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Traumatic brain injuries (TBIs) cause direct central nervous system injury. The presentation depends on the location, the type, and the severity of the injury. Additional injury may develop secondary to compression, the disruption of cerebral perfusion, and changes in sodium levels, resulting in either cellular edema or dehydration. Plasma osmolality (Posm) is a critical parameter influenced by solute concentrations, including sodium, glucose, and urea, and is a relevant concern when considering sodium levels in these patients. While Posm can be calculated using a standard formula, direct measurements via osmometry offer better accuracy. It is essential to differentiate between osmolality and tonicity; the latter refers specifically to effective solutes that drive water movement in the extracellular fluid. Sodium and its anions are effective solutes, whereas urea and glucose have variable effects due to their permeability and insulin dependence. Following TBI, the dysregulation of osmoregulation may occur and affect neurological outcomes. Osmoreceptors in the brain regulate arginine vasopressin secretion in response to changes in effective solute concentrations, with sodium chloride and mannitol being potent stimuli. The regulation of plasma osmolality, typically maintained within ±5% of the 280–295 mOsm/kg H2O range, is crucial for homeostasis and relies on antidiuresis and thirst mechanisms. This review narrative underscores the complexities of osmoregulation in the context of TBIs and their clinical implications, particularly concerning the development of conditions such as diabetes insipidus, the syndrome of inappropriate antidiuretic hormone secretion, and abnormal thirst. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) has emerged as a critical regulatory mechanism in the initiation and progression of various pathological conditions. PCD in microglia, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, occurs in a variety of central nervous system (CNS) diseases. Dysregulation of microglia can lead to excessive tissue damage or neuronal death in CNS injury. Various injury stimuli trigger aberrant activation of the PCD pathway of microglia, which then further leads to inflammatory cascades that exacerbates CNS pathology in a vicious cycle. Therefore, targeting PCD in microglia is considered an important avenue for the treatment of various neurodegenerative diseases and CNS injury. In this review, we summarize the major and recent findings focusing on the mechanisms of PCD in microglia modulating functions in neurodegenerative diseases and CNS injury and provide a systematic overview of the current inhibitors targeting various PCD pathways, which may provide important therapeutic targets that merit further investigation. [ABSTRACT FROM AUTHOR]

Astrocytes have a beneficial role in tissue repair after central nervous system (CNS) injury. Although astrocyte proliferation is activated in response to injury, the intracellular mechanisms of astrocyte proliferation during acute phase of injury are not fully clarified. In this study, by functionally screening the highly expressed genes in the pathological state of spinal astrocytes, heterogeneous nuclear ribonucleoprotein U (Hnrnpu) is identified as a potential endogenous molecule that regulates astrocyte proliferation and the following scar formation. Inhibition of Hnrnpu in astrocytes impairs the formation of astrocytic glial scar, motor function recovery, and neuronal regeneration after spinal cord injury (SCI) in mice. In human astrocytes, HNRNPU knockdown downregulates the genes related to the astrocyte functions in scar formation and neuronal regeneration. These findings uncover that modulation of endogenous astrocytic function would be a promising therapeutic avenue to restore neurological function after CNS injury. [ABSTRACT FROM AUTHOR]

This article discusses the peculiarities of microglia behaviour and their interaction with other cells of the central nervous system (CNS) during neural tissue injury with a focus on spinal cord injury (SCI). Taking into account the plasticity of microglia, the influence of the microenvironment should be taken into account to establish the mechanisms determining the polarization pathways of these cells. Determination of the system of microglia interactions with other CNS cells during injury will reveal the patterns of post-traumatic microglia responses, in particular, determining both pro-inflammatory and anti-inflammatory responses. This review compiles information on changes in microglia activation, migration and phagocytosis, as well as their reciprocal effects on other CNS cells, such as neurons, astrocytes and oligodendrocytes, in the background of SCI. The information contained in this article may be of interest not only to scientists studying traumatic injuries of the central nervous system, but also to specialists in the field of studying and treating neurodegenerative diseases, since the mechanisms occurring in the injured spinal cord may also be characteristic of pathological events in degenerative processes. [ABSTRACT FROM AUTHOR]

Brain metastasis leads to poor outcomes and CNS injury, significantly reducing quality of life and survival rates. Advances in understanding the tumor immune microenvironment have revealed the promise of immunotherapies, which, alongside surgery, chemotherapy, and radiation, offer improved survival for some patients. However, resistance to immunotherapy remains a critical challenge. This review explores the immune landscape of brain metastases, current therapies, clinical trials, and the need for personalized, biomarker-driven approaches to optimize outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the clinical features and prognosis of severe central nervous system (CNS) injury in children caused by coronavirus disease 2019 (COVID-19). Method: We retrospectively studied confirmed pediatric cases of COVID-19 complicated with CNS injury. Results: Nine patients diagnosed with COVID-19 complicated with severe CNS injury were admitted to the pediatric intensive care unit of the Affiliated Hospital of Jining University from December 1, 2022 to January 12, 2023. Of the nine patients, seven were male (77.78%). Five children were aged ≥ 10 years, and the others were 1–2 years old. All children had fever, eight had convulsions, seven had progressed to multiple organ failure, and all suffered varying degrees of coma. Most of the children had elevated interleukin-6 (100%), lactic acid (100%), alanine transaminase (87.5%), aspartate transaminase (87.5%), creatine kinase MB (87.5%), and lactate dehydrogenase (85.7%) levels. Four children had cerebrospinal fluid proteinnacell separation. The cranial imaging results of five children were abnormal. One child had lost his vital signs when admitted to hospital, and the remaining eight received hormonal shock, human immunoglobulin transfusion, antinainfection, cranial pressure reduction, and tracheal intubation, among others, during hospitalization. Ultimately, eight children died, and the remaining child has serious neurological sequelae and is undergoing rehabilitation. Conclusions: Severe CNS injury caused by COVID-19 has an acute onset, rapid progression, high disability rate, and high fatality rate. A low cerebrospinal fluid protein level may be a protective factor for children with severe nervous system injury caused by COVID-19. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) injuries, such as ischemic stroke (IS), intracerebral hemorrhage (ICH) and traumatic brain injury (TBI), are a significant global burden. The complex pathophysiology of CNS injury is comprised of primary and secondary injury. Inflammatory secondary injury is incited by damage-associated molecular patterns (DAMPs) which signal a variety of resident CNS cells and infiltrating immune cells. Extracellular cold-inducible RNA-binding protein (eCIRP) is a DAMP which acts through multiple immune and non-immune cells to promote inflammation. Despite the well-established role of eCIRP in systemic and sterile inflammation, its role in CNS injury is less elucidated. Recent literature suggests that eCIRP is a pleiotropic inflammatory mediator in CNS injury. eCIRP is also being evaluated as a clinical biomarker to indicate prognosis in CNS injuries. This review provides a broad overview of CNS injury, with a focus on immune-mediated secondary injury and neuroinflammation. We then review what is known about eCIRP in CNS injury, and its known mechanisms in both CNS and non-CNS cells, identifying opportunities for further study. We also explore eCIRP's potential as a prognostic marker of CNS injury severity and outcome. Next, we provide an overview of eCIRP-targeting therapeutics and suggest strategies to develop these agents to ameliorate CNS injury. Finally, we emphasize exploring novel molecular mechanisms, aside from neuroinflammation, by which eCIRP acts as a critical mediator with significant potential as a therapeutic target and prognostic biomarker in CNS injury. [ABSTRACT FROM AUTHOR]

