Changes In Glial Cells Research Articles

Dynamics of ultrastructural changes in glial cells and nerve fibers of the optic nerve of rats after intra-abdominal injection of a mixture of 40% Ethanol solution and 100% Methanol

There are, quite often, cases of poisoning of human population with poor-quality alcoholic drinks, which include methanol. The optic nerve, retina and brain tissues are initially affected. A long-term study aimed at identifying initial structural changes in the visual analyzer in the application of various doses of methanol and its mixture with ethanol was carried out. Purpose: to study the dynamics of ultrastructural changes in glial cells and nerve fibers of the optic nerve, which are caused by mixture of ethanol 40% and methanol 100% in a ratio of 3:1 with a dose of methanol of 0.75 g/kg of rat weight. We examined the ultrastructure of the orbit part of the optic nerve of 43 adult rats (Wistar line) in the period from 3 hours to 14 days after one-time intra-abdominal injection of ethanol 40% and methanol 100%, 100% methanol, the dose of methanol is 0.75 g/kg of rat weight. In rats, LD50 is 9.5 g/kg of their weight. It was found out, that within 3 hours after the injection of the mixture of alcohols, the myelin sheath of large-caliber nerve fibers exfoliated, the axoplasm swelled and the mitochondria in their axons pathologically changed, the mitochondria altered in glial cells, which influenced the quality of nerve impulses and axoplasmic transport of substances. In the dynamics of the study, alterative changes in structures of the optic nerve progressed with the complete destruction of part of glial cells by 7 days, mainly in the first 3 days. After the use of methanol 100%, changes in structures of the optic nerve were similar to changes in them after the use of a mixture of alcohols, but with more significant pathology at all periods of observation with the peak of their manifestation on the 7th day. In glial cells and axons of nerve fibers from the 1st day of the study, signs of compensatory and restorative processes were found: they increased protein-synthesizing and energy-forming functions that were aimed at restoring the damaged ultrastructure. It is established, that 3 hours after the injection of a mixture of alcohols, reactive changes in the structures of the optic nerve of rats took place, which from the 1st day develop into pathological changes and are observed up to 14 days with the peak of their activity on the 7th day of the study. After the use of methanol 100%, the ultrastructure of the optic nerve of rats is more damaged than after the injection of a mixture of alcohols. It is proved, that methanol has a leading place in the development of pathological changes in structures of the optic nerve after the injection of a mixture of alcohols.

Histochemistry of microinfarcts in the mouse brain after injection of fluorescent microspheres into the common carotid artery.

The mouse model of multiple cerebral infarctions, established by injecting fluorescent microspheres into the common carotid artery, is a recent development in animal models of cerebral ischemia. To investigate its effectiveness, mouse models of cerebral infarction were created by injecting fluorescent microspheres, 45-53 µm in diameter, into the common carotid artery. Six hours after modeling, fluorescent microspheres were observed directly through a fluorescence stereomicroscope, both on the brain surface and in brain sections. Changes in blood vessels, neurons and glial cells associated with microinfarcts were examined using fluorescence histochemistry and immunohistochemistry. The microspheres were distributed mainly in the cerebral cortex, striatum and hippocampus ipsilateral to the side of injection. Microinfarcts were found in the brain regions where the fluorescent microspheres were present. Here the lodged microspheres induced vascular and neuronal injury and the activation of astroglia and microglia. These histopathological changes indicate that this animal model of multiple cerebral infarctions effectively simulates the changes of various cell types observed in multifocal microinfarcts. This model is an effective, additional tool to study the pathogenesis of ischemic stroke and could be used to evaluate therapeutic interventions. This study was approved by the Animal Ethics Committee of the Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences (approval No. D2021-03-16-1) on March 16, 2021.

