Glial Cell Injury Research Articles

Glial cell injury and atrophied lesion volume as measures of chronic multiple sclerosis inflammation

BackgroundAtrophied lesion volume (aLV), a proposed biomarker of disability progression in multiple sclerosis (MS) and transition into progressive MS (PMS), depicts chronic periventricular white matter (WM) pathology. Meningeal infiltrates, imaged as leptomeningeal contrast enhancement (LMCE), are linked with greater cortical pathology. ObjectivesTo determine the relationship between serum-derived proteomic data with the development of aLV and LMCE in a heterogeneous group of people with MS (pwMS). MethodsProteomic and MRI data for 202 pwMS (148 clinically isolated syndrome /relapsing-remitting MS and 54 progressive MS (PMS)) were acquired at baseline and at 5.4-year follow-up. The concentrations of 21 proteins related to multiple MS pathophysiology pathways were derived using a custom-developed Proximity Extension Assay on the Olink™ platform. The accrual of aLV was determined as the volume of baseline T2-weighted lesions that were replaced by cerebrospinal fluid over the follow-up. Regression models and age-adjusted analysis of covariance (ANCOVA) were used. ResultsOlder age (standardized beta = 0.176, p = 0.022), higher glial fibrillary acidic protein (standardized beta = 0.312, p = 0.001), and lower myelin oligodendrocyte glycoprotein levels (standardized beta = −0.271, p = 0.002) were associated with accrual of aLV over follow-up. This relationship was driven by the pwPMS population. The presence of LMCE at the follow-up visit was not predicted by any baseline proteomic biomarker nor cross-sectionally associated with any protein concentration. ConclusionProteomic markers of glial activation are associated with chronic lesional WM pathology (measured as aLV) and may be specific to the progressive MS phenotype. LMCE presence in MS does not appear to relate to proteomic measures.

The Application Value of Combined Detection of Serum IL-6, LDH, S100, NSE, and GFAP in the Early Diagnosis of Brain Damage Caused by Neonatal Asphyxia.

We aimed to investigate the correlation and clinical significance between a group of serum biomarkers and brain damage caused by neonatal asphyxia, and to provide sensitive and effective detection methods for early diagnosis and prognosis improvement. We enrolled neonates hospitalized in the neonatal department of The Affiliated Hospital of Inner Mongolia Medical University of China from June 2020 to June 2021 as the study subjects. The levels of inter-leukin-6 (IL-6), lactate dehydrogenase (LDH), S100 protein, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP) in serum samples were measured using electrochemiluminescence (ECL), enzyme-linked immunosorbent assay (ELISA) or rate method and the correlations between these serum biomarkers and the degree of neonatal asphyxia and brain damage were statistically analyzed using Spearman test. The levels of serum IL-6, LDH, S100, NSE, and GFAP in the neonatal asphyxia with brain damage group within 12 hours after birth were significantly higher than those in the neonatal asphyxia without brain damage group (all P<0.05). Additionally, these levels were positively correlated with the degree of asphyxia. The Area Under the Curve (AUC) of receiver operating characteristic (ROC) curves of IL-6 (0.8819), LDH (0.8108), S100 (0.8719), NSE (0.8719), and GFAP (0.8073) were revealed. The combined detection of serum marker levels can simultaneously reflect neuronal injury, glial cell injury, and inflammatory injury, improve the accuracy of diagnosis of neonatal asphyxia with brain damage, and enable the formulation of treatment strategies as early as possible to reduce the incidence of complications of brain damage.

Ginkgo biloba extract ameliorates hyperglycaemia-induced enteric glial cell injury via regulation of the TLR2-related pathway.