Introduction: There is a need for a predictive tool for adverse discharge disposition in the injured elderly patient population. However, many measurements of frailty are not practical and radiographic measurements of muscle and adipose tissue have yet to be correlated with adverse discharge disposition in this population. Methods: A retrospective review of a prospectively gathered trauma database at a level one trauma center was performed, studying all adult trauma patients aged 55 years or older with an inpatient stay of greater than 2 days. Patients with a non-survivable head trauma (head Abbreviated Injury Score of 6) or serious central nervous system injury, history of cirrhosis or solid organ transplantation, those actively being treated with immunosuppressive medications, and those without an abdominal computerized tomography (CT) scan within the first 48 h of admission were excluded. Sarcopenia, sarcopenic obesity (SO), and five-item frailty index (5-iFI) score were obtained and analyzed against adverse discharge disposition. Results: The study evaluated 444 patients, of which 48.9% were male with a median age of 78 years (range 55–99 years). All patients sustained blunt trauma, shock index was positive in 13.7%, and median ISS was 10 (range 1–43). SO was not independently predictive of adverse discharge disposition. Additionally, neither sarcopenia nor 5-iFI scores were found to be independently predictive. Lower ISS and age were found to be protective against adverse discharge disposition. Conclusion: CT-based measurements of muscle and adipose tissue may not add value over traditional injury scores in older trauma patients. [ABSTRACT FROM AUTHOR]

Introduction Genitourinary (GU) trauma resulting from combat and the treatment of these injuries is an inadequately explored subject. While historically accounting for 2 to 5% of combat-related injuries, GU-related injuries escalated considerably during U.S. involvements in Iraq and Afghanistan due to improvised explosive devices (IEDs). Advanced body armor increased survivability while altering injury patterns, with a shift toward bladder and external genitalia injuries. Forward-deployed surgeons and military medics manage treatment, with Role 2 facilities addressing damage control resuscitation and surgery, including GU-specific procedures. The review aims to provide an overview of GU trauma and enhance medical readiness for battlefield scenarios. Materials and Methods This review examined urologic trauma management in combat, searching PubMed, Cochrane Central, Scopus, and Web of Science databases with search terms "wounds" OR "injuries" OR "hemorrhage" AND "trauma" AND "penile" OR "genital" AND "combat." Records were then screened for inclusion of combat-related urologic trauma in conflicts after 2001 and which were English-based publications. No limits based on year of publication, study design, or additional patient-specific demographics were implemented in this review. Results Ultimately, 33 articles that met the inclusion criteria were included. Included texts were narrowed to focus on the management of renal injuries, ureteral trauma, bladder injuries, penile amputations, urethral injuries, testicular trauma, Central nervous system (CNS) injuries, and female GU injuries. Conclusions In modern conflicts, treatment of GU trauma at the point of injury should be secondary to Advanced Trauma Life Support (ATLS) care in addition to competing non-medical priorities. This review highlights the increasing severity of GU trauma due to explosive use, especially dismounted IEDs. Concealed morbidity and fertility issues underscore the importance of protection measures. Military medics play a crucial role in evaluating and managing GU injuries. Adherence to tactical guidelines and trained personnel is vital for effective management, and GU trauma's integration into broader polytrauma care is essential. Adequate preparation should address challenges for deploying health care providers, prioritizing lifesaving and quality-of-life care for casualties affected by GU injuries. [ABSTRACT FROM AUTHOR]

Neuroprotection is a proactive approach to safeguarding the nervous system, including the brain, spinal cord, and peripheral nerves, by preventing or limiting damage to nerve cells and other components. It primarily defends the central nervous system against injury from acute and progressive neurodegenerative disorders. Oxidative stress, an imbalance between the body's natural defense mechanisms and the generation of reactive oxygen species, is crucial in developing neurological disorders. Due to its high metabolic rate and oxygen consumption, the brain is particularly vulnerable to oxidative stress. Excessive ROS damages the essential biomolecules, leading to cellular malfunction and neurodegeneration. Several neurological disorders, including Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, multiple sclerosis, and ischemic stroke, are associated with oxidative stress. Understanding the impact of oxidative stress in these conditions is crucial for developing new treatment methods. Researchers are exploring using antioxidants and other molecules to mitigate oxidative stress, aiming to prevent or slow down the progression of brain diseases. By understanding the intricate interplay between oxidative stress and neurological disorders, scientists hope to pave the way for innovative therapeutic and preventive approaches, ultimately improving individuals' living standards. Oxidative stress triggers a catastrophic cascade: mitochondrial dysfunction, neuronal death, neuroinflammation, and neurodegeneration, leading to devastating neurodegenerative diseases, necessitating advanced therapies to halt this destructive process. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and aim: The administration of growth and neurotrophic factors has been attempted experimentally as a new therapeutic strategy for severe facial paralysis. Granulocyte colony-stimulating factor (G-CSF) has an effect on the treatment of central nervous system injuries, such as cerebral infarction and spinal cord injury. This study aimed at examining the effects of G-CSF on facial nerve regeneration in rats. Methods: The left facial nerve of rats was either partially resected (resection group) or severed and sutured (suture group) at the main trunk outside the temporal bone. In each surgical group, saline or G-CSF was administered via the gelatin hydrogel drug delivery system. The suture group was further divided into two subgroups for the late administration of G-CSF (2 weeks after surgical treatment) or immediate administration of G-CSF after surgical treatment. Recovery of the facial nerve was assessed by the evaluation of facial movements (after 12 weeks), complex muscle action potential amplitude measurements (after 2, 4, 8, and 12 weeks), electroneurography values (after 12 weeks), and histological evaluation (comparison of myelinated axon diameters among the groups). Results: Recovery of the function and morphology of damaged nerves was faster in the suture groups than in the resection group. In the suture groups, recovery was faster for G-CSF-treated rats than for saline-treated rats. Furthermore, recovery was faster in the group that received G-CSF immediately after surgical treatment than in the group that received G-CSF 2 weeks later. However, the group that received G-CSF 2 weeks later also showed faster recovery than did the control group. Conclusion: G-CSF effectively promoted nerve regeneration during facial nerve paralysis. Thus, G-CSF may be a potential treatment strategy for injured facial nerves as it has been safely administered in clinical treatments for hematological diseases. [ABSTRACT FROM AUTHOR]

