ERNEST COST action overview on the (patho)physiology of GPCRs and orphan GPCRs in the nervous system.

G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that play a critical role in nervous system function by transmitting signals between cells and their environment. They are involved in many, if not all, nervous system processes, and their dysfunction has been linked to various neurological disorders representing important drug targets. This overview emphasises the GPCRs of the nervous system, which are the research focus of the members of ERNEST COST action (CA18133) working group 'Biological roles of signal transduction'. First, the (patho)physiological role of the nervous system GPCRs in the modulation of synapse function is discussed. We then debate the (patho)physiology and pharmacology of opioid, acetylcholine, chemokine, melatonin and adhesion GPCRs in the nervous system. Finally, we address the orphan GPCRs, their implication in the nervous system function and disease, and the challenges that need to be addressed to deorphanize them.

Traumatic and iatrogenic sciatic nerve injury in 38 dogs and 10 cats: Clinical and electrodiagnostic findings.

BACKGROUND: Reports describing sciatic nerve injuries (SNI) and their outcome are scarce in veterinary medicine. HYPOTHESIS: Describe the causes of traumatic and iatrogenic SNI and evaluate which clinical and electrodiagnostic findings predict outcome. ANIMALS: Thirty-eight dogs and 10 cats with confirmed SNI referred for neurologic and electrodiagnostic evaluation. METHODS: Clinical and electrodiagnostic examination results, including electromyography (EMG), motor nerve conduction studies, muscle-evoked potential (MEP), F-waves, sensory nerve conduction studies, and cord dorsum potential (CDP), were retrospectively evaluated. Quality of life (QoL) was assessed based on owner interviews. RESULTS: Surgery (42%) and trauma (33%) were the most common causes of SNI; in dogs, 24% were caused by bites from wild boars. Ability to flex and extend the tarsus was significantly associated with positive outcome in dogs. Mean time from onset of clinical signs until electrodiagnostic evaluation was 67 ± 65 (range, 7-300) days and 65 ± 108 (range, 7-365) days for dogs and cats, respectively. A cut-off amplitude of 1.45 mV for compound motor action potentials (CMAP) was predictive of positive outcome in dogs (P = .01), with sensitivity of 58% and specificity of 100%. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical motor function predicts recovery better than sensory function. Electrodiagnostic findings also may play a role in predicting the outcome of SNI. Application of the proposed CMAP cut-off amplitude may assist clinicians in shortening the time to reassessment or for earlier suggestion of salvage procedures. Owners perceived a good quality of life (QoL), even in cases of hindlimb amputation.

Isoflurane preconditioning induced genomic changes in mouse cortex.

Background: Altered patterns of genetic expression induced by isoflurane preconditioning in mouse brain have not yet been investigated. The aim of our pilot study is to examine the temporal sequence of changes in the transcriptome of mouse brain cortex produced by isoflurane preconditioning. Methods: Twelve-wk-old wild-type (C57BL/6J) male mice were randomly assigned for the experiments. Mice were exposed to isoflurane 2% in air for 1 h and brains were harvested at the following time points-immediately (0 h), and at 6, 12, 24, 36, 48, and 72 h after isoflurane exposure. A separate cohort of mice were exposed to three doses of isoflurane on days 1, 2, and 3 and brains were harvested after the third exposure. The NanoString mouse neuropathology panel was used to analyse isoflurane-induced gene expression in the cortex. The neuropathology panel included 760 genes covering pathways involved in neurodegeneration and other nervous system diseases, and 10 internal reference genes for data normalisation. Results: Genes involving several pathways were upregulated and downregulated by isoflurane preconditioning. Interestingly, a biphasic response was noted, meaning, an early expression of genes (until 6 h), followed by a transient pause (until 24 h), and a second wave of genomic response beginning at 36 h of isoflurane exposure was noted. Conclusions: Isoflurane preconditioning induces significant alterations in the genes involved in neurodegeneration and other nervous system disorders in a temporal sequence. These data could aid in the identification of molecular mechanisms behind isoflurane preconditioning-induced neuroprotection in various central nervous system diseases.

Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases.

Currently, one of the most significant and rapidly growing unmet medical challenges is the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This challenge encompasses the imperative development of efficacious therapeutic agents and overcoming the intricacies of the blood-brain barrier for successful drug delivery. Here we focus on the delivery aspect with particular emphasis on cell-penetrating peptides (CPPs), widely used in basic and translational research as they enhance drug delivery to challenging targets such as tissue and cellular compartments and thus increase therapeutic efficacy. The combination of CPPs with nanomaterials such as nanoparticles (NPs) improves the performance, accuracy, and stability of drug delivery and enables higher drug loads. Our review presents and discusses research that utilizes CPPs, either alone or in conjugation with NPs, to mitigate the pathogenic effects of neurodegenerative diseases with particular reference to AD and PD.

