Neuroglia

In homeostasis, the glial cells support pivotal functions, such as neuronal differentiation, neuroprotection, nutrition, drug metabolism, and immune response in the central nervous system (CNS). Among these cells, astrocytes and microglia have been highlighted due to their role in the pathogenesis of several diseases or due to their role in the defense against several insults (ex., chemicals, and pathogens). In Vitro cytological analysis of astrocytes and microglia has contributed to the understanding of the role of morphological changes in glial cells associated with a neuroprotective or neurotoxic phenotype. Currently, the main tools used for the investigation of glial cell morphology in culture are phase contrast microscopy or immunolabeling/fluorescence microscopy. However, generally, phase contrast microscopy does not generate images with high resolution and therefore does not contribute to visualizing a single cell morphology in confluent cell cultures. On the other hand, immunolabeling requires high-cost consumable antibodies, epifluorescence microscope or confocal microscope, and presents critical steps during the procedure. Therefore, identifying a fast, reproducible, low-cost alternative method that allows the evaluation of glial morphology is essential, especially for neuroscientists from low-income countries. This article aims to revise the use of Rosenfeld’s staining, as an alternative low-cost and easy-to-reproduce method to analyze astrocytic and microglial morphology in culture. Additionally, it shows Rosenfeld’s staining as a valuable tool to analyze changes in neural cell morphology in toxicological studies. Full article

In recent decades, substantial evidence has highlighted the integral roles of neuroglia, particularly astrocytes, microglia, oligodendrocytes, and ependymal cells, in the regulation of synaptic transmission, metabolic support, and immune mechanisms within the central nervous system. In addition to their structural role, these cells actively modulate neurotransmitter homeostasis and influence neuronal plasticity, thereby affecting cognition, mood, and behavior. This review discusses how neuroglial alterations contribute to the pathophysiology of five common psychiatric disorders: major depression, bipolar disorder, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. We synthesized preclinical and clinical findings illustrating that glial dysfunction, including impaired myelination and aberrant neuroinflammatory responses, often parallels disease onset and severity. Moreover, we outline how disruptions in astrocytic glutamate uptake, microglia-mediated synaptic pruning, and blood–brain barrier integrity may underlie the neurobiological heterogeneity observed in these disorders. The therapeutic implications range from anti-inflammatory agents to investigational compounds that aim to stabilize glial function or promote remyelination. However, challenges due to interindividual variability, insufficient biomarkers, and the multifactorial nature of psychiatric illnesses remain. Advances in neuroimaging, liquid biopsy, and more precise molecular techniques may facilitate targeted interventions by stratifying patient subgroups with distinct glial phenotypes. Continued research is essential to translate these insights into clinically efficacious and safe treatments. Full article

The central nervous system (CNS) relies on complex and dynamic interactions between neurons and glial cells. Among glial cells, astrocytes regulate the chemical environment surrounding neurons and supply essential nutrients for brain metabolism whereas microglia, the resident macrophages of the CNS, play critical roles in homeostasis, defense, and responses to injury. Both microglia and astrocytes contribute to the regulation of excitotoxicity and inflammation mediated by the metabolism of tryptophan (Trp) via the kynurenine pathway. Trp metabolism generates several bioactive metabolites, including quinolinic acid (QUIN) and kynurenic acid (KYNA), which have opposing effects. QUIN, produced by activated microglia, acts as an agonist for NMDA receptors; excessive stimulation of these receptors can lead to excitotoxicity and neuronal death. Conversely, KYNA, primarily produced by astrocytes via kynurenine 2,3-aminotransferases (KAT), acts as an NMDA receptor antagonist, conferring neuroprotection by mitigating excitotoxicity. Dysregulation of the Trp metabolism is implicated in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis, as well as in various neuropsychiatric disorders. This review examines the cellular and molecular mechanisms underlying Trp metabolism in glial cells, highlighting the unique contributions of each glial phenotype, the implications for CNS pathologies, and the potential biomarkers and therapeutic targets for restoring homeostasis and preventing disease progression. Full article