• Modulation of microglia polarization is essential for CNS injury repair. • Exosomes derived from microglia stimulated by different environments have different effects on the repair of CNS injury. • miRNAs in microglia-derived exosomes play critical role in repairing CNS injury. The intercellular communication within the central nervous system (CNS) is of great importance for in maintaining brain function, homeostasis, and CNS regulation. When the equilibrium of CNS is disrupted or injured, microglia are immediately activated and respond to CNS injury. Microglia-derived exosomes are capable of participating in intercellular communication within the CNS by transporting various bioactive substances, including nucleic acids, proteins, lipids, amino acids, and metabolites. Nevertheless, microglia activation is a double-edged sword. Activated microglia can coordinate the neural repair process and, conversely, can amplify tissue injury and impede CNS repair. This work reviewed the roles of exosomes derived from microglia stimulated by different environments (mainly lipopolysaccharide, interleukin-4, and other specific preconditioning) in CNS injury and their possible therapeutic potentials. This work focuses on the regulation of exosomes derived from microglia stimulated by different environments on nerve cells. Meanwhile, we summarized the molecular mechanisms by which the relevant exosomes exert regulatory effects. Exosomes, derived from microglia stimulated by different environments, regulate other nerve cells during the repair of CNS injury, having beneficial or detrimental effects on CNS repair. A comprehensive understanding of the molecular mechanisms underlying their role can provide a robust foundation for the clinical treatment of CNS injury. [ABSTRACT FROM AUTHOR]

Military breachers are routinely exposed to repetitive low-level blast overpressure, placing them at elevated risk for long-term neurological sequelae. Mounting evidence suggests that circulating brain-reactive autoantibodies, generated following CNS injury, may serve as both biomarkers of cumulative damage and drivers of secondary neuroinflammation. In this study, we compared circulating autoantibody profiles in military breachers (n = 18) with extensive blast exposure against unexposed military controls (n = 19). Using high-sensitivity immunoassays, we quantified IgG and IgM autoantibodies targeting glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and pituitary (PIT) antigens. Breachers exhibited significantly elevated levels of anti-GFAP IgG (p < 0.001) and anti-PIT IgG (p < 0.001) compared to controls, while anti-MBP autoantibody levels remained unchanged. No significant differences were observed for any IgM autoantibody measurements. These patterns suggest that repetitive blast exposure induces a chronic, adaptive immune response rather than a short-lived acute phase. The elevated IgG autoantibodies highlight the vulnerability of astrocytes, myelin, and the hypothalamic–pituitary axis to ongoing immune-mediated injury following repeated blast insults, likely reflecting sustained blood–brain barrier disruption and neuroinflammatory processes. Our findings underscore the potential of CNS-targeted IgG autoantibodies as biomarkers of cumulative brain injury and immune dysregulation in blast-exposed populations. Further research is warranted to validate these markers in larger, more diverse cohorts, and to explore their utility in guiding interventions aimed at mitigating neuroinflammation, neuroendocrine dysfunction, and long-term neurodegenerative risks in military personnel and similarly exposed groups. [ABSTRACT FROM AUTHOR]

Central nervous system diseases include central nervous system injury diseases, neurodegenerative diseases, and other conditions. MicroRNAs (miRNAs) are important regulators of gene expression, with therapeutic potential in modulating genes, pathways, and cells associated with central nervous system injury diseases. This article comprehensively reviews the therapeutic role of exosomal miRNAs in various central nervous system injury diseases, including traumatic brain injury, ischemic stroke, intracerebral hemorrhage, optic nerve injury, and spinal cord injury. This review covers the pathophysiology, animal models, miRNA transfection, administration methods, behavioral tests for evaluating treatment efficacy, and the mechanisms of action of miRNA-based therapies. Finally, this article discusses the future directions of miRNA therapy for central nervous system injury diseases. [ABSTRACT FROM AUTHOR]

• Ligand-gated ion channel-linked receptor-mediated signaling affects neuronogenesis, neuronal and remyelination. • The roles of enzyme-linked receptors in CNS regeneration are basically consistent with their functions in nerve development. • There have already been molecular drugs targeting G-protein-coupled receptors for clinical treatment. Degenerative diseases and injuries of central nervous system (CNS) often cause nerve cell apoptosis and neural dysfunction. Protection of surviving cells or inducing the differentiation of stem cells into functional cells is considered to be an important way of neurorepair. In addition, transdifferentiation technology emerged recently is expected to provide new solutions for nerve regeneration. Cell surface receptors are transmembrane proteins embedded in cytoplasmic membrane, and play crucial roles in maintaining communication between extracellular signals and intracellular signaling processes. The extracellular microenvironment changed dramatically upon neural lesion, exploring the biological function of signals mediated by cell surface receptors will help to develop molecular strategies for nerve regeneration. An increasing number of studies have reported that cell surface receptor-mediated signaling affects the survival, differentiation, and functioning of neural cells, and even regulate their trans -lineage reprogramming. Here, we provide a review on the roles of cell surface receptors in CNS regeneration, thus providing new cues for better treatment of neurodegenerative diseases or nerve injury. [ABSTRACT FROM AUTHOR]

Tissue engineering research for neurological applications has demonstrated that biomaterial-based structural bridges present a promising approach for promoting regeneration. This is particularly relevant for penetrating traumatic brain injuries, where the clinical prognosis is typically poor, with no available regeneration-enhancing therapies. Specifically, repurposing clinically approved biomaterials offers many advantages (reduced approval time and achieving commercial scaleup for clinical applications), highlighting the need for detailed screening of potential neuromaterials. A major challenge in experimental testing is the limited availability of neuromimetic, technically accessible, cost-effective, and humane models of neurological injury for efficient biomaterial testing in injury-simulated environments. Three dimensional (3D) organotypic brain slices bridge the gap between live animal models and simplified co-cultures and are a versatile tool for studies on neural development, neurodegenerative disease and in drug testing. Despite this, their utility for investigation of neural cell responses to biomaterial implantation is poorly investigated. We demonstrate that murine brain organotypic slices can be used to develop a model of penetrating traumatic brain injury, wherein a surgical-grade biomaterial scaffold can be implanted into the lesion cavity. Critically, the model allowed for examination of key cellular responses involved in CNS injury pathology/biomaterial handling: astrogliosis, microglial activation and axonal sprouting. The approach offers a technically simple and versatile methodology to study biomaterial interventions as a regenerative therapy for neurological injuries. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia inhibits organ damage by suppressing metabolism, which makes it a therapy of choice for treating various diseases. Specifically, it is often used to treat conditions involving central nervous system disorders where it is expected to positively impact functional prognosis. Although keeping the body temperature at a hypothermic level has been conventionally used, how to manage the body temperature correctly remains a topic of debate. Recently, the concept of temperature management has been proposed to improve the quality of body temperature control and avoid hyperthermia. This review focuses on the effect of temperature on the central nervous system in conditions involving central nervous system disorders and the practice of temperature management in clinical situations. [ABSTRACT FROM AUTHOR]

Diseases and traumatic injuries to the central nervous system (CNS) demand the development of new biomaterials to improve healing and treatment options. Matching material mechanical properties to specific tissues and optimizing material porous structures are central goals for improving biomaterials. However, biomaterials with both precision-controlled porous structures and brain-matched mechanical properties (low modulus) are still lacking. In this study, we developed soft hydrogel scaffolds with mechanical properties similar to that of CNS tissues, and a uniform 40 µm porous structure—40 µm pores have been shown to be optimal for healing in many tissues. The two characteristics were achieved by a new fabrication process combining phase separation and sphere templating. The resulting scaffolds are non-cytotoxic according to the ISO 10993-5 standard. In addition, the three-dimensional culture of microglial cells within the scaffolds demonstrates cell attachment and maintenance of a rounded, quiescent morphology, potentially due to spatial confinement. These results justify further in vivo studies and suggest broad potential in CNS applications, such as brain-computer interfaces, neural regeneration, and basic neurobiology. Subject classification codes: Neural Interfaces, soft hydrogel, synthetic biomaterials [ABSTRACT FROM AUTHOR]