Agricultural groundwater with high nitrates and dissolved salts given to pregnant mice alters brain development in the offspring

Groundwater is the main source of drinking water for a significant portion of the human population. In many agricultural areas, diffuse pollution such as high levels of total dissolved salts including nitrate, puts the quality of this resource at risk. However, the effect of exposure to these water contaminants on brain development is currently poorly understood. Here we characterised water from a borewell located in an intensely cultivated area (agricultural) or water from a borewell located in a nearby pristine forest. The agricultural borewell water was rich in nitrates with high total dissolved salts. We then studied the consequence of drinking the agricultural water on mouse brain development. For this, the agricultural borewell water or forest water was given to mice for 6 weeks before and during pregnancy and lactation. The brains of the offspring born to these dams were analysed at postnatal day (P)5 and P21 and compared using immunohistochemistry for changes in glial cells, neurons, myelin, and cell death across many brain regions. Brains from offspring born to dams who had been given agricultural water (versus forest control water) were significantly smaller, and at P21 had a significant degeneration of neurons and increased numbers of microglia in the motor cortex, had fewer white matter astrocytes and an increase in cell death, particularly in the dentate gyrus. This study shows that brain development is sensitive to water composition. It points to the importance of assessing neurodevelopmental delays when considering the effect of water contaminated with agricultural run offs on human health. Main findingPregnant and lactating mice were given borewell water from intensely cultivated land. Offspring brains reveal degeneration of neurons and a loss of astrocytes, increase in microglial cells and cell death, pointing to neurodevelopmental problems.

Pathogenesis of Neurological and Mental Disorders in Patients with Covid-19: Possible Role of Reactive Nitrogen and Oxygen Species

The pathogenesis of neuronal and mental disorders are analyzed according to the literature and compared with other neuronal damage during hypoxia/ischemia, inflammatory processes, and immune/autoimmune diseases. The free radical component of the development of the pathogenesis of COVID-19 is analyzed, which is activated at all stages of the disease, starting with the first manifestations of inflammatory reactions, during the development of a «cytokine storm», hypoxia/ischemia, as well as activation of immune/autoimmune reactions and processes. These free radical components are realized against the background of disruption of the cycles of nitric oxide and superoxide anion radical, and, leads to the formation of extremely high concentrations of very active radicals of nitrogen dioxide (NO2 ), OH-radicals, peroxynitrites. As a result of these processes, nonspecific reactions are activated that are characteristic of the development of any typical pathological process, which is a common component of almost all known pathological processes. It is suggested that the similarity of structural and ultrastructural changes in neurons and glial cells of the brain during hypoxia/ischemia, glutamate neurotoxicity, traumatic brain injury have similarities with those changes that are characteristic of all stages of COVID-19 development and are due to the activation of oxidative and nitrosative stress and increased formation of highly reactive nitrogen species (RNS) and reactive oxygen species (ROS) capable of damaging almost all molecular, biochemical and chemical components of cells.

Long-Lasting Changes in Glial Cells Isolated From Rats Subjected to the Valproic Acid Model of Autism Spectrum Disorder.

Synaptic alterations concomitant with neuroinflammation have been described in patients and experimental models of autism spectrum disorder (ASD). However, the role of microglia and astroglia in relation to synaptic changes is poorly understood. Male Wistar rats prenatally exposed to valproic acid (VPA, 450 mg/kg, i.p.) or saline (control) at embryonic day 10.5 were used to study synapses, microglia, and astroglia in the prefrontal cortex (PFC) at postnatal days 3 and 35 (PND3 and PND35). Primary cultures of cortical neurons, microglia, and astroglia isolated from control and VPA animals were used to study each cell type individually, neuron-microglia and microglia-astroglia crosstalk. In the PFC of VPA rats, synaptic changes characterized by an increase in the number of excitatory synapses were evidenced at PND3 and persisted until PND35. At PND3, microglia and astroglia from VPA animals were morphologically similar to those of age-matched controls, whereas at PND35, reactive microgliosis and astrogliosis were observed in the PFC of VPA animals. Cortical neurons isolated from VPA rats mimicked in vitro the synaptic pattern seen in vivo. Cortical microglia and astroglia isolated from VPA animals exhibited reactive morphology, increased pro-inflammatory cytokines, and a compromised miRNA processing machinery. Microglia from VPA animals also showed resistance to a phagocytic challenge. In the presence of neurons from VPA animals, microglia isolated from VPA rats revealed a non-reactive morphology and promoted neurite outgrowth, while microglia from control animals displayed a reactive profile and promoted dendritic retraction. In microglia-astroglia co-cultures, microglia from VPA animals displayed a reactive profile and exacerbated astrocyte reactivity. Our study indicates that cortical microglia from VPA animals are insensitive or adapted to neuronal cues expressed by neurons from VPA animals. Further, long-term in vivo microgliosis could be the result of altered microglia-astroglia crosstalk in VPA animals. Thus, our study highlights cortical microglia-astroglia communication as a new mechanism implicated in neuroinflammation in ASD; consequently, we propose that this crosstalk is a potential target for interventions in this disorder.