Innate lymphoid cells in neuroinflammation.

Innate lymphoid cells (ILCs) are largely tissue-resident cells that participate in the maintenance of tissue homeostasis and react early to inflammatory events. Mature ILCs are divided into three major groups based on the transcription factors required for their development and function. Under physiological conditions, ILCs are present within the choroid plexus and meninges while the CNS parenchyma is almost devoid of these cells. However, pathological conditions such as autoimmune neuroinflammation and viral infections of the CNS result in the infiltration of ILCs into parenchyma. In this article, we provide an overview of the involvement and function of the ILCs within the CNS during physiological conditions and in infections, autoimmune diseases, neurodegeneration, and injury.

Ceftriaxone-Induced Encephalopathy in a Patient With Chronic Kidney Disease.

Neurotoxicity is an acknowledged side effect of third and fourth-generation cephalosporins, but its occurrence with ceftriaxone is not widely recognized. This article presents a case involving a 56-year-old woman with multiple comorbidities who sought medical attention after experiencing lipothymia. The initial diagnosis suggested a urinary tract infection with acute kidney failure, leading to the initiation of ceftriaxone and hemodialysis. Subsequently, the patient exhibited a progressive deterioration of her neurological state, characterized by agitation and chorea. Metabolic encephalopathy, seizure/nonconvulsive status epilepticus, and acute central nervous system lesions were considered primary differential diagnoses, all of which were subsequently ruled out through thorough investigations. Days later, a remarkable recovery of the patient's neurological state was observed. A retrospective analysis revealed a correlation between the improvement and the fourth day of antimicrobial suspension. Consequently, a presumptive diagnosis of ceftriaxone-induced encephalopathy was made. This unusual case underscores the importance of recognizing the potential for pharmacological encephalopathy, particularly with ceftriaxone, and emphasizes its reversibility upon discontinuation of the implicated drug. Clinicians should remain vigilant to this uncommon adverse effect, promoting timely intervention and improved patient outcomes.

Autoimmune central nervous system disorders: Antibody testing and its clinical utility.

A rapidly expanding repertoire of neural antibody biomarkers exists for autoimmune central nervous system (CNS) disorders. Following clinical recognition of an autoimmune CNS disorder, the detection of a neural antibody facilitates diagnosis and informs prognosis and management. This review considers the phenotypes, diagnostic assay methodologies, and clinical utility of neural antibodies in autoimmune CNS disorders. Autoimmune CNS disorders may present with a diverse range of clinical features. Clinical phenotype should inform the neural antibodies selected for testing via the use of phenotype-specific panels. Both serum and cerebrospinal fluid (CSF) are preferred in the vast majority of cases but for some analytes either CSF (e.g. N-methyl-D-aspartate receptor [NMDA-R] IgG) or serum (e.g. aquaporin-4 [AQP4] IgG) specimens may be preferred. Screening using 2 methods is recommended for most analytes, particularly paraneoplastic antibodies. We utilize murine tissue-based indirect immunofluorescence assay (TIFA) with subsequent confirmatory protein-specific testing. The cellular location of the target antigen informs choice of confirmatory diagnostic assay (e.g. blot for intracellular antigens such as Hu; cell-based assay for cell surface targets such as leucine-rich glioma inactivated 1 [LGI1]). Titers of positive results have limited diagnostic utility with the exception of glutamic acid decarboxylase (GAD) 65 IgG autoimmunity, which is associated with neurological disease at higher values. While novel antibodies are typically discovered using established techniques such as TIFA and immunoprecipitation-mass spectrometry, more recent high-throughput molecular technologies (such as protein microarray and phage-display immunoprecipitation sequencing) may expedite the process of antibody discovery. Individual neural antibodies inform the clinician regarding the clinical associations, oncological risk stratification and tumor histology, the likely prognosis, and immunotherapy choice. In the era of neural antibody biomarkers for autoimmune CNS disorders, access to appropriate laboratory assays for neural antibodies is of critical importance in the diagnosis and management of these disorders.