High-grade gliomas are aggressive, primary, central nervous system tumors with low survival rates due to recurrence and resistance to current therapy models. Recent studies have highlighted the importance between the interaction of glioma cancer cells and cells of the tumor microenvironment (TME). Cancer stem cells and immune cells play a critical role in the TME of gliomas. TMEs in glioma include the perivascular TME, hypoxic TME, and invasive TME, each of which have evolved as our understanding of the involved cellular players has improved. This review discusses the multidimensional aspects of the current targeted therapies and interactions between glioma cells and the TME with specific focus on targeted immunotherapies. Understanding the complexities of the TME and elucidating the various tumor-cell interactions will be critical for facilitating the development of novel precision strategies, ultimately enabling better patient outcomes. Full article

Background/Objectives: Spinal cord injury (SCI) is a devastating condition that leads to a cascade of cellular and molecular events, resulting in both primary and secondary damage. Among the many cells involved in the post-SCI environment, glial cells in the spinal cord and brain are pivotal in determining the trajectory of injury and repair. Methods: While recent SCI studies have shown changes in the genotype of glial cells following injury, exactly how these alterations occur after damage remains unknown. In this sense, the systemic inflammatory molecules could be involved in the connection between the spinal cord and brain, inducing glial activation by different signaling pathways. Preclinical studies have shown that nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathways are involved in the change in glial type. Results: These cells, which include astrocytes and microglia, exhibit dynamic responses following spinal injury, contributing to both neuroprotection and neurodegeneration. These different effects indicate that the molecular environment causes changes in the type of astrocytes and microglia, leading to different actions. Conclusions: Understanding the mechanisms of glial cell activation, it is possible to clarify the roles of these glial cells in pathophysiology and their potential repair mechanisms post-injury. Full article

Background/Objectives: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by challenges in social communication, restricted interests, and repetitive behaviors. Recent studies highlight the crucial roles of neuroglial cells—astrocytes, microglia, and oligodendrocytes—in synaptic function, neural connectivity, and neuroinflammation. These findings offer a fresh perspective on ASD pathophysiology. This review synthesizes current knowledge on neuroglial dysfunction in ASD, emphasizing its role in pathophysiological mechanisms, genetic influences, and potential therapeutic strategies. Methods: We conducted a comprehensive literature review, integrating insights from neuroscience, molecular biology, and clinical studies. Special focus was given to glial-mediated neuroinflammatory mechanisms, synaptic plasticity regulation, and the impact of genetic mutations on neuroglial signaling and homeostasis. Results: Neuroglial dysfunction in ASD is evident in abnormal synaptic pruning by microglia, impaired astrocytic glutamate regulation, and defective oligodendrocyte-driven myelination, which collectively disrupt neuronal architecture. Emerging therapies targeting these pathways, including anti-inflammatory drugs, microglial modulators, and cell-based approaches, show promise in alleviating key ASD symptoms. Additionally, advanced interventions such as gene editing and glial progenitor therapy present opportunities to correct underlying neuroglial dysfunction. Conclusions: This review establishes a comprehensive framework for understanding neuroglial contributions to ASD. By integrating insights from diverse disciplines, it enhances our understanding of ASD pathophysiology and paves the way for novel therapeutic strategies targeting neuroglial pathways. Full article

Vestibular disorders significantly affect individuals by impairing balance, spatial orientation, and quality of life. Despite the focus on neuronal mechanisms, emerging research emphasizes the importance of neuroglia—astrocytes, microglia, oligodendrocytes, and Schwann cells—in the onset, progression, and resolution of these conditions. This narrative review explores the roles of neuroglia in vestibular disorders, including vestibular migraines and unilateral and bilateral vestibulopathies. It discusses established facts, challenges, and future perspectives, offering insights into their pathophysiological roles and therapeutic implications, and the limitations of current research. By understanding the interplay between neuroglia and vestibular function, this review aims to advance diagnostic and treatment strategies for these disorders Full article