Neuroprotective Effect of Taurine against Cell Death, Glial Changes, and Neuronal Loss in the Cerebellum of Rats Exposed to Chronic-Recurrent Neuroinflammation Induced by LPS.

The present study investigated the neuroprotective effect of taurine against the deleterious effects of chronic-recurrent neuroinflammation induced by LPS in the cerebellum of rats. Adult male Wistar rats were treated with taurine for 28 days. Taurine was administered at a dose of 30 or 100 mg/kg, by gavage. On days 7, 14, 21, and 28, the animals received LPS (250 μg/kg) intraperitoneally. The vehicle used was saline. The animals were divided into six groups: vehicle, taurine 30 mg/kg, taurine 100 mg/kg, LPS, LPS plus taurine 30 mg/kg, and LPS plus taurine 100 mg/kg. On day 29, the animals were euthanized, and the cerebellum was removed and prepared for immunofluorescence analysis using antibodies of GFAP, NeuN, CD11b, and cleaved caspase-3. LPS group showed a reduction in the immunoreactivity of GFAP in the arbor vitae and medullary center and of NeuN in the granular layer of the cerebellar cortex. LPS increased the immunoreactivity of CD11b in the arbor vitae and in the medullary center. Taurine protected against these effects induced by LPS in immunoreactivity of GFAP, NeuN, and CD11b, with the 100 mg/kg dose being the most effective. LPS induced an increase in the number of positive cleaved caspase-3 cells in the Purkinje cell layers, granular layer, arbor vitae, and medullary center. Taurine showed its antiapoptotic activity by reducing the cleaved caspase-3 cells in relation to the LPS group. Here, a potential neuroprotective role of taurine can be seen since this amino acid was effective in protecting the cerebellum of rats against cell death and changes in glial and neuronal cells in the face of chronic-recurrent neuroinflammation.

Single Nuclear RNA Sequencing Reveals Activation of Neuroinflammation Within the Pre‐Bötzinger Complex Following Repeated Seizures

Epilepsy is one of the most common neurological diseases in the world. Treatment with anti-epileptic drugs (AEDs) prevents recurrent seizures in ~70% of patients with epilepsy, but the remaining 30% of patients with refractory epilepsies continue to experience seizures. The consequences of repeated seizures include but are not limited to memory impairments and a high risk of post-ictal cardiorespiratory failure, and Sudden Unexpected Death in Epilepsy (SUDEP). Fundamental gaps exist in understanding how repeated seizures disrupt the vital cardiorespiratory control system and neural networks facilitating memory formation in refractory epilepsy. A factor commonly identified in many neurological conditions is neuroinflammation, which may support beneficial health functions but is dysregulated in neurological disease. Key cells within the CNS that mediate beneficial and/or pathological neuroinflammation are resident microglia and astrocytes, which have been shown to be dysfunctional in human epilepsy and alter neuronal function. However, it is not known what mechanistic role they play in contributing to epilepsy-related memory impairment, impairment in cardiorespiratory control, or increased SUDEP risk. Here, we tested the hypothesis that repeated seizures lead to activation of neuroinflammation mediated by microglia and astrocytes in CNS regions of memory and ventilatory control, leading to a progressive decline in neurologic function. Preliminary data in our novel rat model with genetic mutations in Kcnj16, a gene encoding an inwardly-rectifying potassium channel Kir5.1 in Dahl salt-sensitive rat (SSkcnj16-/) show that repeated sound-induced seizures lead to a progressively more severe post-ictal suppression of breathing frequency and heart rate, and impaired memory. Single nuclear RNA sequencing of pre-Bötzinger Complex/nucleus ambiguous cells was performed from rats exposed to 0, 3, 7, or 10 seizures to measure cell type-specific gene expression changes induced by seizures. Bioinformatic analyses of transcriptomic changes in microglia, neuronal, and glial cells within these regions point to activation of specific inflammatory pathways following repeated seizures such as IL-1Beta signaling and Toll-like Receptor signaling. Identifying neuroinflammatory signals/pathways induced by repeated seizures within distinct neural circuits will enhance understanding of pathophysiological consequences of uncontrolled seizures in patients with refractory epilepsy and hold the potential for identifying new therapeutic targets aimed at improving memory and cardiorespiratory function to reduce the risk of SUDEP.