• cDAMPs are endogenous molecules released by necrotic CNS-resident cells after injury. • cDAMPs such as IL-1α, IL-33, nucleotides (e.g. ATP), and HMGB1 are key actors of neuroinflammation. • cDAMPs can initiate both proinflammatory mechanisms (e.g. IL-1α, ATP, HMGB1) and anti-inflammatory reprogramming (e.g. IL-33). • Interfering with the HMGB1/RAGE axis is a promising therapy for treating spinal cord and brain injuries, and stroke. Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways. [ABSTRACT FROM AUTHOR]

• Meningeal-based myeloid cell infiltrates mediate neurotoxicity in a chronic multiple sclerosis model. • Targeting compartmentalized neuroinflammation effectively chronic-progressive experimental autoimmune encephalomyelitis. • Selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury. Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+ cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach. [ABSTRACT FROM AUTHOR]

The article discusses the importance of pediatric organ donation, highlighting the impact children and adolescents have on saving lives through organ transplantation. A retrospective study conducted in a Portuguese hospital from 2006 to 2021 found that 62 pediatric patients were eligible for organ donation, resulting in 252 solid organs being collected and benefiting 202 recipients. Kidneys were the most frequently donated organs, with a median of four organs donated per child. The study emphasizes the need for further research to better understand the contribution of pediatric organ donation to both adults and children awaiting transplants. [Extracted from the article]

Pain serves as a vital innate defense mechanism that can significantly impact an individual's quality of life. Understanding the physiological effects of pain well plays an important role in developing novel pain treatments. Nociceptor neurons play a key role in pain and inflammation. Interactions between nociceptors and the immune system occur both at the site of injury and within the central nervous system. Modulating chemical mediators and nociceptor activity offers promising new approaches to pain management. Essentially, the sensory nervous system is essential for modulating the body's protective response, making it critical to understand these interactions to discover new pain treatment strategies. New innovations in neuromodulation have led to alternatives to opioids individuals with chronic pain with consequent improvement in disease-based treatment and nerve targeting. New neural targets from cellular and structural perspectives have revolutionized the field of neuromodulation. This narrative review aims to elucidate the mechanisms of pain transmission and processing, examine the characteristics and properties of nociceptors, and explore how the immune system influences pain perception. It further provides an updated overview of the physiology of pain and neuromodulatory mechanisms essential for managing acute and chronic pain. We assess the current understanding of different pain types, focusing on key molecules involved in each type and their physiological effects. Additionally, we compare painful and painless neuropathies and discuss the neuroimmune interactions involved in pain manifestation. [ABSTRACT FROM AUTHOR]

Injuries to the central nervous system (CNS) can cause severe neurological deficits. Axonal regrowth is a fundamental process for the reconstruction of compensatory neuronal networks after injury; however, it is extremely limited in the adult mammalian CNS. In this study, we conducted a loss-of-function genetic screen in cortical neurons, combined with a Web resource-based phenotypic screen, and identified synaptotagmin 4 (Syt4) as a novel regulator of axon elongation. Silencing Syt4 in primary cultured cortical neurons inhibits neurite elongation, with changes in gene expression involved in signaling pathways related to neuronal development. In a spinal cord injury model, inhibition of Syt4 expression in cortical neurons prevented axonal sprouting of the corticospinal tract, as well as neurological recovery after injury. These results provide a novel therapeutic approach to CNS injury by modulating Syt4 function. [ABSTRACT FROM AUTHOR]

Record-breaking heat waves over the past 20 years have led to a global increase in heat-related deaths, including heatstroke. Heat-related illnesses occur when the body cannot adapt to the elevated temperatures in the environment, leading to various symptoms. In severe situations, such as heatstroke, the body temperature can rise above 40°C, leading to significant injury to body systems, with particular susceptibility of the central nervous system (CNS). Neuroimaging studies conducted months or years after a heatstroke have revealed cellular damage in the cerebellum and other brain regions, including the hippocampus, midbrain, and thalamus, with the potential for long-term neurological complications in survivors of a heatstroke. This mini review aimed to describe the mechanisms and pathways underlying the development of brain injury induced by heatstroke and identify diagnostic imaging tools and biomarkers for injury to the CNS due to a heatstroke. [ABSTRACT FROM AUTHOR]

Complement C5a protein has been shown to play a major role in tissue regeneration through interaction with its receptor (C5aR) on target cells. Expression of this receptor has been reported in the nervous system which, upon injury, has no treatment to restore the lost functions. This work aimed at investigating the Complement C5a effect on axonal growth after axotomy in vitro. Primary hippocampal neurons were isolated from embryonic Wistar rats. Cell expression of C5aR mRNA was verified by RT-PCR while its membrane expression, localization, and phosphorylation were investigated by immunofluorescence. Then, the effects of C5a on injured axonal growth were investigated using a 3D-printed microfluidic device. Immunofluorescence demonstrated that the primary cultures contained only mature neurons (93%) and astrocytes (7%), but no oligodendrocytes or immature neurons. Immunofluorescence revealed a co-localization of NF-L and C5aR only in the mature neurons where C5a induced the phosphorylation of its receptor. C5a application on injured axons in the microfluidic devices significantly increased both the axonal growth speed and length. Our findings highlight a new role of C5a in regeneration demonstrating an enhancement of axonal growth after axotomy. This may provide a future therapeutic tool in the treatment of central nervous system injury. [ABSTRACT FROM AUTHOR]

Ependymal cells are arranged along the inner surfaces of the ventricles and the central canal of the spinal cord, providing anatomical, physiological and immunological barriers that maintain cerebrospinal fluid (CSF) homeostasis. Based on this, studies have found that alterations in gene expression, cell junctions, cytokine secretion and metabolic disturbances can lead to dysfunction of ependymal cells, thereby participating in the onset and progression of central nervous system (CNS) infections. Additionally, ependymal cells can exhibit proliferative and regenerative potential as well as secretory functions during CNS injury, contributing to neuroprotection and post-injury recovery. Currently, studies on ependymal cell primarily focus on the basic investigations of their morphology, function and gene expression; however, there is a notable lack of clinical translational studies examining the molecular mechanisms by which ependymal cells are involved in disease onset and progression. This limits our understanding of ependymal cells in CNS infections and the development of therapeutic applications. Therefore, this review will discuss the molecular mechanism underlying the involvement of ependymal cells in CNS infections, and explore their potential for application in clinical treatment modalities. Key points: Ependymal cells play an important role in the maintenance of CSF homeostasis and CNS health by forming physical and immune barriers against pathogen invasion. PPRs signaling pathways, cilia and intercellular junctions, cytokine secretion or senescence of ependymal cells can lead to dysfunction, which in turn is involved in the onset and progression of CNS infection. We propose potential therapeutic applications including gene transfer and novel biomarkers. Studies of ependymal cells have provided new ideas for pathophysiology and treatment, but further research is needed to fully understand their role in CNS infection and evaluate therapeutic effect. [ABSTRACT FROM AUTHOR]