Background: Neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and spinal cord injury (SCI) are significant global health challenges due to their complex pathology and limited therapeutic options. Conventional treatments often fail to efficiently cross the blood–brain barrier (BBB), leading to poor bioavailability and systemic toxicity. This narrative review explores the potential of nanomedicine in addressing these limitations and advancing targeted therapies for neural disorders. Methods: This review examines recent studies on the use of engineered nanoparticles (NPs), including liposomes, dendrimers, micelles, and nanogels, for targeted drug delivery and multifunctional theranostics in neural diseases. It evaluates their role in promoting axon regeneration, reducing neuroinflammation, and repairing neural damage. Additionally, innovative applications in gene therapy and RNA-based treatments, such as CRISPR-Cas9 and RNA interference (RNAi), are discussed. Challenges related to toxicity, scalability, affordability, and regulatory barriers are highlighted, along with potential strategies to address these issues. Results: Nanoparticles have shown significant promise in crossing the BBB, delivering therapeutic agents to neural tissues, and minimizing off-target effects. Emerging applications in gene and RNA-based therapies demonstrate their versatility in addressing disease-specific challenges. However, unresolved issues such as long-term safety, manufacturing scalability, and cost continue to pose challenges. Conclusions: Nanomedicine offers a promising approach to overcoming current limitations in the treatment of neural disorders. This review emphasizes the need for continued interdisciplinary efforts to address translational barriers and highlights the potential for nanomedicine to improve the outcomes and quality of life for patients with neural disorders, stroke, and SCI. Full article

Background: Angiogenesis is a key factor necessary for tissue growth but becomes often dysregulated in cancer, driving tumour progression. Glioblastoma multiforme (GBM) induces abnormal vascular remodelling via Hypoxia-activated VEGF, FGF and PDGF. Despite increased vascularization, hypoxia persists, worsening malignancy. Additionally, emerging evidence highlights extracellular vesicles (EVs) as key mediators of angiogenesis as conduits transferring bioactive cargo modulating cellular signaling. By promoting neovascularization, EVs can facilitate tumour growth, hinder drug delivery, and contribute to therapeutic resistance, making them potential therapeutic targets. Objective: This study explores the role of GBM-derived EVs in promoting aberrant angiogenesis by modulating VEGF and MMP signalling and correlating them with EV biogenesis to better understand tumour vascularisation and therapeutic paucities. Methods: This study investigates the role of GBM-derived EVs in angiogenesis dysregulation, via in silico and in vitro approaches, making use of available databases to study the enrichment profiles of key angiogenic drivers enriched in GBM and EVs followed by validation studies using 2D cell culture of HUVEC and U87MG cells on treatment with EV inhibitor. Results: We observed that GBM-derived EVs can be key collaborators of promoting angiogenesis by upregulating key pro-angiogenic genes (VEGFA, NRP1, MMP9) and EV biogenesis markers (CD9, CD81, TSG101), facilitating endothelial cell migration and vascular remodelling. Functional assays further confirmed that EVs act as vectors for pro-angiogenic signals, while their inhibition with GW4869 significantly reduced angiogenic activity, highlighting their role in tumour vascularization. Conclusions: Targeting EV-mediated angiogenesis presents a promising therapeutic strategy for GBM, warranting further validation in preclinical and clinical models. Full article