Eutanasia y suicidio asistido en enfermedades neurológicas: una revisión sistemática / Euthanasia and assisted suicide in neurological diseases: a systematic review

Objetivo Identificar las enfermedades neurológicas por las que con mayor frecuencia se solicita la eutanasia y el suicidio asistido en los países donde están legalizados, las particularidades de la eutanasia en algunas de ellas y mostrar la evolución de sus cifras. Métodos Revisión bibliográfica sistemática. Resultados Las demencias, enfermedad de motoneurona, esclerosis múltiple y enfermedad de Parkinson son las enfermedades neurológicas que más frecuentemente motivan la petición de eutanasia o suicidio asistido. Las solicitudes por demencia son las más numerosas, están creciendo y plantean problemas éticos y legales adicionales al disminuir la capacidad de decisión. En algunos países la proporción de solicitudes respecto al total de casos de esclerosis múltiple, enfermedad de motoneurona o enfermedad de Huntington es mayor que en cualquier otra enfermedad. Conclusiones Después del cáncer las enfermedades neurológicas son el motivo más frecuente de pedir la eutanasia y el suicidio asistido. (AU)

Objective To identify the neurological diseases for which euthanasia and assisted suicide are most frequently requested in the countries where these medical procedures are legal and the specific characteristics of euthanasia in some of these diseases, and to show the evolution of euthanasia figures. Methods We conducted a systematic literature review. Results Dementia, motor neuron disease, multiple sclerosis, and Parkinson's disease are the neurological diseases that most frequently motivate requests for euthanasia or assisted suicide. Claims related to dementia constitute the largest group, are growing, and raise additional ethical and legal issues due to these patients’ diminished decision-making capacity. In some countries, the ratios of euthanasia requests to all cases of multiple sclerosis, motor neuron disease, or Huntington disease are higher than for any other disease. Conclusions After cancer, neurological diseases are the most frequent reason for requesting euthanasia or assisted suicide. (AU)

Neuropharmacological insights into Gardenia jasminoides Ellis: Harnessing therapeutic potential for central nervous system disorders.

BACKGROUND: In China, Gardenia jasminoides Ellis (GJE) has a longstanding history of application. The Ministry of Health has listed it as one of the first pharmaceutical or food resources. In ethnic, traditional, and folk medicine, GJE has been used to treat fever and cold and relieve nervous anxiety. Recent studies have confirmed the significant efficacy of GJE for treating central nervous system (CNS) disorders, including Alzheimer's disease, Parkinson's disease, and major depressive disorder; however, GJE has not been systematically evaluated. PURPOSE: This research systematically summarizes global studies on the use of GJE for treating CNS disorders and explores the potential applications and underlying mechanisms via intestinal flora analysis and network pharmacology, aiming to establish a scientific basis for innovative CNS disorder treatment with GJE. METHODS: The PRISMA guidelines were used, and electronic databases such as the Web of Science, PubMed, and China National Knowledge Infrastructure were searched using the following search terms: "Gardenia jasminoides Ellis" with "central nervous system disease," "neuroprotection," "Alzheimer's disease," "Parkinson's disease," "ischemic stroke," "Epilepsy," and "major depressive disorder." The published literature up to September 2023 was searched to obtain relevant information on the application of GJE for treating CNS disorders. RESULTS: There has been an increase in research on the material formulation and mechanisms of action of GJE for treating CNS disorders, with marked effects on CNS disorder treatment in different countries and regions. We summarized the research results related to the role of GJE in vitro and in vivo via multitargeted interventions in response to the complex mechanisms of action of CNS disorders. CONCLUSION: We systematically reviewed the research progress on traditional treatment for GJE and preclinical mechanisms of CNS disorders and explored the potential of optimizing network pharmacology strategies and intestinal flora analysis to elucidate the mechanisms of action of GJE. The remarkable therapeutic efficacy of GJE, an important resource in traditional medicine, has been well documented in the literature, highlighting its significant medicinal potential.

Comparing the difference of adverse events with HER2 inhibitors: a study of the FDA adverse event reporting system (FAERS).