Diabetic gastrointestinal dysfunction (DGD) is a common complication in diabetic patients, and enteric glial cells (EGCs) found in the gastrointestinal tract have been shown to play an essential role in gastrointestinal dysfunction. Thus, targeting EGCs may be helpful for the control of DGD. This study aimed to evaluate the protective effect of Ginkgo biloba extract (GBE) from G. biloba dropping pills against hyperglycaemic stress-induced EGCs injury and its underlying mechanism. In vitro, the protective effect of GBE on CRL-2690 cells was evaluated by MTT assay and TUNEL assay. The expression of related markers was evaluated by RNA sequencing and validated by using western blotting. In vivo, STZ-induced C57BL/6J WT mice were used as models to evaluate the effects of GBE on blood glucose, body weight, and EGCs' activity and relevant signalling pathways were validated by immunofluorescence. The results showed that GBE (25 μg/ml) treatment significantly attenuated hyperglycaemic stress-induced cytotoxicity and cell apoptosis in CRL-2690 cells, which was verified in an STZ-induced (100 mg/kg, 3 days) diabetic mouse model with continuous GBE administration (25/100 mg/kg/day, 6/12 weeks). Further mechanistic study based on transcriptomic data revealed that GBE exerted its beneficial effect by regulating immune-related pathways, and TLR2/BTK/NF-κB/IL-1α/IL-10 comprised the main targets of this drug. This study demonstrates the protective effect of GBE against hyperglycaemic stress-induced EGCs injury using both in vitro and in vivo models and further reveals that the effect was achieved by targeting TLR2 and its downstream molecules BTK/NF-κB/IL-1α/IL-10. This study may be helpful for expanding the clinical application of GBE in treating DGD.

Characteristics of structural and functional alterations following traumatic brain injury in neurons and glial cells of the sensorimotor cortex

Introduction and Aim: Traumatic brain injury (TBI) is regarded as a significant worldwide health issue and a significant contributor to mortality and disability. The objective of this study was to examine the parameters and nature of the regenerative and destructive processes that occur in the rat cerebral cortex depending on the degree and time of the TBI. Materials and Methods: The experiments were carried out on 24 sexless adult mice weighing 180–220 g. The primary group of mice had severe TBI. To assess the severity of the TBI model, histological data, animal survival rates, and motor and cognitive dysfunctions were examined. Both light and electron microscopy were used to study the animal brains in each group. Results: The areas of injury were filled with blood, and microscopic examination revealed that the foci of contusion had destroyed brain tissue in the form of tissue and blood vessel fragments. Most dystrophic neuronal changes in mice with severe TBI between 1 and 21 days after the injury were acute neuronal swelling, hydropic dystrophy of nerve cells with clear cytoplasmic vacuolization, localized and complete chromatolysis, hyperchromatism, and homogeneous cytoplasm. Conclusion: Brain tissue lesions develop in the early stages of a TBI through rapid necrotic cell death.

Apoptosis in the neuroprotective effect of α7 nicotinic receptor in neurodegenerative models.

The α7 subtype of nicotinic receptors (α7 nAChRs) is one of the most abundant nicotinic receptor subtypes in the central nervous system (CNS) and both neurons and nonneuronal cells express α7 nAChRs. When activated, α7 nAChRs become permeable to cations and promote cellular responses such as anti-apoptotic signaling by modulating the caspases and proteins of the Bcl-2 family. Neuroprotection is an important function of these receptors, promoting neuronal survival under pathological conditions, including situations of stress and neuronal degeneration. Studies have demonstrated the relationship between the activation of these receptors and the reduction of neuronal or glial cell injury, by controlling apoptotic processes in different models, including neurodegenerative diseases such as Alzheimer's disease. Therefore, one of the most important signaling pathways activated by α7 nAChRs is the PI3K/Akt signaling cascade, which promotes the stimulation of anti-apoptotic molecules of the Bcl-2 family, Bcl-2 and Bcl-xl, and reduces the expression of caspases and proapoptotic molecules, resulting in cell survival. In Alzheimer's models, the literature shows that α7 nAChR activation attenuates Aβ-induced neurotoxicity through modulation of different intrinsic apoptotic pathways via PI3K/Akt and mitogen-activated protein kinase (MAPK). In this review, we provide an up-to-date summary of the current evidence on the relationship between the activation of α7 nAChRs, a subtype of nicotinic acetylcholine receptor, and its role in neuroprotection by modulating apoptotic pathways.