Background: The Notch signaling pathway is an important regulator of stem cell activity in various tissues, including the central nervous system. It has been implicated in neurodevelopmental processes, including neuronal differentiation and synaptic plasticity. Research suggests that its expression may be associated with certain epileptogenic lesions, particularly those with neurodevelopmental origin. The aim of this study was to investigate the expression of Notch-1 in brain biopsies from various cases of pharmacoresistant epilepsy. Methods: Here, we used immunohistochemistry staining to retrospectively analyze 128 developmental lesions associated with pharmacoresistant epilepsy, including 13 cases with focal cortical dysplasia (FCD) type I, 39 with FCD type II, 37 with hippocampal sclerosis (HS), 23 with FCD IIIc, 9 with mild malformations of cortical development (MCD), 4 cases with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE), and 3 with tuberous sclerosis (TS). The tissues were stained for Neurofilament protein, Vimentin, S-100 protein, NeuN, and GFAP, as well as the stem cell marker Notch-1. Tissue that stained positively for Notch-1 was further characterized. Results: A positive Notch-1 reaction was found in all cases of FCD type IIb and TS, where it appeared in balloon cells but not in dysmorphic neurons, and in a single case of meningioangiomatosis (FCD IIIc), where it stained spider-like cells. Notch-1-positive cells showed a stem-like, glio-neuronal precursor immunophenotype. No staining was observed in the remaining cases with FCD type I, type III, HS, mild MCD, and MOGHE. Conclusions: Notch-1 displays a distinct pattern of expression in some epileptogenic lesions, potentially highlighting a stem cell-like origin or neurodevelopmental abnormalities contributing to pharmacoresistant epilepsy; however, it is not a general marker of such lesions. Its differential expression may prove useful in distinguishing between different types of FCD or other cortical malformations, which could assist in both their diagnosis and potentially in the development of more targeted therapeutic approaches. Further studies with different stem cell markers are needed in this direction. Full article

This review aims to provide a comprehensive overview of the main types, subtypes, clinical manifestations, and current therapeutic strategies for multiple sclerosis, emphasizing recent advancements and clinical challenges. Multiple Sclerosis (MS) is a demyelinating, chronic, autoimmune, and inflammatory disease that affects the Central Nervous System (CNS). Its classification has the following subtypes: Relapsing-Remitting (RRMS), Secondary-Progressive (SPMS), and Primary-Progressive (PPMS), including rarer subtypes such as Clinically Isolated Syndrome (CIS), Radiologically Isolated Syndrome (RIS), Balo’s Concentric Sclerosis (BCS), Schilder’s Disease (SD), and Progressive-Relapsing MS (PRMS). This article divides the various treatments for MS into the following three categories: acute relapse management, symptomatic treatments, and Disease-Modifying Treatments (DMTs). The latter represents revolutionary research in MS, since they are the drugs considered as the best treatment alternatives for this disease. Full article

Gliomas, ranging from low-grade pilocytic astrocytomas to highly malignant glioblastomas, are primary brain tumors that originate from neural or glial stem cells. Classified by the WHO into grades 1 to 4, these tumors exhibit varying prognoses, with oligodendrogliomas and astrocytomas having better and intermediate outcomes, respectively, while glioblastomas are associated with a poor prognosis. Despite advancements in molecular and genetic research that have improved diagnosis and the development of targeted therapies, treating high-grade gliomas remains a significant challenge due to their diffuse nature. In this context, lectins, carbohydrate-binding proteins, have shown promise as diagnostic and therapeutic agents for cancer, including gliomas. Plant lectins, particularly those from legumes, exhibit significant antiproliferative effects on glioma cells. These effects include decreased cell viability and migration, alongside the induction of autophagy and apoptosis, suggesting their potential as therapeutic agents. Although the mechanisms underlying these effects are not yet fully understood, molecular targets and pathways involved in the antiglioma activity of lectins have been identified. Key targets include matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), CD98 (xc^- system), AMPA receptor, and CD73. This review focuses on the antiglioma potential of legume lectins, their applications, and the main molecular targets based on their functions, structures, and associated molecular mechanisms. Full article