Human brain pathology in myotonic dystrophy type 1: A systematic review.

Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974–2017) and MEDLINE (index period 1887–2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full‐text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.

Scutellaria barbata Flavonoids Improve the Composited Aβ-induced Abnormal Changes in Glial Cells of the Brains of Rats.

It has been reported that glial cells are involved in Alzheimer's disease (AD). In our previous research, Scutellaria barbata flavonoids (SBFs) were found to protect the AD-like rats from neuronal disorder and memory impairment; however, the effect of SBFs on the glial cells disorder in AD-like rats has been less studied. The effects of SBFs on astrocytes (ASs), microglial cells (MGs), and oligodendrocytes (Ols), as well as heat shock protein 70 (Hsp70) and apolipoprotein E (ApoE), were investigated in the present study. The successful model rats, screened by Morris water maze, were orally administrated daily with 35, 70, and 140 mg/kg SBFs for 36 d. The number of brain astrocytes (ASs), microglial cells (MGs), and oligodendrocytes (Ols) was examined by immunohistochemistry. The expressions of cortical glial fibrillary acidic protein (GFAP), leukocyte common antigen (LCA) (CD45), Claudin 11, and heat shock protein 70 (Hsp70) protein were assayed by Western blotting, and the expression of apolipoprotein E (ApoE) mRNA was analyzed by real-time quantitative polymerase chain reaction (qPCR). Compared with the sham-operated group, the number of ASs and MGs in the brain was significantly increased in the model group (P<0.05, P<0.01), accompanied by an increase in the expressions of GFAP, CD45, Hsp70 protein, and ApoE mRNA (P<0.05, P<0.01). Both Ols number and the expression of Claudin 11 protein decreased in the brain in the model group (P<0.05, P<0.01). However, the above-mentioned abnormal changes induced by composited Aβ were differently reversed by the treatment of SBFs at three doses of 35, 70, and 140 mg/kg (P<0.05, P<0.01). SBFs can dramatically improve the abnormal changes in glial cells of the brains of rats, induced by composited Aβ, which may be utilized as a helpful treatment for neurodegenerative diseases.

Inhibitors of Src Family Kinases, Inducible Nitric Oxide Synthase, and NADPH Oxidase as Potential CNS Drug Targets for Neurological Diseases.

Neurological diseases share common neuroinflammatory and oxidative stress pathways. Both phenotypic and molecular changes in microglia, astrocytes, and neurons contribute to the progression of disease and present potential targets for disease modification. Src family kinases (SFKs) are present in both neurons and glial cells and are upregulated following neurological insults in both human and animal models. In neurons, SFKs interact with post-synaptic protein domains to mediate hyperexcitability and neurotoxicity. SFKs are upstream of signaling cascades that lead to the modulation of neurotransmitter receptors and the transcription of pro-inflammatory cytokines as well as producers of free radicals through the activation of glia. Inducible nitric oxide synthase (iNOS/NOS-II) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), the major mediators of reactive nitrogen/oxygen species (RNS/ROS) production in the brain, are also upregulated along with the pro-inflammatory cytokines following neurological insult and contribute to disease progression. Persistent neuronal hyperexcitability, RNS/ROS, and cytokines can exacerbate neurodegeneration, a common pathognomonic feature of the most prevalent neurological disorders such as Alzheimer's disease, Parkinson's disease, and epilepsy. Using a wide variety of preclinical disease models, inhibitors of the SFK-iNOS-NOX2 signaling axis have been tested to cure or modify disease progression. In this review, we discuss the SFK-iNOS-NOX2 signaling pathway and their inhibitors as potential CNS targets for major neurological diseases.

Food-Origin Mycotoxin-Induced Neurotoxicity: Intend to Break the Rules of Neuroglia Cells.

