Search Results (988)

There is a preliminary record suggesting that β₂-adrenergic agonists may have therapeutic value in Parkinson’s disease; recent studies have proposed a possible role of these agents in suppressing the formation of α-synuclein protein, a component of Lewy bodies. The present study focuses on the importance of the prototypical β₂-adrenergic agonist epinephrine in relation to the incidence of Parkinson’s disease in humans, and its further investigation via synthetic selective β₂-receptor agonists, such as levalbuterol. Levalbuterol exerts significant anti-inflammatory activity, a property that may suppress cytokine-mediated degeneration of dopaminergic neurons and progression of Parkinsonism. In a completely novel finding, epinephrine and certain other adrenergic agents modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of anti-inflammatory glucocorticoids. This prompted in vivo confirmation in mice engrafted with human peripheral blood mononuclear cells (PBMCs). Upon toxic activation with mononuclear antibodies, levalbuterol inhibited (1) the release of the eosinophil attractant chemokine eotaxin-1, which is implicated in CNS and peripheral inflammatory disorders, (2) elaboration of the tumor-promoting angiogenic factor VEGFa, and (3) release of the pro-inflammatory cytokine IL-13 from activated PBMCs. These observations suggest possible translation to Parkinson’s disease, other neurodegenerative syndromes, and malignancies, via several mechanisms. Full article

The human central nervous system is convolutedly connected to the gut microbiome, a diverse community of microorganisms residing in the gastrointestinal tract. Recent research has highlighted the bidirectional communication between the gut microbiome and neuroglial cells, which include astrocytes, microglia, oligodendrocytes, and ependymal cells. These neuroglial cells are essential for maintaining CNS homeostasis, supporting neuronal function, and responding to pathological conditions. This review examines the interactions between the gut microbiome and neuroglia, emphasizing their critical roles in brain health and the development of neurological disorders. Dysbiosis, or imbalance in the gut microbiome, has been associated with various neurological and psychiatric conditions, such as autism spectrum disorder, anxiety, depression, and neurodegenerative diseases like Alzheimer’s and Parkinson’s. The microbiome influences brain function through microbial metabolites, immune modulation, and neuroinflammatory responses. Understanding these interactions paves the way for new therapeutic targets and strategies for preventing and treating CNS disorders. This scoping review aims to highlight the mechanisms of the microbiome-neuroglia axis in maintaining brain health and its potential as a therapeutic target. Full article

Glutathione (GSH), a tripeptide synthesized intracellularly, serves as a pivotal antioxidant, neutralizing reactive oxygen species (ROS) and reactive nitrogen species (RNS) while maintaining redox homeostasis and detoxifying xenobiotics. Its potent antioxidant properties, particularly attributed to the sulfhydryl group (-SH) in cysteine, are crucial for cellular health across various organelles. The glutathione-glutathione disulfide (GSH-GSSG) cycle is facilitated by enzymes like glutathione peroxidase (GPx) and glutathione reductase (GR), thus aiding in detoxification processes and mitigating oxidative damage and inflammation. Mitochondria, being primary sources of reactive oxygen species, benefit significantly from GSH, which regulates metal homeostasis and supports autophagy, apoptosis, and ferroptosis, playing a fundamental role in neuroprotection. The vulnerability of the brain to oxidative stress underscores the importance of GSH in neurological disorders and regenerative medicine. Nebulization of glutathione presents a novel and promising approach to delivering this antioxidant directly to the central nervous system (CNS), potentially enhancing its bioavailability and therapeutic efficacy. This method may offer significant advantages in mitigating neurodegeneration by enhancing nuclear factor erythroid 2-related factor 2 (NRF2) pathway signaling and mitochondrial function, thereby providing direct neuroprotection. By addressing oxidative stress and its detrimental effects on neuronal health, nebulized GSH could play a crucial role in managing and potentially ameliorating conditions such as Parkinson’s Disease (PD) and Alzheimer’s Disease (AD). Further clinical research is warranted to elucidate the therapeutic potential of nebulized GSH in preserving mitochondrial health, enhancing CNS function, and combating neurodegenerative conditions, aiming to improve outcomes for individuals affected by brain diseases characterized by oxidative stress and neuroinflammation. Full article

