Neuroglia, Volume 5, Issue 2 (June 2024) – 10 articles

Background: Chronic neuroinflammation mediated by persistent microglial activation is strongly linked to neurodegeneration. Therefore, targeting microglial activation could be beneficial in treating neurodegenerative disorders. Angiotensin receptor blockers (ARBs), commonly prescribed for high blood pressure, exhibit prominent anti-inflammatory effects in the brain and are considered potential therapies for neurodegenerative diseases and neurotrauma. Although all ARBs are angiotensin II receptor type I antagonists, some ARBs act through other signaling pathways, allowing for multiple mechanisms of action. The anti-inflammatory mechanisms of ARBs are not well understood. Methods: In this study, we compared eight different FDA-approved ARBs for their ability to reduce the LPS stimulation of primary microglia or BV2 cells through analyses of nitric oxide production, reactive oxygen species generation, and the mRNA of proinflammatory cytokines. Finding specific and unique effects of telmisartan, we interrogated signaling pathways and other downstream effectors of telmisartan activity on microglia. Results: Our findings indicate that telmisartan showed the greatest efficacy in reducing the LPS induction of reactive oxygen species (ROS) and nitric oxide production in microglia. Uniquely amongst ARBs, telmisartan activated AMPK phosphorylation and inhibited mTOR phosphorylation. Telmisartan’s anti-inflammatory activity was partially inhibited by the AMPK inhibitor compound C. Furthermore, telmisartan uniquely induced markers of autophagy in microglia through an AMPK–mTOR–autophagy pathway. Telmisartan also reduced microglial viability. Telmisartan’s cytotoxicity was partially ameliorated by an autophagy inhibitor and a pan-caspase inhibitor, indicating a link between microglial autophagy and apoptosis. Conclusions: We conclude that telmisartan has unique properties relative to other ARBs, including potent anti-inflammatory actions and an induction of microglial autophagy, which may enable specific therapeutic uses. Full article

Background: Angiocentric glioma (AG) is a rare, benign, and slow-growing tumor. First described in 2005, it is now gaining attention with respect to the possibility of being diagnosed. Even with no statistical differences between sex, it has been reported both in children and the elderly. A total of 120 cases have been described in the literature. The aim of this study is to provide new data for a new statistical assessment of the prevalence and incidence of AG in populations. Case report: An 8-year-old male patient with no history of epilepsy and no need for antiepileptic therapy underwent surgery for a left-parietal brain lesion, revealed through MRI. Imaging was acquired after his first absence episode. The lesion was completely resected. Histological findings indicated angiocentric glioma. No signs of recurrency after two years of follow-up. Conclusion: AG is usually an epilepsy-related low-grade glioma. Few cases exhibit disease progression and exitus. Surgical management should aim for a gross total resection to avoid recurrence and persisting epilepsy. Surgery represents the gold standard in diagnosis and treatment and must be performed as soon as possible in consideration of its healing properties and its useful diagnosis. Full article

The current lack of a comprehensive understanding of brain metastasis mechanisms presents a significant gap in cancer research. This review outlines the role that Schwann cells (SCs) have in this process. SCs are already known for their role in myelination and nerve repair within the peripheral nervous system (PNS), but there is less information on their function in facilitating the transport and activation of neoplastic cells to aid in the invasion of the blood–brain barrier and brain. Detailed insights into SCs’ interactions with various cancers, including lung, breast, melanoma, colon, kidney, and pancreatic cancers, reveal how these cells are coerced into repair-like phenotypes to accelerate cancer spread and modulate immune responses. By outlining SCs’ involvement in perineural invasion and BBB modification, this review highlights their functions in facilitating brain metastasis. Full article