Comparative transcriptional analysis of satellite glial cell injury response

Background: Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNA sequencing (scRNAseq) technologies has enabled a new approach to investigate SGCs. Methods: In this study we used scRNAseq to investigate SGCs from mice subjected to sciatic nerve injury. We used a meta-analysis approach to compare the injury response with that found in other published datasets. Furthermore, we also used scRNAseq to investigate how cells from the dorsal root ganglion (DRG) change after 3 days in culture. Results: From our meta-analysis of the injured conditions, we find that SGCs share a common signature of 18 regulated genes following sciatic nerve crush or sciatic nerve ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state while others start resembling Schwann cell-like precursors. Conclusion: By using integrated analyses of new and previously published scRNAseq datasets, this study provides a consensus view of which genes are most robustly changed in SGCs after injury. Our results are available via the Broad Institute Single Cell Portal, so that readers can explore and search for genes of interest.

Comparative transcriptional analysis of satellite glial cell injury response

Background: Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNA sequencing (scRNAseq) technologies has enabled a new approach to investigate SGCs. Methods: In this study we used scRNAseq to investigate SGCs from mice subjected to sciatic nerve injury. We used a meta-analysis approach to compare the injury response with that found in other published datasets. Furthermore, we also used scRNAseq to investigate how cells from the dorsal root ganglion (DRG) change after 3 days in culture. Results: From our meta-analysis of the injured conditions, we find that SGCs share a common signature of 18 regulated genes following sciatic nerve crush or sciatic nerve ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state while others start resembling Schwann cell-like precursors. Conclusion: By using integrated analyses of new and previously published scRNAseq datasets, this study provides a consensus view of which genes are most robustly changed in SGCs after injury. Our results are available via the Broad Institute Single Cell Portal, so that readers can explore and search for genes of interest.

Dexmedetomidine reduces enteric glial cell injury induced by intestinal ischaemia-reperfusion injury through mitochondrial localization of TERT.

This study was performed to uncover the effects of dexmedetomidine on oxidative stress injury induced by mitochondrial localization of telomerase reverse transcriptase (TERT) in enteric glial cells (EGCs) following intestinal ischaemia‐reperfusion injury (IRI) in rat models. Following establishment of intestinal IRI models by superior mesenteric artery occlusion in Wistar rats, the expression and distribution patterns of TERT were detected. The IRI rats were subsequently treated with low or high doses of dexmedetomidine, followed by detection of ROS, MDA and GSH levels. Calcein cobalt and rhodamine 123 staining were also carried out to detect mitochondrial permeability transition pore (MPTP) and the mitochondrial membrane potential (MMP), respectively. Moreover, oxidative injury of mtDNA was determined, in addition to analyses of EGC viability and apoptosis. Intestinal tissues and mitochondria of EGCs were badly damaged in the intestinal IRI group. In addition, there was a reduction in mitochondrial localization of TERT, oxidative stress, whilst apoptosis of EGCs was increased and proliferation was decreased. On the other hand, administration of dexmedetomidine was associated with promotion of mitochondrial localization of TERT, whilst oxidative stress, MPTP and mtDNA in EGCs, and EGC apoptosis were all inhibited, and the MMP and EGC viability were both increased. A positive correlation was observed between different doses of dexmedetomidine and protective effects. Collectively, our findings highlighted the antioxidative effects of dexmedetomidine on EGCs following intestinal IRI, as dexmedetomidine alleviated mitochondrial damage by enhancing the mitochondrial localization of TERT.