The ability to screen for agents that can promote the development and/or maintenance of neuronal networks creates opportunities for the discovery of novel agents for the treatment of central nervous system (CNS) disorders. Over the past 10 years, advances in robotics, artificial intelligence, and machine learning have paved the way for the improved implementation of live-cell imaging systems for drug discovery. These instruments have revolutionized our ability to quickly and accurately acquire large standardized datasets when studying complex cellular phenomena in real-time. This is particularly useful in the field of neuroscience because real-time analysis can allow efficient monitoring of the development, maturation, and conservation of neuronal networks by measuring neurite length. Unfortunately, due to the relative infancy of this type of analysis, standard practices for data acquisition and processing are lacking, and there is no standardized format for reporting the vast quantities of data generated by live-cell imaging systems. This paper reviews the current state of live-cell imaging instruments, with a focus on the most commonly used equipment (IncuCyte systems). We provide an in-depth analysis of the experimental conditions reported in publications utilizing these systems, particularly with regard to studying neurite outgrowth. This analysis sheds light on trends and patterns that will enhance the use of live-cell imaging instruments in CNS drug discovery. Full article

Exosomes, natural nanovesicles that contain a cargo of biologically active molecules such as lipids, proteins, and nucleic acids, are released from cells to the extracellular environment. They then act as autocrine, paracrine, or endocrine mediators of communication between cells by delivering their cargo into recipient cells and causing downstream effects. Exosomes are greatly enriched in miRNAs, which are small non-coding RNAs that act both as cytoplasmic post-transcriptional repression agents, modulating the translation of mRNAs into proteins, as well as nuclear transcriptional gene activators. Neuronal exosomal miRNAs have important physiologic functions in the central nervous system (CNS), including cell-to-cell communication, synaptic plasticity, and neurogenesis, as well as modulating stress and inflammatory responses. Stress-induced changes in exosomal functions include effects on neurogenesis and neuroinflammation, which can lead to the appearance of various neuropsychiatric disorders such as schizophrenia, major depression, bipolar disorder, and Alzheimer’s and Huntington’s diseases. The current knowledge regarding the roles of exosomes in the pathophysiology of common mental disorders is discussed in this review. Full article

Transmembrane protein 106B (TMEM106B), which is a type II transmembrane protein, is believed to be involved in intracellular dynamics and morphogenesis in the lysosome. TMEM106B is known to be a risk factor for frontotemporal lobar degeneration and has been recently identified as the receptor needed for the entry of SARS-CoV-2, independently of angiotensin-converting enzyme 2 (ACE2). A missense mutation, p.Asp252Asn, of TMEM106B is associated with hypomyelinating leukodystrophy 16 (HLD16), which is an oligodendroglial cell-related white matter disorder causing thin myelin sheaths or myelin deficiency in the central nervous system (CNS). However, it remains to be elucidated how the mutated TMEM106B affects oligodendroglial cells. Here, we show that the TMEM106B mutant protein fails to exhibit lysosome distribution in the FBD-102b cell line, an oligodendroglial precursor cell line undergoing differentiation. In contrast, wild-type TMEM106B was indeed localized in the lysosome. Cells harboring wild-type TMEM106B differentiated into ones with widespread membranes, whereas cells harboring mutated TMEM106B failed to differentiate. It is of note that the output of signaling through the lysosome-resident mechanistic target of rapamycin (mTOR) was greatly decreased in cells harboring mutated TMEM106B. Furthermore, treatment with hesperetin, a citrus flavonoid known as an activator of mTOR signaling, restored the molecular and cellular phenotypes induced by the TMEM106B mutant protein. These findings suggest the potential pathological mechanisms underlying HLD16 and their amelioration. Full article