Aim and background: This study attempted to identify similarities and differences in adverse events (AEs) between human epidermal growth factor receptor 2 (HER2) inhibitors, especially those related to hemorrhagic events and nervous system disorders. Methods: This study summarized the types, frequencies, and system organ classes (SOCs) of AEs of HER2 inhibitors. The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from January 2004 through March 2022 was collected and analyzed. Disproportionality analyses were conducted to detect AEs signals for every HER2 inhibitor. The chi-square test, Wilcoxon test, and descriptive analysis were used to compare the differences of AEs for specific SOCs or drugs. Results: A total of 47,899 AE reports were obtained for eight HER2 inhibitors. Trastuzumab-related AEs were reported in the highest number and combination of regimens. In monotherapy, trastuzumab had the highest reported rate of cardiac disorders-related AEs (24.0%). However, small-molecule drugs exceeded other drugs in the reported rates of AEs related to gastrointestinal disorders, metabolism and nutrition disorders. The highest reported rates of respiratory disorders (47.3%) and hematologic disorders (22.4%) were associated with treatment with trastuzumab deruxtecan (T-DXd). Patients treated with trastuzumab emtansine (TDM-1) had the highest reported rate (7.28%) of hemorrhagic events, especially intracranial haemorrhage events. In addition, patients treated with TDM-1 with concomitant thrombocytopenia were likely to experience hemorrhagic events compared to other HER2 inhibitors (p < 0.001). The median time to onset of intracranial haemorrhage associated with trastuzumab (0.5 months) and TDM-1 (0.75 months) was short. However, there was no significant difference in median time to onset intracranial haemorrhage between patients in different age groups or with different outcomes. Disproportionality analysis results reveal that cerebral haemorrhage is a positive signal associated with T-DXd and TDM-1. In addition, tucatinib was the drug with the highest rate of reported nervous system disorders (31.38%). Memory impairment (83 cases) is a positive signal for tucatinib. Conclusion: The types and reporting rates of AEs associated with different HER2 inhibitors vary across multiple systems. In addition, hemorrhagic events concomitant with TDM-1 treatment and nervous system disorders concomitant with tucatinib treatment may be worthy of attention.

Orphan GPR52 as an emerging neurotherapeutic target.

GPR52 is a highly conserved, brain-enriched, Gs/olf-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL'149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed.

The evolving concept of multimorbidity and migraine.

Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical-cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually.

CLDN5: From structure and regulation to roles in tumors and other diseases beyond CNS disorders.

Claudin-5 (CLDN5) is an essential component of tight junctions (TJs) and is critical for the integrity of the blood-brain barrier (BBB), ensuring homeostasis and protection from damage to the central nervous system (CNS). Currently, many researchers have summarized the role and mechanisms of CLDN5 in CNS diseases. However, it is noteworthy that CLDN5 also plays a significant role in tumor growth and metastasis. In addition, abnormal CLDN5 expression is involved in the development of respiratory diseases, intestinal diseases, cardiac diseases, and diabetic ocular complications. This paper aims to review the structure, expression, and regulation of CLDN5, focusing on its role in tumors, including its expression and regulation, effects on malignant phenotypes, and clinical significance. Furthermore, this paper will provide an overview of the role and mechanisms of CLDN5 in respiratory diseases, intestinal diseases, cardiac diseases, and diabetic ocular complications.

Euthanasia and assisted suicide in neurological diseases: a systematic review.

OBJECTIVE: To identify the neurological diseases for which euthanasia and assisted suicide are most frequently requested in the countries where these medical procedures are legal and the specific characteristics of euthanasia in some of these diseases, and to show the evolution of euthanasia figures. METHODS: We conducted a systematic literature review. RESULTS: Dementia, motor neuron disease, multiple sclerosis, and Parkinson's disease are the neurological diseases that most frequently motivate requests for euthanasia or assisted suicide. Requests related to dementia constitute the largest group, are growing, and raise additional ethical and legal issues due to these patients' diminished decision-making capacity. In some countries, the ratios of euthanasia requests to all cases of multiple sclerosis, motor neuron disease, or Huntington disease are higher than for any other disease. CONCLUSIONS: After cancer, neurological diseases are the most frequent reason for requesting euthanasia or assisted suicide.

Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases.

Central nervous system (CNS) diseases have become one of the leading causes of death in the global population. The pathogenesis of CNS diseases is complicated, so it is important to find the patterns of the disease to improve the treatment strategy. Microglia are considered to be a double-edged sword, playing both harmful and beneficial roles in CNS diseases. Therefore, it is crucial to understand the progression of the disease and the changes in the polar phenotype of microglia to provide guidance in the treatment of CNS diseases. Microglia activation may evolve into different phenotypes: M1 and M2 types. We focused on the roles that M1 and M2 microglia play in regulating intercellular dialogues, pathological reactions and specific diseases in CNS diseases. Importantly, we summarized the strategies used to modulate the polarization phenotype of microglia, including traditional pharmacological modulation, biological therapies, and physical strategies. This review will contribute to the development of potential strategies to modulate microglia polarization phenotypes and provide new alternative therapies for CNS diseases.

Unveiling the neuroprotective potential of dietary polysaccharides: a systematic review.