Role of Monocyte-to-lymphocyte Ratio, Mean Platelet Volume-to-Platelet Count Ratio, C-Reactive Protein and Erythrocyte Sedimentation Rate as Predictor of Severity in Secondary Traumatic Brain Injury: A Literature Review

BACKGROUND: Secondary traumatic brain injury (TBI) is injury to the brain following primary TBI because of neuroinflammation as consequences of neuronal and glial cell injury which cause release of various inflammation cytokine and chemokine. Biomarker examination to predict the severity of secondary TBI is important to provide appropriate treatment to the patient. This article reviews possibility several common laboratory parameter such as monocyte-to-lymphocyte ratio (MLR), mean platelet volume-to-platelet count (PC) ratio (MPV-PCR), c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) to predict severity of secondary TBI. LITERATURE REVIEW: TBI activates microglia which increase infiltration and proliferation of monocyte. Neuroinflammation also increases thrombopoiesis which leads to increase megakaryocytes production. In the other hand, due to disruption of brain blood vessels because of trauma, coagulation cascade is also activated and leads to consumptive coagulopathy. These are reflected as high monocyte count, low PC, and high MPV. Lymphocyte count is reported low in TBI especially in poor outcome patients. CRP is an acute phase reactant that increased in inflammation condition. In TBI, increased production of Interleukin-6 leads to increase CRP production. In head injured patients, ESR level does not increase significantly in the acute phase of inflammation but last longer when compared to CRP. CONCLUSION: MLR, MPV-PCR, CRP, and ESR could be predictor of severity in secondary TBI.

HDAC1 Expression, Histone Deacetylation, and Protective Role of Sodium Valproate in the Rat Dorsal Root Ganglia After Sciatic Nerve Transection.

Nerve injury is an important reason of human disability and death. We studied the role of histone deacetylation in the response of the dorsal root ganglion (DRG) cells to sciatic nerve transection. Sciatic nerve transection in the rat thigh induced overexpression of histone deacetylase 1 (HDAC1) in the ipsilateral DRG at 1-4h after axotomy. In the DRG neurons, HDAC1 initially upregulated at 1h but then redistributed from the nuclei to the cytoplasm at 4h after axotomy. Histone H3 was deacetylated at 24h after axotomy. Deacetylation of histone H4, accumulation of amyloid precursor protein, a nerve injury marker, and GAP-43, an axon regeneration marker, were observed in the axotomized DRG on day 7. Neuronal injury occurred on day 7 after axotomy along with apoptosis of DRG cells, which were mostly the satellite glial cells remote from the site of sciatic nerve transection. Administration of sodium valproate significantly reduced apoptosis not only in the injured ipsilateral DRG but also in the contralateral ganglion. It also reduced the deacetylation of histones H3 and H4, prevented axotomy-induced accumulation of amyloid precursor protein, which indicated nerve injury, and overexpressed GAP-43, a nerve regeneration marker, in the axotomized DRG. Therefore, HDAC1 was involved in the axotomy-induced injury of DRG neurons and glial cells. HDAC inhibitor sodium valproate demonstrated the neuroprotective activity in the axotomized DRG.

High Serum Levels of Serum 100 Beta Protein, Neuron-specific Enolase, Tau, Active Caspase-3, M30 and M65 in Children with Autism Spectrum Disorders.

ObjectiveThe purpose of this study was therefore to investigate whether neuronal, axonal, and glial cell markers (Neuron-specific enolase [NSE], tau, serum 100 beta protein [S100B], respectively) and apoptosis markers (active caspase 3, M30, M65) and whether these parameters can be used as diagnostic biomarkers in autism spectrum disorders (ASD).MethodsThis study measured the serum S100B, NSE, tau, active caspase 3, M30, and M65 levels in 43 patients with ASD (aged 3−12 years) and in 41 age- and sex-matched healthy controls. ASD severity was rated using the Childhood Autism Rating Scale. The serum levels were determined in the biochemistry laboratory using the ELISA technique. The receiver operator characteristics curve method was employed to evaluate the accuracy of the parameters in diagnosing ASD.ResultsSerum S100B, tau, NSE, active caspase-3, M30, and M65 levels were significantly higher in the patient group than in the control group (p < 0.001, p = 0.002, p = 0.002, p = 0.005, p < 0.001, and p = 0.004, respectively). The cut-off value of S100B was 48.085 pg/ml (sensitivity: 74.4%, specificity: 80.5%, areas under the curve: 0.879, p < 0.001).ConclusionApoptosis increased in children with ASD, and neuronal, axonal, and glial cell injury was observed. In addition, S100B may be an important diagnostic biomarker in patients with ASD. Apoptosis, and neuronal, axonal and astrocyte pathologies may play a significant role in the pathogenesis of ASD, and further studies are now required to confirm this.