Carnitine palmitoyltransferase 2 (CPT2) is an inner mitochondrial membrane protein of the carnitine shuttle and is involved in the beta-oxidation of long chain fatty acids. Beta-oxidation provides an alternative pathway of energy production during early development and starvation. CPT2 deficiency is a genetic disorder that we recently showed can be associated with schizophrenia. We hypothesize that CPT2 deficiency during early brain development causes transcriptional, structural, and functional abnormalities that may contribute to a CNS environment that is susceptible to the emergence of schizophrenia. To investigate the effect of CPT2 deficiency on early vertebrate development and brain function, CPT2 was knocked down in a zebrafish model system. CPT2 knockdown resulted in abnormal lipid utilization and deposition, reduction in body size, and abnormal brain development. Axonal projections, neurotransmitter synthesis, electrical hyperactivity, and swimming behavior were disrupted in CPT2 knockdown zebrafish. RT-qPCR analyses showed significant increases in the expression of schizophrenia-associated genes in CPT2 knockdown compared to control zebrafish. Taken together, these data demonstrate that zebrafish are a useful model for studying the importance of beta-oxidation for early vertebrate development and brain function. This study also presents novel findings linking CPT2 deficiency to the regulation of schizophrenia and neurodegenerative disease-associated genes. Full article

Isoliquiritigenin (ISL) has excellent neuroprotective effects. However, its limitations, including poor solubility, low bioavailability, and low accumulation in the brain, restrict its clinical promotion. In this study, a novel type of ISL-loaded liposome (ISL-LP) modified with the brain-targeting polypeptide angiopep-2 was prepared to improve these properties. The zeta potential, morphology, particle size, encapsulation efficiency, drug loading, and in vitro release of ISL-LP were evaluated. The pharmacokinetics and tissue distribution of ISL and ISL-LP were also investigated. The results demonstrated that ISL-LP had an average particle size of 89.36 ± 5.04 nm, a polymer dispersity index of 0.17 ± 0.03, a zeta potential of −20.27 ± 2.18 mV, and an encapsulation efficiency of 75.04 ± 3.28%. The in vitro release experiments indicate that ISL-LP is a desirable sustained-release system. After intravenous administration, LPC-LP prolonged the circulation time of ISL in vivo and enhanced its relative brain uptake. In conclusion, ISL-LP could serve as a promising brain-targeting system for the treatment and prevention of central nervous system (CNS) disorders. Full article

Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. Methods: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. Results: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05–0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A’s inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. Conclusions: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders. Full article

Alzheimer’s disease is the most common cause of dementia globally. The pathogenesis is multifactorial and includes deposition of amyloid-β in the central nervous system, presence of intraneuronal neurofibrillary tangles and a decreased amount of synapses. It remains uncertain what causes the progression of the disease. Nowadays, it is suggested that the brain is connected to the gastrointestinal tract, especially the enteric nervous system and gut microbiome. Studies have found a positive association between AD and gastrointestinal diseases such as periodontitis, Helicobacter pylori infection, inflammatory bowel disease and microbiome disorders. H. pylori and its metabolites can enter the CNS via the oropharyngeal olfactory pathway and may predispose to the onset and progression of AD. Periodontitis may cause systemic inflammation of low severity with high levels of pro-inflammatory cytokines and neutrophils. Moreover, lipopolysaccharide from oral bacteria accompanies beta-amyloid in plaques that form in the brain. Increased intestinal permeability in IBS leads to neuronal inflammation from transference. Chronic inflammation may lead to beta-amyloid plaque formation in the intestinal tract that spreads to the brain via the vagus nerve. The microbiome plays an important role in many bodily functions, such as nutrient absorption and vitamin production, but it is also an important factor in the development of many diseases, including Alzheimer’s disease. Both the quantity and diversity of the microbiome change significantly in patients with AD and even in people in the preclinical stage of the disease, when symptoms are not yet present. The microbiome influences the functioning of the central nervous system through, among other things, the microbiota–gut–brain axis. Given the involvement of the microbiome in the pathogenesis of AD, antibiotic therapy, probiotics and prebiotics, and faecal transplantation are being considered as possible therapeutic options. Full article