Mycotoxins are key risk factors in human food and animal feed. Most of food-origin mycotoxins could easily enter the organism and evoke systemic toxic effects, such as aflatoxin B1 (AFB1), ochratoxin A (OTA), T-2 toxin, deoxynivalenol (DON), zearalenone (ZEN), fumonisin B1 (FB1), and 3-nitropropionic acid (3-NPA). For the last decade, the researches have provided much evidences in vivo and in vitro that the brain is an important target organ on mycotoxin-mediated neurotoxic phenomenon and neurodegenerative diseases. As is known to all, glial cells are the best regulator and defender of neurons, and a few evaluations about the effects of mycotoxins on glial cells such as astrocytes or microglia have been conducted. The fact that mycotoxin contamination may be a key factor in neurotoxicity and glial dysfunction is exactly the reason why we reviewed the activation, oxidative stress, and mitochondrial function changes of glial cells under mycotoxin infection and summarized the mycotoxin-mediated glial cell proliferation disorders, death pathways, and inflammatory responses. The purpose of this paper is to analyze various pathways in which common food-derived mycotoxins can induce glial toxicity and provide a novel perspective for future research on the neurodegenerative diseases.

Lycopene supplementation protects vascular dementia gerbils against the impairment of learning and memory.

In this study, we investigated the neuroprotective effects of lycopene (Lyc) on vascular dementia (VaD) gerbils and its related mechanisms of anti-inflammatory, anti-apoptotic and anti-oxidant activity. Gerbils were treated with bilateral common carotid arteries. Animals were divided into 1) Sham, 2) VaD model, and 3) VaD model + Lyc (20 mg/kg) groups. Each group (3) was administered intergalactic Lyc twice a day for 28 days. Morris water mazes were used to evaluate learning and memory ability. Nissl, NeuN, and GFAP staining were used to observe histomorphologicalchanges of neural and glial cells in the hippocampus CA1 region. Western blotting was used to detect hippocampus caspase-3, B-cell lymphoma-2 (Bcl-2), Bcl-2 related × protein (Bax), and interleukin (IL)-1, IL-6 and tumour necrosis factor a (TNF-a) expression amongst other inflammatory factors. Secreted IL-1, IL-6 and TNF-a levels were assessed by ELISA in addition to superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), glutathione (GSH) and malondialdehyde (MDA). We found that Lyc increased the learning and memory ability of gerbils by reducing the latency time in the Morris water maze, and increasing spatial memory. Lyc also reduced pathological changes in the hippocampus caused by VaD, reduced apoptosis, and decreased VaD mediated Bcl-2/Bax expression. The levels of inflammatory factors and oxidative stress were also reduced by Lyc in the VaD models. We therefore conclude that Lyc can improve the learning and memory ability of VaD gerbils, the mechanism of which may be related to reduced oxidative stress and apoptosis in VaD hippocampus neurons.

Cortical transcriptome analysis after spinal cord injury reveals the regenerative mechanism of central nervous system in CRMP2 knock-in mice.

Recent studies have shown that mutation at Ser522 causes inhibition of collapsin response mediator protein 2 (CRMP2) phosphorylation and induces axon elongation and partial recovery of the lost sensorimotor function after spinal cord injury (SCI). We aimed to reveal the intracellular mechanism in axotomized neurons in the CRMP2 knock-in (CRMP2KI) mouse model by performing transcriptome analysis in mouse sensorimotor cortex using micro-dissection punching system. Prior to that, we analyzed the structural pathophysiology in axotomized or neighboring neurons after SCI and found that somatic atrophy and dendritic spine reduction in sensorimotor cortex were suppressed in CRMP2KI mice. Further analysis of the transcriptome has aided in the identification of four hemoglobin genes Hba-a1, Hba-a2, Hbb-bs, and Hbb-bt that are significantly upregulated in wild-type mice with concomitant upregulation of genes involved in the oxidative phosphorylation and ribosomal pathways after SCI. However, we observed substantial upregulation in channel activity genes and downregulation of genes regulating vesicles, synaptic function, glial cell differentiation in CRMP2KI mice. Moreover, the transcriptome profile of CRMP2KI mice has been discussed wherein energy metabolism and neuronal pathways were found to be differentially regulated. Our results showed that CRMP2KI mice displayed improved SCI pathophysiology not only via microtubule stabilization in neurons, but also possibly via the whole metabolic system in the central nervous system, response changes in glial cells, and synapses. Taken together, we reveal new insights on SCI pathophysiology and the regenerative mechanism of central nervous system by the inhibition of CRMP2 phosphorylation at Ser522. All these experiments were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee at Waseda University, Japan (2017-A027 approved on March 21, 2017; 2018-A003 approved on March 25, 2018; 2019-A026 approved on March 25, 2019).