Summary: Neuroinflammation, characterized by a complex interplay among innate and adaptive immune responses within the central nervous system (CNS), is crucial in responding to infections, injuries, and disease pathologies. However, the dysregulation of the neuroinflammatory response could significantly affect neurons in terms of function and structure, leading to profound health implications. Although tremendous progress has been made in understanding the relationship between neuroinflammatory processes and alterations in neuronal integrity, the specific implications concerning both structure and function have not been extensively covered, with the exception of perspectives on glial activation and neurodegeneration. Thus, this review aims to provide a comprehensive overview of the multifaceted interactions among neurons and key inflammatory players, exploring mechanisms through which inflammation influences neuronal functionality and structural integrity in the CNS. Further, it will discuss how these inflammatory mechanisms lead to impairment in neuronal functions and architecture and highlight the consequences caused by dysregulated neuronal functions, such as cognitive dysfunction and mood disorders. By integrating insights from recent research findings, this review will enhance our understanding of the neuroinflammatory landscape and set the stage for future interventions that could transform current approaches to preserve neuronal integrity and function in CNS‐related inflammatory conditions. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), which is a global public health concern, can take various forms, from mild concussions to blast injuries, and each damage type has a particular mechanism of progression. However, TBI is a condition with complex pathophysiology and heterogenous clinical presentation, which makes it difficult to model for in vitro and in vivo studies and obtain relevant results that can easily be translated to the clinical setting. Accordingly, the pharmacological options for TBI management are still scarce. Since a wide spectrum of processes, such as glucose homeostasis, food intake, body temperature regulation, stress response, neuroprotection, and memory, were demonstrated to be modulated after delivering glucagon-like peptide 1 (GLP-1) or GLP-1 receptor agonists into the brain, we aimed to speculate on their potential role in TBI management by comprehensively overviewing the preclinical and clinical body of evidence. Based on promising preclinical data, GLP-1 receptor agonists hold the potential to extend beyond metabolic disorders and address unmet needs in neuroprotection and recovery after TBI, but also other types of central nervous system injuries such as the spinal cord injury or cerebral ischemia. This overview can lay the basis for tailoring new research hypotheses for future in vitro and in vivo models in TBI settings. However, large-scale clinical trials are crucial to confirm their safety and efficacy in these new therapeutic applications. [ABSTRACT FROM AUTHOR]

This preface introduces the Special Issue on Neuroimmunology in the Journal of Neurochemistry. The basis of neuroimmunology is to understand functional interactions between cells of the immune system and the central nervous system (CNS). These cells communicate across systems because they share signaling molecules and corresponding receptors. Moreover, this cell signaling allows for dynamic bidirectional communication between the immune system and the brain both within the CNS proper as well as across peripheral organs. Because of this, Neuroimmunology intersects with many biological processes including immunity, behavior, endocrinology, metabolism, and pathology. Understanding neuroimmune interactions that influence CNS homeostasis is especially relevant in health and disease. This special issue comprises of 14 articles, representing 9 review articles and 5 original articles, covering the roles of neuroimmunology relevant to CNS injury, CNS & peripheral infections, cancer, Alzheimer's disease, and COVID‐19. Thus, these articles highlight different aspects of neuroimmunology and signaling, and represent progress in understanding the consequences of inflammation on key communication pathways between the immune system and the brains. [ABSTRACT FROM AUTHOR]

Ependymal cells form a specialized brain–cerebrospinal fluid (CSF) interface and regulate local CSF microcirculation. It is becoming increasingly recognized that ependymal cells assume a reactive state in response to aging and disease, including conditions involving hypoxia, hydrocephalus, neurodegeneration, and neuroinflammation. Yet what transcriptional signatures govern these reactive states and whether this reactivity shares any similarities with classical descriptions of glial reactivity (i.e., in astrocytes) remain largely unexplored. Using single‐cell transcriptomics, we interrogated this phenomenon by directly comparing the reactive ependymal cell transcriptome to the reactive astrocyte transcriptome using a well‐established model of autoimmune‐mediated neuroinflammation (MOG35‐55 EAE). In doing so, we unveiled core glial reactivity‐associated genes that defined the reactive ependymal cell and astrocyte response to MOG35‐55 EAE. Interestingly, known reactive astrocyte genes from other CNS injury/disease contexts were also up‐regulated by MOG35‐55 EAE ependymal cells, suggesting that this state may be conserved in response to a variety of pathologies. We were also able to recapitulate features of the reactive ependymal cell state acutely using a classic neuroinflammatory cocktail (IFNγ/LPS) both in vitro and in vivo. Taken together, by comparing reactive ependymal cells and astrocytes, we identified a conserved signature underlying glial reactivity that was present in several neuroinflammatory contexts. Future work will explore the mechanisms driving ependymal reactivity and assess downstream functional consequences. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an anti‐aquaporin 4 (anti‐AQP4) autoantibodies‐mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro‐inflammatory factors and increase the resolution of inflammation in patients with NMOSD. Methods: Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)‐10, IL‐1β, IL‐6, C‐X‐C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme‐linked immunosorbent assay before and after IVMP treatment. Results: High levels of TRAIL, CXCL12, and IL‐1β were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003–2.495; CXCL12: OR, 3.610; 95% CI, 1.011–12.889; IL‐1β: OR, 4.500; 95% CI, 1.129–17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538–0.976; MaR1: OR, 0.985; 95% CI, 0.970–0.999; LXA4: OR, 0.849; 95% CI, 0.727–0.993). Among patients with NMOSD, serum levels of IL‐6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL‐1β, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05). Conclusion: Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD. [ABSTRACT FROM AUTHOR]

Astrocytes respond to infection, injury, and disease with a robust and heterogeneous set of responses often associated with inflammation. Astrocyte heterogeneity is largely modeled at the descriptive level, with the identification of novel signatures of gene expression, proteins, and lipids that are tightly spatiotemporally controlled. While traditionally thought of as passive responders, astrocytes are active contributors to inflammation and release several effector cytokines and chemokines that help to modulate immune responses. In vertebrates, some astrocytes may even be involved in the presentation of antigens to infiltrating T cells. This places them as key initiators of the earliest response to inflammation, without the need for a myeloid cell intermediary. Astrocytes are key modulators of the inflammatory immune response in the mammalian central nervous system (CNS). While traditionally thought of as having only passive roles in the response to inflammatory insults, recent evidence indicates that astrocytes are active players in the earliest stages of inflammation, and may even have a role as atypical antigen-presenting cells. The astrocyte, a major glial cell type in the central nervous system (CNS), is widely regarded as a functionally diverse mediator of homeostasis. During development and throughout adulthood, astrocytes have essential roles, such as providing neuron metabolic support, modulating synaptic function, and maintaining the blood–brain barrier (BBB). Recent evidence continues to underscore their functional heterogeneity and importance for CNS maintenance, as well as how these cells ensure optimal CNS and immune responses to disease, acute trauma, and infection. Advances in our understanding of neuroimmune interactions complement our knowledge of astrocyte functional heterogeneity, where astrocytes are now regarded as key effectors and propagators of immune signaling. This shift in perspective highlights the role of astrocytes not merely as support cells, but as active participants in CNS immune responses. [ABSTRACT FROM AUTHOR]