In 2022, stroke emerged as the most significant cerebrovascular disorder globally, causing 6.55 million deaths. Microglia, crucial for CNS preservation, can exacerbate brain damage in ischemic stroke by triggering neuroinflammation. This process is mediated by receptors on microglia, triggering receptors expressed on myeloid cells (TREM-1 and TREM-2), which have contrasting roles in neuroinflammation. In this study, we recruited 38 patients within 4.5 h from the onset of ischemic stroke. The degree of severity was evaluated by means of the National Institutes of Health Stroke Scale (NIHSS) at admission (T0) and after one week of ischemic events (TW) and the Modified Rankin Scale (mRS) at three months. The plasma concentration of TREMs (sTREM) was analyzed by next-generation ELISA at T0 and TW. The sTREM-1 concentrations at T0 were associated with mRS, while the sTREM-2 concentrations at T0 were associated with both the NIHSS at T0 and the mRS. A strong correlation between sTREM-1 and sTREM-2 was observed, suggesting a dependent modulation of the levels. This study provides insights into the potential pathway of TREM-1 and TREM-2 as a future biomarker for stratifying high-risk patients with ischemic stroke. Full article

Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron–microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle. Full article

Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS. Full article

Thyroidectomy, a pivotal treatment for various thyroid disorders, has seen its indications evolve, particularly with the 2014 American Thyroid Association (ATA) Guidelines advocating for conservative surgical approaches like lobectomy. This retrospective study analyzes thyroidectomy practices at a high-volume center from January 2014 to December 2023, focusing on patients potentially eligible for lobectomy per ATA guidelines. The inclusion criteria were tumors < 4 cm, indeterminate thyroid nodules, or differentiated thyroid carcinoma with clinically uninvolved lymph nodes (cN0). This study analyzed the proportion of patients undergoing lobectomy versus total thyroidectomy (TT) and the oncological outcomes. Of 357 patients, 243 underwent TT and 114 underwent lobectomy. The prevalence of lobectomies rose markedly, comprising 73.9% of surgeries in 2023. TT patients were predominantly female (83.5%) and had higher rates of autoimmune thyroiditis (67.5%) and malignancy (89.7%). Lobectomy patients had larger nodules and more indeterminate cytology. Among 301 malignant cases, TT was associated with higher lymph node metastasis, but similar recurrence rates, compared to lobectomy. This study underscores a shift towards lobectomy, reflecting adherence to ATA guidelines and suggesting conservative surgery is feasible without compromising outcomes. Further research on long-term outcomes and refined patient selection criteria is needed to optimize surgical approaches. Full article

Sleep disorders can have harmful consequences in both the short and long term. They can lead to attention deficits, as well as cardiac, neurological and behavioral repercussions. One of the most widely used methods for assessing sleep disorders is polysomnography (PSG). A major challenge associated with this method is all the cables needed to connect the recording devices, making the examination more intrusive and usually requiring a clinical environment. This can have potential consequences on the test results and their accuracy. One simple way to assess the state of the central nervous system (CNS), a well-known indicator of sleep disorder, could be the use of a portable medical device. With this in mind, we implemented a simple model using both the RR interval (RRI) and its second derivative to accurately predict the awake and napping states of a subject using a feature classification model. For training and validation, we used a database providing measurements from nine healthy young adults (six men and three women), in which heart rate variability (HRV) associated with light-on, light-off, sleep onset and sleep offset events. Results show that using a 30 min RRI time series window suffices for this lightweight model to accurately predict whether the patient was awake or napping. Full article