Whole body vibration training improves depression-like behaviors in a rat chronic restraint stress model

Major depressive disorder (MDD) is a prevalent psychiatric disorder that brings great harm and burden to both patients and society. This study aimed to examine the effects of whole-body vibration (WBV) training on a chronic restraint stress (CRS) induced depression rat model and provide an initial understanding of related molecular mechanisms. Adult Sprague-Dawley male rats were randomly divided into the following three groups: a) control group, b) depressive disorder group, and c) depression with WBV training treatment group. Daily food intake, body weight, sucrose preference test, open field test, elevated plus maze, forced swimming test, and Barnes maze task tests were performed. Immunofluorescence staining and ELISA analysis were used to assess neuronal damage, synaptic proteins, glial cells, and trophic factors. The data of behavioral tests and related biochemical indicators were statistically analyzed and compared between groups. Rats undergoing CRS showed increased anxiety-like behavior and memory impairment, along with synaptic atrophy and neuronal degeneration. WBV could reverse behavioral dysfunction, inhibit the degeneration of neurons, alleviate the damage of neurons and the pathological changes of glial cells, enhance trophic factor expression, and ameliorate the downregulation of dendritic and synaptic proteins after CRS. The effect of WBV in rats may be mediated via the reduction of hippocampal neuronal degeneration and by improving expression of synaptic proteins. WBV training exerts multifactorial benefits on MDD that supports its use as a promising new therapeutic option for improving depression-like behaviors in the depressive and/or potentially depressive.

In vitro priming response in dorsal root ganglia partially mimics injury-driven pre-conditioning response and reprograms neurons for enhanced outgrowth

Peripheral nerve injuries have the potential to bring about long-term disabilities in individuals. The major issue in repairing nerve injuries is the poor growth rate of axons. Although several molecules have been identified as potential candidates for improving axon growth, their potential translation into clinical practice is preliminary and largely unexplored. This necessitates identifying additional molecular candidates with superior potential to improve axon growth. Lack of a simple non-surgical screening model also poses a hurdle in rapidly screening potential candidate molecules. In this work, we developed a novel, rapid screening model for nerve regeneration therapeutics that retains a focus on adult neurons. The model involves simple incubation of sensory ganglia over a period of 24 h prior to dissociation. Surprisingly, this model features unique events that reprogram both sensory neurons and supporting glia favoring axon growth. Moreover, several associated cellular and molecular changes involved in this model partially mimic classic axotomy-induced changes in sensory ganglia. Overall, this model presents with a platform that not only allows rapid screening of drug candidates but offers opportunities in studying novel intrinsic molecular changes in both neurons and glial cells directed towards improving the pace of axon growth.

Regulation and role of Acyl-CoA synthetase 4 in glial cells

Acyl-CoA synthetase 4 (Acsl4), an enzyme involved in arachidonic acid (AA) metabolism, participates in physiological and pathological processes such as steroidogenesis and cancer. The role of Acsl4 in neurons and in nervous system development has also been documented but little is known regarding its functionality in glial cells. In turn, several processes in glial cells, including neurosteroidogenesis, stellation and AA uptake, are regulated by cyclic adenosine monophosphate (cAMP) signal. In this context, the aim of this work was to analyze the expression and functional role of Acsl4 in primary rat astrocyte cultures and in the C6 glioma cell line by chemical inhibition and stable silencing, respectively. Results show that Acsl4 expression was regulated by cAMP in both models and that cAMP stimulation of steroidogenic acute regulatory protein mRNA levels was reduced by Acsl4 inhibition or silencing. Also, Acsl4 inhibition reduced progesterone synthesis stimulated by cAMP and also affected cAMP-induced astrocyte stellation, decreasing process elongation and increasing branching complexity. Similar effects were observed for Acsl4 silencing on cAMP-induced C6 cell morphological shift. Moreover, Acsl4 inhibition and silencing reduced proliferation and migration of both cell types. Acsl4 silencing in C6 cells reduced the capacity for colony proliferation and neurosphere formation, the latter ability also being abolished by Acsl4 inhibition. In sum, this work presents novel evidence of Acsl4 involvement in neurosteroidogenesis and the morphological changes of glial cells promoted by cAMP. Furthermore, Acsl4 participates in migration and proliferation, also affecting cell self-renewal. Altogether, these findings provide insights into Acsl4 functions in glial cells.