Zebrafish‐inspired strategies for spinal cord repair.

Spinal cord injury (SCI) causes irreversible loss of sensory and motor functions in mammals. In contrast to mammals, adult zebrafish are capable of efficient, spontaneous recovery after SCI. Whereas glial scarring and neuron loss accentuate spinal cord (SC) damage and inhibit regeneration in mammals, zebrafish are capable of pro‐regenerative glial bridging and effective adult neurogenesis post‐injury. Emerging evidence suggests that in mammals these pro‐regenerative processes are either inefficient or overshadowed by anti‐regenerative effects. We propose that developing efficient SCI treatments will require a deeper understanding of endogenous SC regenerative capacity, and that adult zebrafish present a valuable model to uncover fundamental, evolutionarily concealed mechanisms of mammalian SC regeneration.Although glial bridging and neurogenesis are hallmarks of the robust SC repair observed in zebrafish, the mechanisms that direct these processes are underexplored. Using expression profiling and genetic loss‐of‐function, we screened for and identified a suite of molecular factors and cell populations that are activated after injury and required for SC regeneration. These studies revealed that discrete lineage‐restricted niches of progenitor cells differentially contribute to glial bridging and neurogenesis after SCI in zebrafish. Using a battery of genetic and molecular tools, we identified yap‐ctgfa‐twist1a as a central glial bridging signaling axis, generated the first transcriptional profiles of zebrafish bridging glia, and elucidated glial cell injury responses at the single cell level in zebrafish. We are currently using our understanding of the bridging glial cell fate in zebrafish to perform molecular comparisons with mammalian glial cells, and to reprogram mammalian glia into scarless, pro‐regenerative scaffolds that promote SC regrowth. Taken together, our studies elucidate fundamental mechanisms that direct innate SC regeneration in zebrafish, and use natural SC regeneration as a platform to enhance mammalian SC repair at the molecular and cellular levels.Support or Funding InformationWe acknowledge support from NIH (R01‐NS113915), the Missouri Spinal Cord Injury/Disease Research Program, the McDonnell Center for Cellular and Molecular Neuroscience, the Institute of Clinical and Translational Sciences, and from Washington University School of Medicine to M.H.M.

Glial Cell AMPA Receptors in Nervous System Health, Injury and Disease.

Glia form a central component of the nervous system whose varied activities sustain an environment that is optimised for healthy development and neuronal function. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptors (AMPAR) are a central mediator of glutamatergic excitatory synaptic transmission, yet they are also expressed in a wide range of glial cells where they influence a variety of important cellular functions. AMPAR enable glial cells to sense the activity of neighbouring axons and synapses, and as such many aspects of glial cell development and function are influenced by the activity of neural circuits. However, these AMPAR also render glia sensitive to elevations of the extracellular concentration of glutamate, which are associated with a broad range of pathological conditions. Excessive activation of AMPAR under these conditions may induce excitotoxic injury in glial cells, and trigger pathophysiological responses threatening other neural cells and amplifying ongoing disease processes. The aim of this review is to gather information on AMPAR function from across the broad diversity of glial cells, identify their contribution to pathophysiological processes, and highlight new areas of research whose progress may increase our understanding of nervous system dysfunction and disease.