Background: Infection by cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) play a prognostic role in multiple sclerosis (MS). Objectives: To explore whether humoral immune responses to HCMV and EBV at disease onset were associated with changes in serum and cerebrospinal fluid (CSF) levels of inflammatory and neurodegeneration biomarkers. Methods: Ninety-eight MS patients with a median follow-up of 20 years were included in the study. The levels of a panel of nine biomarkers were measured in serum (N = 60) and CSF (N = 61) samples of patients at the time of the first demyelinating event. Results: Immune responses to HCMV inversely correlated with serum neurofilament light chain (sNfL) levels (rho = −0.367; p = 0.039). sNfL levels were reduced in patients with high immune responses to HCMV (p = 0.006). Elevated sNfL levels were associated with higher risk of Expanded Disability Status Scale (EDSS) 3.0 (p = 0.016), 4.0 (p = 0.009) and 6.0 (p = 0.003), and with higher risk of developing secondary progressive MS (p = 0.003) and to receive treatment (p = 0.032). Serum soluble CD21 levels were increased in patients with high immune responses to EBV nuclear antigen 1 (p = 0.020). Conclusions: High immune responses to HCMV are associated with limited disease progression and central nervous system (CNS) injury in MS patients. These findings reinforce the protective role of HCMV infection in MS. [ABSTRACT FROM AUTHOR]

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology. Author summary: We measured more than 1,400 proteins in 303 cerebrospinal fluid (CSF) specimens from a representative broad range of untreated and treated people living with HIV-1 infection (PLWH) along with uninfected controls who volunteered for our studies. The results defined a complex, but generally coherent set of changes in many immune-inflammatory proteins and several central nervous system injury biomarkers as systemic HIV-1 infection progressed. There was a marked increase in many of these protein biomarkers in individuals with HIV-associated dementia and neurosymptomatic CSF viral escape, two conditions distinguished by overt, and characteristically severe, neurological impairment. The resultant data and initial analyses advance the characterization and understanding of the evolution of HIV-driven neuropathogenesis. The large dataset from this study is posted online and available to other investigators for further analyses, extending the utility of these data and potentially aiding in developing future prevention, diagnosis and mitigation of the deleterious impact of HIV-1 infection on the brain. [ABSTRACT FROM AUTHOR]

Assessment of muscle tone in a clinical setting is important for the physiotherapist to better analyse and establish appropriate treatments for CNS disorders. This study aims to review and summarise how to assess changes in tone in the context of adult rehabilitation. Secondarily, this study aimed to identify the central nervous system disorders, the respective variable/concept under study, and the testing procedures employed. PRISMA-ScR guidelines were followed using the "population", "concept", and "context" to define the eligibility criteria and to delineate the research question. PubMed®, Science Direct®, Web of Science™, and Google Scholar® databases were used to search the literature. The search included studies published between 2011 and March 2023 in Portuguese, English, French, and Spanish that assessed an adult population (>19 years) with CNS injury. Review articles, qualitative studies, conference proceedings, letters to the editor, and editorials were excluded. Initially, 1519 references were identified, of which eight met the eligibility criteria. The measurement instruments included the Modified Ashworth Scale (n = 5), the Modified Modified Ashworth Scale (n = 3), the BioTone™ system (n = 2), the Montreal Spasticity Measurement (n = 1), and the Tone Evaluation Scale (n = 1). The health conditions considered included stroke sequelae (n = 7), multiple sclerosis (n = 4), spinal cord injuries (n = 4), cerebral palsy (n = 2), brain tumour (n = 2), and traumatic brain injuries (n = 3). The concepts of spasticity (n = 7) and muscle tone (n = 2) were explored. Considering the variables spasticity and muscle tone in different CNS disorders, mainly stroke, subjective instruments were preferred compared to objective ones, with the Modified Ashworth Scale being highlighted. [ABSTRACT FROM AUTHOR]

Introduction: Coxsackievirus A6 (CV-A6) has emerged as the predominant epidemic strain responsible for hand, foot and mouth disease (HFMD). CV-A6 infection can result in severe clinical manifestations, including encephalitis, meningitis, and potentially life-threatening central nervous system disorders. Our previous research findings demonstrated that neonatal mice infected with CV-A6 exhibited limb weakness, paralysis, and ultimately succumbed to death. However, the underlying mechanism of CV-A6-induced nervous system injury remains elusive. Numerous reports have highlighted the pivotal role of miRNAs in various viral infections. Methods: Separately established infection and control groups of mice were used to create miRNA profiles of the brain tissues before and after CV-A6 transfection, followed by experimental verification, prediction, and analysis of the results. Results: At 2 days post-infection (dpi), 4 dpi, and 2dpi vs 4dpi, we identified 175, 198 and 78 significantly differentially expressed miRNAs respectively using qRT-PCR for validation purposes. Subsequently, we predicted target genes of these differentially expressed miRNAs and determined their potential targets through GO (Gene Ontology) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Finally, we verified the miRNA-mRNA pairing via double luciferase experiments while confirming functional enrichment of target genes through Western Blotting analyses. Discussion: The results from this study suggest that transcriptional regulation, neuronal necrosis, pro-inflammatory cytokine release, and antiviral immunity are all implicated in the pathogenesis of central nervous systeminjury in mice infected with CV-A6. Brain injury resulting from CV-A6 infection may involve multiple pathways, including glial cell activation, neuronal necrosis, synaptic destruction, degenerative diseases of the nervous system. It can even encompass destruction of the blood-brain barrier, leading to central nervous system injury. The dysregulated miRNAs and signaling pathways discovered in this study provide valuable insights for further investigations into the pathogenesis of CV-A6. [ABSTRACT FROM AUTHOR]

Ketone bodies are considered alternative fuels for the brain when glucose availability is limited. To determine the neuroregenerative potential of D,L-sodium-beta-hydroxybutyrate (D/L-BHB), Sprague Dawley rat primary cortical neurons were exposed to simulated central nervous system injury using a scratch assay. The neuronal cell migration, cell density and degree of regeneration in the damaged areas (gaps) in the absence (control) and presence of BHB (2 mM) were documented with automated live-cell imaging by the CytoSMART system over 24 h, which was followed by immunocytochemistry, labeling synapsin-I and β3-tubulin. The cell density was significantly higher in the gaps with BHB treatment after 24 h compared to the control. In the control, only 1.5% of the measured gap areas became narrower over 24 h, while in the BHB-treated samples 49.23% of the measured gap areas became narrower over 24 h. In the control, the gap expanded by 63.81% post-injury, while the gap size decreased by 10.83% in response to BHB treatment, compared to the baseline. The cell density increased by 97.27% and the gap size was reduced by 74.64% in response to BHB, compared to the control. The distance travelled and velocity of migrating cells were significantly higher with BHB treatment, while more synapsin-I and β3-tubulin were found in the BHB-treated samples after 24 h, compared to the control. The results demonstrate that D/L-BHB enhanced neuronal migration and molecular processes associated with neural regeneration and axonogenesis. These results may have clinical therapeutic applications in the future for nervous system injuries, such as for stroke, concussion and TBI patients. [ABSTRACT FROM AUTHOR]