Central nervous system (CNS) disorders present a growing and costly global health challenge, accounting for over 11% of the diseases burden in high-income countries. Despite current treatments, patients often experience persistent symptoms that significantly affect their quality of life. Dietary polysaccharides have garnered attention for their potential as interventions for CNS disorders due to their diverse mechanisms of action, including antioxidant, anti-inflammatory, and neuroprotective effects. Through an analysis of research articles published between January 5, 2013 and August 30, 2023, encompassing the intervention effects of dietary polysaccharides on Alzheimer's disease, Parkinson's disease, depression, anxiety disorders, autism spectrum disorder, epilepsy, and stroke, we have conducted a comprehensive review with the aim of elucidating the role and mechanisms of dietary polysaccharides in various CNS diseases, spanning neurodegenerative, psychiatric, neurodevelopmental disorders, and neurological dysfunctions. At least four categories of mechanistic bases are included in the dietary polysaccharides' intervention against CNS disease, which involves oxidative stress reduction, neuronal production, metabolic regulation, and gut barrier integrity. Notably, the ability of dietary polysaccharides to resist oxidation and modulate gut microbiota not only helps to curb the development of these diseases at an early stage, but also holds promise for the development of novel therapeutic agents for CNS diseases. In conclusion, this comprehensive review strives to advance therapeutic strategies for CNS disorders by elucidating the potential of dietary polysaccharides and advocating interdisciplinary collaboration to propel further research in this realm.

Bioinspired Approaches for Central Nervous System Targeted Gene Delivery.

Disorders of the central nervous system (CNS) which include a wide range of neurodegenerative and neurological conditions have become a serious global issue. The presence of CNS barriers poses a significant challenge to the progress of designing effective therapeutic delivery systems, limiting the effectiveness of drugs, genes, and other therapeutic agents. Natural nanocarriers present in biological systems have inspired researchers to design unique delivery systems through biomimicry. As natural resource derived delivery systems are more biocompatible, current research has been focused on the development of delivery systems inspired by bacteria, viruses, fungi, and mammalian cells. Despite their structural potential and extensive physiological function, making them an excellent choice for biomaterial engineering, the delivery of nucleic acids remains challenging due to their instability in biological systems. Similarly, the efficient delivery of genetic material within the tissues of interest remains a hurdle due to a lack of selectivity and targeting ability. Considering that gene therapies are the holy grail for intervention in diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's Disease, and Huntington's disease, this review centers around recent advances in bioinspired approaches to gene delivery for the prevention of CNS disorders.

Unraveling the Interplay: Exploring the Links Between Gut Microbiota, Obesity, and Psychological Outcomes.

This narrative review delves into the complex and intricate mechanisms of the gut-brain axis. Gut microbiota has gained immense importance in the treatment of various diseases. The therapeutic potential of gut-microbial modulation is slowly coming to light. With good preclinical evidence, some human studies shed light on the translation potential of gut-microbial modulation. The concept of gut-microbial modulation has been studied for over a few decades. The relationship between gut microbiota and various homeostatic mechanisms is fascinating. Over the years, we have started understanding the immense role of gut microbiota in various homeostatic mechanisms. There are a good number of clinical studies that have shown the therapeutic potential of gut-microbial modulation in obesity and psychological diseases, especially depression and anxiety. The gut-microbial modulation can be achieved by dietary factors or supplementation. In this review, we explore the mechanisms by which prebiotics, probiotics, and synbiotics alter the gut-brain axis. The review limits its discussion to the most recent clinical studies that have shown promise as therapeutic strategies.

Pterostilbene as a Therapeutic Alternative for Central Nervous System Disorders: A Review of the Current Status and Perspectives.

Neurological disorders are diverse, have complex causes, and often result in disability; yet, effective treatments remain scarce. The resveratrol derivative pterostilbene possesses numerous physiological activities that hold promise as a novel therapy for the central nervous system (CNS) disorders. This review aimed to summarize the protective mechanisms of pterostilbene in in vitro and in vivo models of CNS disorders and the pharmacokinetics and safety to assess its possible effects on CNS disorders. Available evidence supports the protective effects of pterostilbene in CNS disorders involving mechanisms such as antioxidant and anti-inflammatory activity, regulation of lipid metabolism and vascular smooth muscle cell proliferation, improvement of synaptic function and neurogenesis, induction of glioma cell cycle arrest, and inhibition of glioma cell migration and invasion. Studies have identified possible molecular targets and pathways for the protective actions of pterostilbene in CNS disorders including the AMPK/STAT3, Akt, NF-κB, MAPK, and ERK signaling pathways. The possible pharmacological effects and molecular pathways of pterostilbene in CNS disorders are critically discussed in this review. Future studies should aim to increase our understanding of pterostilbene in animal models and humans to further evaluate its role in CNS disorders and the detailed mechanisms.