Glioma, a highly aggressive cancer, presents a daunting prognosis, with only 5% of glioblastoma patients surviving beyond five years post diagnosis. Current therapeutic strategies, including surgical intervention, radiotherapy, chemotherapy, and immune checkpoint blockade (ICB), while promising, often encounter limited efficacy, particularly in glioblastoma cases. Addressing this challenge requires a proactive approach to anticipate treatment response and resistance. In this study, we analyzed 117 glioma patients who underwent ICB treatment to uncover the mechanisms underlying treatment resistance. Through a meticulous examination of mutational profiles post ICB, we identified several mutations associated with varied survival outcomes. Notably, mutations such as STAG2 Missense, EGFR A289V Missense, TP53 Nonsense, and RB1 FS del were linked to prolonged overall survival, while others, including IF del, FAT1 E1206Tfs*4 FS del, PDGFRA FS del, PIK3R1 M326Vfs*6 FS del, Y463* Nonsense, NF1 Missense, and R1534*, were associated with poorer survival post ICB. Leveraging these insights, we employed machine learning algorithms to develop predictive models. Remarkably, our model accurately forecasted glioma patient survival post ICB within an error of 4 months based on their distinct mutational profiles. In conclusion, our study advocates for personalized immunotherapy approaches in glioma patients. By integrating patient-specific attributes and computational predictions, we present a promising avenue for optimizing clinical outcomes in immunotherapy. Full article

Several protocols have been developed with the aim of characterizing glial and immune cells from the central and peripheral nervous systems. However, a small number of these protocols have demonstrated the ability to yield satisfactory results following conventional isolation. Considering this necessity and the difficulties encountered in enzymatic and bead isolation, our work proposes a method for the isolation of glial and immune cells from the spinal cord utilizing a Percoll gradient. For this purpose, C57BL/6J spinal cords were dissected, and the lumbar intumescence was dissociated and subjected to a Percoll gradient centrifugation (70%, 50%, 37%, and 10%). Each layer was then separated and labeled for astrocytes (anti-GFAP, TNF-α, IFN-γ, IL-10, IL-4), microglia (anti-CD45, CD11b, CD206, CD68, TNF-α, IFN-γ), and lymphocytes (anti-CD3, CD4, IFN-γ, IL-4). The gate detections were mathematically performed by computational analysis utilizing the K-means clustering algorithm. The results demonstrated that astrocytes were concentrated at the Percoll 10/37 interface, microglia at the Percoll 37/50 layer, and lymphocytes at the Percoll 50/70 layer. Our findings indicate that astrocytes in healthy animals are putative of the A1 profile, while microglia and lymphocytes are more frequently labeled with M1 and Th1 markers, suggesting a propensity towards inflammatory responses. The computational method enabled the semi-autonomous gate detection of flow cytometry data, which might facilitate and expedite the processing of large amounts of data. Full article

Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are clinically distinct, yet share synaptic dysfunction as a common brain pathophysiology. Neurodegenerative diseases such as Huntington’s disease (HD) entail a neuroinflammatory cascade of molecular and cellular events which can contribute to the death of neurons. Emerging roles for supportive glial cells such as microglia and astrocytes in the ongoing regulation of neural synapses and brain excitability raise the possibility that some of the synaptic pathology and/or inflammatory events could be a direct consequence of malfunctioning glial cells. Focusing on microglia, we cross-examined 12 recently published studies in which microglial dysfunction was induced/identified in a cell-autonomous manner and its functional consequence on neural development, brain volume, functional connectivity, inflammatory response and synaptic regulation were evaluated; in many cases, the onset of symptoms relevant to all three neurodevelopmental disorders were assessed behaviorally. Challenging the classic notion of microglial activation as an inflammatory response to neuropathology, our compilation clarifies that microglial dyshomeostasis itself can consequently disrupt neural homeostasis, leading to neuropathology and symptom onset. This further warranted defining the molecular signatures of context-specific microglial pathology relevant to human diseases. Full article