Activation of Sigma Receptors With Afobazole Modulates Microglial, but Not Neuronal, Apoptotic Gene Expression in Response to Long-Term Ischemia Exposure

Stroke continues to be a leading cause of death and serious long-term disability. The lack of therapeutic options for treating stroke at delayed time points (≥6 h post-stroke) remains a challenge. The sigma receptor agonist, afobazole, an anxiolytic used clinically in Russia, has been shown to reduce neuronal and glial cell injury following ischemia and acidosis; both of which have been shown to play important roles following an ischemic stroke. However, the mechanism(s) responsible for this cytoprotection remain unknown. Experiments were carried out on isolated microglia from neonatal rats and cortical neurons from embryonic rats to gain further insight into these mechanisms. Prolonged exposure to in vitro ischemia resulted in microglial cell death, which was associated with increased expression of the pro-apoptotic protein, Bax, the death protease, caspase-3, and reduced expression in the anti-apoptotic protein Bcl-2. Incubation of cells with afobazole during ischemia decreased the number of microglia expressing both Bax and caspase-3, and increased cells expressing Bcl-2, which resulted in a concomitant enhancement in cell survival. In similar experiments, incubation of neurons under in vitro ischemic conditions resulted in higher expression of Bax and caspase-3, while at the same time expression of Bcl-2 was decreased. However, unlike observations made in microglial cells, afobazole was unable to modulate the expression of these apoptotic proteins, but a reduction in neuronal death was still noted. The functional state of surviving neurons was assessed by measuring metabolic activity, resting membrane potential, and responses to membrane depolarizations. Results showed that these neurons maintained membrane potential but had low metabolic activity and were unresponsive to membrane depolarizations. However, while these neurons were not fully functional, there was significant protection by afobazole against long-term ischemia-induced cell death. Thus, the effects of sigma receptor activation on microglial and neuronal responses to ischemia differ significantly.

Reactivity of microglia and astrocytes after an excitotoxic injury induced by kainic acid in the rat spinal cord.

After injury of the nervous system glial cells react according to the stimuli by modifying their morphology and function. Glia activation was reported in different kainic acid (KA)-induced neurodegeneration models. Here, we describe glial morphometric changes occurring in an excitotoxic KA-induced cervical spinal cord injury model. Concomitant degenerative and apoptotic processes are also reported. Male rats injected at the spinal cord C5 segment either with KA or saline were euthanized at post-injection (PI) days 1, 2, 3 or 7. Anti-IBA-1 and anti-GFAP antibodies were used to identify microglia and activated astrocytes, respectively, and to morphometrically characterized them. Fluoro-Jade B staining and TUNEL reaction were used to determine neuronal and glial degeneration and apoptosis. KA-injected group showed a significant increase in microglia number at the ipsilateral side by PI day 3. Different microglia reactive phenotypes were observed. Reactive microglia was still present by PI day 7. Astrocytes in KA-injected group showed a biphasic increase in number at PI days 1 and 3. Degenerative and apoptotic events were only observed in KA-injected animals, increasing mainly by PI day 1. Understanding the compromise of glia in different neurodegenerative processes may help to define possible common or specific therapeutic approaches directed towards neurorestorative strategies.

Protective Efffects of Melatonin in Corpus Callosum Astrocytes during Ischemia in Transgenic Mice