Overexposure of humans to heavy metals and essential metals poses a significant risk for the development of neurological and neurodevelopmental disorders. The mechanisms through which these metals exert their effects include the generation of reactive oxygen species, mitochondrial dysfunction, activation of inflammatory pathways, and disruption of cellular signaling. The function of glial cells in brain development and in the maintenance of homeostasis cannot be overlooked. The glial cells are particularly susceptible to metal-induced neurotoxicity. Accumulation of metals in the brain promotes microglial activation, triggering inflammatory responses that can coincide with other mechanisms of neurotoxicity, inducing alteration in synaptic transmission, cognitive deficit, and neuronal damage. In this review, we highlighted the role of glial dysfunction in some selected neurodegenerative diseases and neurodevelopmental disorders. We further dive into how exposure to metals such as nickel, manganese, methyl mercury, cadmium, iron, arsenic, and lead affect the functions of the microglia, astrocytes, and oligodendrocytes and the mechanisms through which they exert the effects on the brain in relation to some selected neurodegenerative diseases and neurodevelopmental disorders. Potential therapeutic interventions such as the use of new and improved chelating agents and antioxidant therapies might be a significant approach to alleviating these metal-induced glial perturbations. Full article

Background/Objectives: Glioblastoma (GBM), a highly aggressive grade IV astrocytoma, poses a major therapeutic challenge due to the resistance of cancer stem cells (CSCs) existing within its cell population to the conventional therapies. Recently, we reported that RNA interference targeting CSC protection mechanism significantly improved therapeutic efficacy. However, challenges remain, including limited transfection efficiency in neural cells and the difficulty of crossing the blood–brain barrier (BBB). Methods: In this study, we investigated the potential of exosome-mediated delivery of therapeutic cargo to GBM cells by engineering the exosomes to carry green fluorescent protein (GFP) and expressing brain-homing peptide (BHP) on their surface, which has high affinity to the neural cells. Results: We found that BHP-modified exosomes doubled GFP delivery efficacy from 20% to 40%, outperforming traditional transfection methods like lipofection in vitro. In vivo, BHP-modified exosomes demonstrated an ability to cross the BBB and targeted cargo delivery to brain regions following intranasal and subcutaneous administration. Conclusions: These results underscore the potential of engineered exosomes for efficient cargo delivery to enhance therapeutic efficacy against brain tumors and suggest novel avenues for delivering biomolecules to the brain in the treatment of neurological disorders. Full article

Microglia are exceptionally dynamic resident innate immune cells within the central nervous system, existing on a continuum of morphologies and functions throughout their lifespan. They play vital roles in response to injuries and infections, clearing cellular debris, and maintaining neural homeostasis throughout development. Emerging research suggests that microglia are strongly influenced by biological factors, including sex, developmental stage, and their local environment. This review synthesizes findings on sex differences in microglial morphology and function in key brain regions, including the frontal cortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum, across the lifespan. Where available, we examine how gonadal hormones influence these microglial characteristics. Additionally, we highlight the limitations of relying solely on morphology to infer function and underscore the need for comprehensive, multimodal approaches to guide future research. Ultimately, this review aims to advance the dialogue on these spatiotemporally heterogeneous cells and their implications for sex differences in brain function and vulnerability to neurological and psychiatric disorders. Full article

Astrocyte activation is a critical aspect of brain health and disease, and the central circadian clock protein BMAL1 has emerged as a regulator of astrogliosis and inflammatory gene expression. Bmal1 deletion in astrocytes reprograms endolysosomal transcriptional pathways, inducing endocytosis, lysosomal degradation, and autophagic activity. This regulation of proteostasis by BMAL1 implicates circadian clock proteins in neurodegenerative diseases. Studies suggest that astrocyte activation is a complex process with diverse phenotypes beyond classic markers such as GFAP, exhibiting neurotoxic and neuroprotective effects. Deletion of Bmal1 in astrocytes has shown protective effects in models of Alzheimer’s disease (AD) and Parkinson’s disease (PD), influencing Aβ accumulation and α-syn pathology, respectively, through a state of protective astrocyte activation that mitigates tauopathy and α-syn pathology, possibly through the induction of the chaperone protein BAG3. These findings suggest that BMAL1 is crucial in regulating astrocytic function and neuroprotection in neurodegenerative diseases. This review explores the relationship between circadian dysfunction and the development/progression of AD and PD. Furthermore, it recapitulates the most recent findings on manipulating the clock protein BMAL1 and its potential protective effects in astrocytes. Full article