Objective: Spinal cord injury (SCI), one of the major disabilities concerning central nervous system injury, results in permanent tissue loss and neurological impairment. The existing therapeutic options for SCI are limited and predominantly consist of chemical compounds. In this study, we delved into the neuroprotective effects of myricetin, a natural flavonoid compound, and the underlying mechanisms, specifically in the context of SCI, utilizing an in vivo model. Previously, our investigations revealed an elevation in the phosphorylated form of Lin-11, Isl-1, and Mec-3 kinase1 (LIMK1) at chronic time points postinjury, coinciding with neuronal loss and scar formation. Our primary objective here was to assess the potential neuroprotective properties of myricetin in SCI and to ascertain if these effects were linked to LIMK inhibition, a hitherto unexamined pathway to date. Methods: Computational docking and molecular dynamics simulation studies were performed to assess myricetin's potential to bind with LIMK. Then, using a rat contusion model, SCI was induced and different molecular techniques (Western blot, Evans Blue assay, quantitative reverse transcription polymerase chain reaction and immunohistochemistry) were performed to determine the effects of myricetin. Results: Remarkably, computational docking models identified myricetin as having a better interaction profile with LIMK than standard. Subsequent to myricetin treatment, a significant downregulation in phosphorylated LIMK expression was observed at chronic time points. This reduction correlated with a notable decrease in glial and fibrotic scar formation, and enhanced neuroprotection indicating a positive outcome in vivo. Conclusion: In summary, our findings underscore myricetin's potential as a bioactive compound capable of attenuating SCI-induced injury cascades by targeting the LIMK pathway. [ABSTRACT FROM AUTHOR]

The article discusses the potential therapeutic role of methane in treating traumatic nervous system diseases. Research has shown that methane has anti-inflammatory, anti-oxidative stress effects, and can protect cells and organs from damage caused by inflammation, oxidation stress, and apoptosis. Studies have focused on traumatic spinal cord injury, traumatic brain injury, and optic nerve crush, highlighting methane's neuroprotective effects and mechanisms of action. The article suggests that further research is needed to clarify the exact molecular and signaling pathways through which methane exerts its neuroprotective effects. [Extracted from the article]

Neurodegenerative disorders, including traumatic injuries to the central nervous system (CNS) and neurodegenerative diseases, are characterized by early axonal damage, which does not regenerate in the adult mammalian CNS, leading to permanent neurological deficits. One of the primary causes of the loss of regenerative ability is thought to be a developmental decline in neurons' intrinsic capability for axon growth. Different molecules are involved in the developmental loss of the ability for axon regeneration, including many transcription factors. However, the function of microRNAs (miRNAs), which are also modulators of gene expression, in axon re-growth is still unclear. Among the various miRNAs recently identified with roles in the CNS, miR-17, which is highly expressed during early development, emerges as a promising target to promote axon regeneration. Here, we used adeno-associated viral (AAV) vectors to overexpress miR-17 (AAV.miR-17) in primary cortical neurons and evaluate its effects on neurite and axon regeneration in vitro. Although AAV.miR-17 had no significant effect on neurite outgrowth and arborization, it significantly enhances neurite regeneration after scratch lesion and axon regeneration after axotomy of neurons cultured in microfluidic chambers. Target prediction and functional annotation analyses suggest that miR-17 regulates gene expression associated with autophagy and cell metabolism. Our findings suggest that miR-17 promotes regenerative response and thus could mitigate neurodegenerative effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuronal growth is an essential process for establishing functional neural networks in developing brain and restoring dysfunctional networks caused by injuries in the adult brain. In the adult central nervous system, injured neurons fail to re-extend their axons due to several axon growth inhibitors mainly expressed in glial cells. We previously reported that LOTUS protein helps injured adult neurons to regenerate by blocking the inhibitors. In this study, we found that LOTUS itself promotes axon growth through an independent mechanism from the blockade of the inhibitors. LOTUS directly binds to Teneurin-4, a cell adhesion molecule expressed on the surface of neurons and the binding promotes axon growth. Thus, LOTUS was found to have two functions in axon growth. This finding may provide a new insight into neural network formation in developing brain and neural regrowth mechanism following the adult injured brain. These functions of LOTUS protein are useful for developing new therapeutic approaches to promote nerve regeneration after injury in the adult central nervous system. Neurite outgrowth is a crucial process for organizing neuronal circuits in neuronal development and regeneration after injury. Regenerative failure in the adult mammalian central nervous system (CNS) is attributed to axonal growth inhibitors such as the Nogo protein that commonly binds to Nogo receptor-1 (NgR1). We previously reported that lateral olfactory tract usher substance (LOTUS) functions as an endogenous antagonist for NgR1 in forming neuronal circuits in the developing brain and improving axonal regeneration in the adult injured CNS. However, another molecular and cellular function of LOTUS remains unknown. In this study, we found that cultured retinal explant neurons extend their neurites on the LOTUS-coating substrate. This action was also observed in cultured retinal explant neurons derived from Ngr1-deficient mouse embryos, indicating that the promoting action of LOTUS on neurite outgrowth may be mediated by unidentified LOTUS-binding protein(s). We therefore screened the binding partner(s) of LOTUS by using a liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis and pull-down assay showed that LOTUS interacts with Teneurin-4 (Ten-4), a cell adhesion molecule. RNAi knockdown of Ten-4 inhibited neurite outgrowth on the LOTUS substrate in retinoic acid (RA)-treated Neuro2A cells. Furthermore, a soluble form of Ten-4 attenuates the promoting action on neurite outgrowth in cultured retinal explant neurons on the LOTUS substrate. These results suggest that LOTUS promotes neurite outgrowth by interacting with Ten-4. Our findings may provide a new molecular mechanism of LOTUS to contribute to neuronal circuit formation in development and to enhance axonal regeneration after CNS injury. [ABSTRACT FROM AUTHOR]

Background: Neuroplasticity as a mechanism to overcome central nervous system injury resulting from different neurological diseases has gained increasing attention in recent years. However, deficiency of these repair mechanisms leads to the accumulation of neuronal damage and therefore long-term disability. To date, the mechanisms by which remyelination occurs and why the extent of remyelination differs interindividually between multiple sclerosis patients regardless of the disease course are unclear. A member of the neurotrophins family, the brain-derived neurotrophic factor (BDNF) has received particular attention in this context as it is thought to play a central role in remyelination and thus neuroplasticity, neuroprotection, and memory. Objective: To analyse the current literature regarding BDNF in different areas of multiple sclerosis and to provide an overview of the current state of knowledge in this field. Conclusion: To date, studies assessing the role of BDNF in patients with multiple sclerosis remain inconclusive. However, there is emerging evidence for a beneficial effect of BDNF in multiple sclerosis, as studies reporting positive effects on clinical as well as MRI characteristics outweighed studies assuming detrimental effects of BDNF. Furthermore, studies regarding the Val66Met polymorphism have not conclusively determined whether this is a protective or harmful factor in multiple sclerosis, but again most studies hypothesized a protective effect through modulation of BDNF secretion and anti-inflammatory effects with different effects in healthy controls and patients with multiple sclerosis, possibly due to the pro-inflammatory milieu in patients with multiple sclerosis. Further studies with larger cohorts and longitudinal follow-ups are needed to improve our understanding of the effects of BDNF in the central nervous system, especially in the context of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: The brain border compartments harbor a diverse population of immune cells and serve as invasion sites for leukocyte influx into the brain following CNS injury. However, how brain‐border myeloid cells affect stroke pathology remains poorly characterized. Methods and Results: Here, we showed that ischemic stroke‐induced expansion of CXCL2+ neutrophils, which exhibit highly proinflammatory features. We tracked CXCL2+ neutrophils in vivo by utilizing a photoconvertible Kik‐GR mouse (fluorescent proteins Kikume Green Red, Kik‐GR) and found that brain‐infiltrating CXCL2+ neutrophils following ischemic stroke were mainly derived from the brain border rather than the periphery. We demonstrated that CXCL2 neutralization inhibited the formation and releasing of neutrophil extracellular traps (NETs) from in vitro cultured primary neutrophils. Furthermore, CXCL2‐neutralizing antibody treatment reduced brain infarcts and improved vascular reperfusion at day 3 postischemic stroke. Conclusions: Collectively, brain border‐derived CXCL2+ neutrophil expansion may impair vascular reperfusion by releasing NETs following ischemic stroke. [ABSTRACT FROM AUTHOR]