The osmotic demyelination syndrome: the resilience of thalamic neurons is verified with transmission electron microscopy

ABSTRACT The development of a murine model of osmotic demyelinating syndrome (ODS) allowed to study changes incurred in extrapontine zones of the CNS and featured neuron and glial cell changes in the relay thalamic ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei before, during and after ODS induction, and characterized without immune response. There, the neuron Wallerian-type deteriorations were verified with fine structure modifications of the neuron cell body, including some nucleus topology and its nucleolus changes. Morphologic analyses showed a transient stoppage of transcriptional activities while myelinated axons in the surrounding neuropil incurred diverse damages, previously reported. Even though the regional thalamus myelin deterioration was clearly recognized with light microscopy 248 h after osmotic recovery of ODS, ultrastructure analyses demonstrated that, at that time, the same damaged parenchyma regions contained nerve cell bodies that have already reactivated nucleus transcriptions and neuroplasm translations because peculiar accumulations of fibro-granular materials, similar to those detected in restored ODS astrocytes, were revealed in these restructuring nerve cell bodies. Their aspects suggested to be accumulations of ribonucleoproteins. The findings suggested that progressive neural function’s recovery in the murine model could imitate some aspects of human ODS recovery cases.

Temporal In Vitro Raman Spectroscopy for Monitoring Replication Kinetics of Epstein-Barr Virus Infection in Glial Cells.

Raman spectroscopy can be used as a tool to study virus entry and pathogen-driven manipulation of the host efficiently. To date, Epstein–Barr virus (EBV) entry and altered biochemistry of the glial cell upon infection are elusive. In this study, we detected biomolecular changes in human glial cells, namely, HMC-3 (microglia) and U-87 MG (astrocytes), at two variable cellular locations (nucleus and periphery) by Raman spectroscopy post-EBV infection at different time points. Two possible phenomena, one attributed to the response of the cell to viral attachment and invasion and the other involved in duplication of the virus followed by egress from the host cell, are investigated. These changes corresponded to unique Raman spectra associated with specific biomolecules in the infected and the uninfected cells. The Raman signals from the nucleus and periphery of the cell also varied, indicating differential biochemistry and signaling processes involved in infection progression at these locations. Molecules such as cholesterol, glucose, hyaluronan, phenylalanine, phosphoinositide, etc. are associated with the alterations in the cellular biochemical homeostasis. These molecules are mainly responsible for cellular processes such as lipid transport, cell proliferation, differentiation, and apoptosis in the cells. Raman signatures of these molecules at distinct time points of infection indicated their periodic involvement, depending on the stage of virus infection. Therefore, it is possible to discern the details of variability in EBV infection progression in glial cells at the biomolecular level using time-dependent in vitro Raman scattering.

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis.

Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

Interleukin 4 Affects Epilepsy by Regulating Glial Cells: Potential and Possible Mechanism

Epilepsy is a chronic brain dysfunction induced by an abnormal neuronal discharge that is caused by complicated psychopathologies. Recently, accumulating studies have revealed a close relationship between inflammation and epilepsy. Specifically, microglia and astrocytes are important inflammatory cells in the central nervous system (CNS) that have been proven to be related to the pathogenesis and development of epilepsy. Additionally, interleukin 4 (IL-4) is an anti-inflammatory factor that can regulate microglia and astrocytes in many aspects. This review article focuses on the regulatory role of IL-4 in the pathological changes of glial cells related to epilepsy. We additionally propose that IL-4 may play a protective role in epileptogenesis and suggest that IL-4 may be a novel therapeutic target for the treatment of epilepsy.