Background: Chronic hypoperfusion is a risk factor for neurodegenerative diseases. However, the sequence of events driving ischemia-induced functional changes in a cell-specific manner is unclear. Methods: To address this gap in knowledge, we used the bilateral common carotid artery stenosis (BCAS) mouse model, and evaluated progressive functional changes to neurons, arterioles, astrocytes, and microglial cells at 14 and 28 days post-BCAS surgery. To assess the neuro-glio-vascular response to an acute ischemic insult, brain slices were superfused with low O₂ conditions. Using whole-cell patch-clamp electrophysiology, we measured basic membrane properties (e.g., resting membrane potential, capacitance, input resistance) in cortical pyramidal neurons. The activity of astrocytes was evaluated by monitoring Ca²⁺ from Aldh1l1-CreERT2; R26-lsl-GCaMP6f mice. Vascular reactivity to low O₂ from the BCAS mice was also assessed ex vivo. Results: Our data showed no changes to the basic membrane properties of cortical pyramidal neurons. On the other hand, astrocyte activity was characterized by a progressive increase in the resting Ca²⁺. Notably, at 14 and 28 days post-BCAS, there was an increased expression of anti-inflammatory-related markers (IL-10, S100A10, TRPA1, and Nrf2). These data suggest that, in young mice, BCAS-induced increases in resting Ca²⁺ were associated with the expression of neuroprotective signals. Contrary to observations in glial cells, vascular function was impaired post-BCAS surgery, as shown by a blunted vasodilatory response to low O₂ and the vasodilatory signal, adenosine. Conclusions: Together, these data suggest that, in young mice, BCAS leads to vascular dysfunction (e.g., impaired vasodilation in parenchymal arterioles), and in the absence of neuronal dysfunction, mild ischemia is associated with the activation of glial-derived neuroprotective signals. Full article

Neurodegenerative diseases represent a significant global health burden, characterized by progressive loss of neuronal function and structure. While traditionally viewed as primarily neuronal disorders, recent research has highlighted the crucial roles of neuroglia-astrocytes, microglia, and oligodendrocytes in the pathogenesis and progression of these diseases. This review explores the dual nature of glial cells in neurodegenerative processes, focusing on their protective and potentially harmful functions in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and other neurodegenerative disorders. We examine the complex interactions between different glial cell types and neurons, highlighting recent discoveries in glial-neuronal metabolic coupling, neuroinflammation, and protein aggregation. Advanced technologies, such as single-cell RNA sequencing and spatial transcriptomics, have revealed unprecedented glial heterogeneity and disease-specific glial states, reshaping our understanding of these cells’ roles in health and disease. The review also discusses emerging concepts in neuroglial research, including the role of extracellular vesicles in disease propagation, epigenetic regulation of glial function, and the application of artificial intelligence in glial biology. Finally, we explore the therapeutic implications of targeting glia in neurodegenerative diseases, addressing both the promising avenues and challenges in developing glial-focused interventions. By integrating recent advances in neuroglial research, this review provides a comprehensive overview of the field and highlights future directions for research and therapeutic development. Understanding the complex roles of neuroglia in neurodegenerative diseases is crucial for developing more effective treatments and ultimately improving patient outcomes. Full article

Parkinsonism is a clinical syndrome characterized by akinesia/bradykinesia, muscle rigidity, resting tremor, and postural instability. Within the group of parkinsonisms is Parkinson’s disease, also known as neurodegenerative parkinsonian syndrome. The group of atypical parkinsonisms was established due to the existence of sporadic parkinsonisms that do not share the exact etiology of Parkinson’s disease. Additionally, parkinsonisms that arise from causes other than neurodegeneration have been classified as secondary parkinsonisms. With this in mind, given the diversity of etiologies that can trigger parkinsonism, it is crucial to understand the symptomatology and its relationship with the basal ganglia (including damage to the nigrostriatal pathway, neuroinflammation, and neuronal damage). Only then will it be possible to propose appropriate treatments for each variant of parkinsonism. Full article