Individuals grappling with severe central nervous system injuries often face significant challenges related to sensorimotor function and communication abilities. In response, brain–computer interface (BCI) technology has emerged as a promising solution by offering innovative interaction methods and intelligent rehabilitation training. By leveraging electroencephalographic (EEG) signals, BCIs unlock intriguing possibilities in patient care and neurological rehabilitation. Recent research has utilized covariance matrices as signal descriptors. In this study, we introduce two methodologies for covariance matrix analysis: multiple tangent space projections (M-TSPs) and Cholesky decomposition. Both approaches incorporate a classifier that integrates linear and nonlinear features, resulting in a significant enhancement in classification accuracy, as evidenced by meticulous experimental evaluations. The M-TSP method demonstrates superior performance with an average accuracy improvement of 6.79% over Cholesky decomposition. Additionally, a gender-based analysis reveals a preference for men in the obtained results, with an average improvement of 9.16% over women. These findings underscore the potential of our methodologies to improve BCI performance and highlight gender-specific performance differences to be examined further in our future studies. [ABSTRACT FROM AUTHOR]

Damage to the central nervous system (CNS) often leads to irreversible neurological deficits, and there are currently few effective treatments available. However, recent advancements in regenerative medicine have identified CNS organoids as promising therapeutic options for addressing CNS injuries. These organoids, composed of various neurons and supporting cells, have shown potential for direct repair at injury sites. CNS organoids resemble the structure and function of actual brain tissue, which allows them to adapt and function well within the physiological environment when transplanted into injury sites. Research findings suggest that CNS organoids can replace damaged neurons, form new neural connections, and promote neural recovery. This review highlights the emerging benefits, evaluates preclinical transplantation outcomes, and explores future strategies for optimizing neuroregeneration using CNS organoids. With continued research and technological advancements, these organoids could provide new hope for patients suffering from neurological deficits. [ABSTRACT FROM AUTHOR]

Abnormal shifts in global climate, leading to extreme weather, significantly threaten the safety of individuals involved in outdoor activities. Hypothermia-induced coma or death frequently occurs in clinical and forensic settings. Despite this, the precise mechanism of central nervous system injury due to hypothermia remains unclear, hindering the development of targeted clinical treatments and specific forensic diagnostic indicators. The GEO database was searched to identify datasets related to hypothermia. Post-bioinformatics analyses, DEGs, and ferroptosis-related DEGs (FerrDEGs) were intersected. GSEA was then conducted to elucidate the functions of the Ferr-related genes. Animal experiments conducted in this study demonstrated that hypothermia, compared to the control treatment, can induce significant alterations in iron death-related genes such as PPARG, SCD, ADIPOQ, SAT1, EGR1, and HMOX1 in cerebral cortex nerve cells. These changes lead to iron ion accumulation, lipid peroxidation, and marked expression of iron death-related proteins. The application of the iron death inhibitor Ferrostatin-1 (Fer-1) effectively modulates the expression of these genes, reduces lipid peroxidation, and improves the expression of iron death-related proteins. Severe hypothermia disrupts the metabolism of cerebral cortex nerve cells, causing significant alterations in ferroptosis-related genes. These genetic changes promote ferroptosis through multiple pathways. [ABSTRACT FROM AUTHOR]

Gliomas are associated with high rates of disability and mortality, and currently, there is a lack of specific and sensitive biomarkers for diagnosis. The ideal biomarkers should be detected early through noninvasive methods. Our research aims to develop a rapid, convenient, noninvasive diagnostic method for gliomas, as well as for grading and differentiation. We retrospectively collected data from patients who underwent surgery for glioma, trigeminal neuralgia/hemifacial spasmschwannoma, and those diagnosed with multiple sclerosis at our institution from January 2018 to December 2020. Inflammatory markers and coagulation factor levels were collected on admission, and neutrophil count (NLR), (WBC count minus neutrophil count) / lymphocyte count, platelet count / lymphocyte count, lymphocyte count / monocyte count, and albumin count [g/L] + total lymphocyte count × 5 were calculated for patients. Analyze the significance of biomarkers in the diagnosis and grading of gliomas, the diagnosis of MS, and the differential diagnosis of them. We evaluated 155 healthy individuals, 64 trigeminal neuralgia/hemifacial spasm patients, 47 MS patients, 316 schwannoma patients, and 814 with glioma patients. Compared with healthy controls and MS group, the preoperative levels of NLR, (WBC count minus neutrophil count) / lymphocyte count, D-dimer, Fibrinogen, Antithrobin, and Factor VIII of glioma patients were significantly higher in glioma patients and positively correlated with the grade of glioma. Conversely, 0020 lymphocyte count / Monocyte count and albumin count [g/L] + total lymphocyte count × 5 were significantly lower and negatively correlated with glioma grading. ROC curves confirmed that for the diagnosis of glioma, NLR showed a maximum area under the curve value of 0.8616 (0.8322–0.8910), followed by D-dimer and Antithrombin, with area under the curve values of 0.8205 (0.7601–0.8809) and 0.8455 (0.8153–0.8758), respectively. NLR and d-dimer also showed great sensitivity in the diagnosis of MS and differential diagnosis with gliomas. Our study demonstrated that multiple inflammatory markers and coagulation factors could be utilized as biomarkers for the glioma diagnosis, grading, and differential diagnosis of MS. Furthermore, the combination of these markers exhibited high sensitivity and specificity. [ABSTRACT FROM AUTHOR]

The embryonal central nervous system (CNS) tumor with PLAGL1 (pleomorphic adenoma gene-like) amplification is a novel type of pediatric neoplasm with a distinct methylation profile, described for the first time in 2022. It may be located anywhere in the neuroaxis and, as its name implies, it is driven by the amplification and overexpression of one of the PLAG family genes. Although the associated clinical, immunohistopathological, and molecular characteristics are well characterized in the seminal report of this entity, data on the radiological features is still lacking. Here, we present a case report of a 4-year-old girl with a biopsy-proven PLAGL1-amplified brainstem tumor and provide a detailed description of the corresponding conventional neuroimaging characteristics, aiming to better delineate this entity and to increase the awareness of this pathology in the radiological community. [ABSTRACT FROM AUTHOR]