Brain tumors necessitate swift detection and classification for optimal patient outcomes. Deep learning has been extensively utilized to recognize complex tumor patterns in magnetic resonance imaging (MRI) images, aiding in tumor diagnosis, treatment, and prognostication. However, model complexity and limited generalizability with unfamiliar data hinder appropriate clinical integration. The objective of this study is to develop a clean-energy cloud-based deep learning platform to classify brain tumors. Three datasets of a total of 2611 axial MRI images were used to train our multi-layer convolutional neural network (CNN). Our platform automatically optimized every transfer learning and data augmentation feature combination to provide the highest predictive accuracy for our classification task. Our proposed system identified and classified brain tumors successfully and efficiently with an overall precision value of 96.8% [95% CI; 93.8–97.6]. Using clean energy supercomputing resources and cloud platforms cut our workflow to 103 min, $0 in total cost, and a negligible carbon footprint (0.0014 kg eq CO₂). By leveraging automated optimized learning, we developed a cost-effective deep learning (DL) platform that accurately classified brain tumors from axial MRI images of different levels. Although studies have identified machine learning tools to overcome these obstacles, only some are cost-effective, generalizable, and usable regardless of experience. Full article

The traditional neuron-centric view of the central nervous system (CNS) is shifting toward recognizing the importance of communication between the neurons and the network of glial cells. This shift is leading to a more comprehensive understanding of how glial cells contribute to CNS function. Alongside this shift, recent discoveries have illuminated the significant role of the human microbiome, comprising trillions of microorganisms, mirroring the number of human cells in an individual. This paper delves into the multifaceted functions of neuroglia, or glial cells, which extend far beyond their traditional roles of supporting and protecting neurons. Neuroglia modulate synaptic activity, insulate axons, support neurogenesis and synaptic plasticity, respond to injury and inflammation, and engage in phagocytosis. Meanwhile, the microbiome, long overlooked, emerges as a crucial player in brain functionality akin to glial cells. This review aims to underscore the importance of the interaction between glial cells and resident microorganisms in shaping the development and function of the human brain, a concept that has been less studied. Through a comprehensive examination of existing literature, we discuss the mechanisms by which glial cells interface with the microbiome, offering insights into the contribution of this relationship to neural homeostasis and health. Furthermore, we discuss the implications of dysbiosis within this interaction, highlighting its potential contribution to neurological disorders and paving the way for novel therapeutic interventions targeting both glial cells and the microbiome. Full article

Glioblastoma (GBM) is the predominant primary malignant brain tumor. Metformin, a well-known antidiabetic medication, has emerged as a potential therapeutic candidate in the treatment of GBM. We have herein investigated two aspects of the effect of MTF on GBM cells: the effect of MTF on GBM cell viability, as previous studies have shown that MTF can selectively affect human GBM tumors; and the immunomodulatory effect of MTF on GBM, as there is evidence that inflammation is associated with GBM growth and progression. The human GBM cell line (U87) was exposed to various doses of MTF (1 mM, 20 mM, and 50 mM), followed by examination of cell viability and inflammatory mediator secretion at various time points. We observed that MTF treatment exerted a dose-response effect on glioblastoma multiforme cell viability. It also had an immunomodulatory effect on GBM cells. Our study identified several mechanisms that led to the overall inhibitory effect of MTF on human GBM. Further inquiry is necessary to gain a better understanding of how these in vitro findings would translate into successful in vivo approaches. Full article

Glioblastoma is a highly aggressive brain tumor that has a poor prognosis despite various treatments like surgery, chemotherapy, and irradiation. However, a restricted ketogenic diet (RKD), which has been proven to be effective in treating drug-resistant epilepsy, could be a potential adjunct in the treatment of certain GBM cases. Our study aimed to highlight the existing knowledge, identify collaboration networks, and emphasize the ongoing research based on highly cited studies. During the literature search, we found 119 relevant articles written between 2010 and 2023. Among the top 20 most cited articles, there were seven laboratory and five clinical studies. The works of Olson LK, Chang HT, Schwartz KA, and Nikolai M from the Michigan State University, followed by Seyfried TN and Mukherjee P from Boston College, and Olieman JF, and Catsman-Berrevoets CE from the University Medical Center of Rotterdam, were significant contributions. The laboratory studies showed that RKD had a significant antitumor effect and could prolong survival in mouse glioblastoma models. The clinical studies verified the tolerability, efficacy, and safety of RKD in patients with GBM, but raised concerns about whether it could be used as a single therapy. The current research interest is focused on the efficacy of using RKD as an adjunct in selected chemotherapy regimens and demonstrates that it could provide GBM patients with better treatment options. Full article