, which have a high disability and mortality rate. Patients are often unable to take care of themselves and their life quality can be seriously declined. Initially, the function research of TRIM proteins mainly focused on cancer. However, in recent years, accumulating attention is paid to the roles they play in CNS diseases. In this review, we integrate the reported roles of TRIM proteins in the pathological process of CNS diseases and related signaling pathways, hoping to provide theoretical bases for further research in treating CNS diseases targeting TRIM proteins. TRIM proteins participated in CNS diseases. TRIM protein family is characterized by a highly conserved RBCC domain, referring to the RING domain, the B-box domain, and the coiled-coil domain. Recent research has discovered the relations between TRIM proteins and various CNS diseases, especially Alzheimer's disease, Parkinson's disease, and ischemic stroke.

Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination.

There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.

Pharmacological modulation of chloride channels as a therapeutic strategy for neurological disorders.

Chloride homeostasis is critical in the physiological functions of the central nervous system (CNS). Its concentration is precisely regulated by multiple ion-transporting proteins such as chloride channels and transporters that are widely distributed in the brain cells, including neurons and glia. Unlike ion transporters, chloride channels provide rapid responses to efficiently regulate ion flux. Some of chloride channels are also permeable to selected organic anions such as glutamate and γ-aminobutyric acid, suggesting neuroexcitatory and neuroinhibitory functions while gating. Dysregulated chloride channels are implicated in neurological disorders, e.g., ischemia and neuroinflammation. Modulation of chloride homeostasis through chloride channels has been suggested as a potential therapeutic approach for neurological disorders. The drug design for CNS diseases is challenging because it requires the therapeutics to traverse the blood-brain-barrier. Small molecules are a well-established modality with better cell permeability due to their lower molecular weight and flexibility for structure optimization compared to biologics. In this article, we describe the important roles of chloride homeostasis in each type of brain cells and introduce selected chloride channels identified in the CNS. We then discuss the contribution of their dysregulations towards the pathogenesis of neurological disorders, emphasizing the potential of targeting chloride channels as a therapeutic strategy for CNS disease treatment. Along with this literature survey, we summarize the small molecules that modulate chloride channels and propose the potential strategy of optimizing existing drugs to brain-penetrants to support future CNS drug discovery.