Objective: Stroke is a leading cause of adult death and disability worldwide. Around 80% of all stroke cases are classed as ischemic stroke, which affects both gray and white matter brain regions. During ischemia, reactive oxygen species are generated and initiate multiple damaging processes such as lipid peroxidation, mitochondrial dysfunction, blood–brain barrier damage and brain edema. Melatonin is a potent antioxidant which can act as a direct oxygen species scavenger. Melatonin can also act at receptors (melatonin receptor 1 and 2), which are expressed in the nervous system cells including astrocytes.&#x0D; Methods: Using live cell imaging of transgenic mice, the viability of astrocytes in the corpus callosum of adult brain sections was monitored during a standard 60 minutes period of modeled ischemia (oxygen-glucose deprivation) and 30 minutes of reperfusion in 8 groups; Control, artificial cerebrospinal fluid + Melatonin, oxygen-glucose deprivation, oxygen-glucose deprivation + Melatonin, oxygen-glucose deprivation + Melatonin + Luzindole (a nonselective melatonin receptor antagonist), oxygen-glucose deprivation + Luzindole, oxygen-glucose deprivation + Melatonin + propionamidotetralin (a selective melatonin receptor 2 antagonist), and oxygen-glucose deprivation + propionamidotetralin.&#x0D; Results: Addition of melatonin significantly reduced the level of astrocyte death during oxygen-glucose deprivation from 71.94% ± 1.45 to 37.84% ± 1.9; p &lt; 0.0001. This protective effect was blocked by luzindole or propionamidotetralin. Following known scoring categories for glial injury, ultrastructural morphology confirmed the protective effect of melatonin against acute ischemic injury in the white matter glial cells.&#x0D; Conclusion: Melatonin is a promising neuroprotective agent during white matter ischemia.

Interactome and reciprocal activation of pathways in topical mesenchymal stem cells and the recipient cerebral cortex following traumatic brain injury

In this study, GFP-MSCs were topically applied to the surface of cerebral cortex within 1 hour of experimental TBI. No treatment was given to the control group. Three days after topical application, the MSCs homed to the injured parenchyma and improved the neurological function. Topical MSCs triggered earlier astrocytosis and reactive microglia. TBI penumbra and hippocampus had higher cellular proliferation. Apoptosis was suppressed at hippocampus at 1 week and reduced neuronal damaged was found in the penumbral at day 14 apoptosis. Proteolytic neuronal injury biomarkers (alphaII-spectrin breakdown products, SBDPs) and glial cell injury biomarker, glial fibrillary acidic protein (GFAP)-breakdown product (GBDPs) in injured cortex were also attenuated by MSCs. In the penumbra, six genes related to axongenesis (Erbb2); growth factors (Artn, Ptn); cytokine (IL3); cell cycle (Hdac4); and notch signaling (Hes1) were up-regulated three days after MSC transplant. Transcriptome analysis demonstrated that 7,943 genes were differentially expressed and 94 signaling pathways were activated in the topical MSCs transplanted onto the cortex of brain injured rats with TBI. In conclusion, topical application offers a direct and efficient delivery of MSCs to the brain.

Blood Biomarkers for Evaluation of Perinatal Encephalopathy.

Recent research in identification of brain injury after trauma shows many possible blood biomarkers that may help identify the fetus and neonate with encephalopathy. Traumatic brain injury shares many common features with perinatal hypoxic-ischemic encephalopathy. Trauma has a hypoxic component, and one of the 1st physiologic consequences of moderate-severe traumatic brain injury is apnea. Trauma and hypoxia-ischemia initiate an excitotoxic cascade and free radical injury followed by the inflammatory cascade, producing injury in neurons, glial cells and white matter. Increased excitatory amino acids, lipid peroxidation products, and alteration in microRNAs and inflammatory markers are common to both traumatic brain injury and perinatal encephalopathy. The blood-brain barrier is disrupted in both leading to egress of substances normally only found in the central nervous system. Brain exosomes may represent ideal biomarker containers, as RNA and protein transported within the vesicles are protected from enzymatic degradation. Evaluation of fetal or neonatal brain derived exosomes that cross the blood-brain barrier and circulate peripherally has been referred to as the “liquid brain biopsy.” A multiplex of serum biomarkers could improve upon the current imprecise methods of identifying fetal and neonatal brain injury such as fetal heart rate abnormalities, meconium, cord gases at delivery, and Apgar scores. Quantitative biomarker measurements of perinatal brain injury and recovery could lead to operative delivery only in the presence of significant fetal risk, triage to appropriate therapy after birth and measure the effectiveness of treatment.

Invited Commentary

Invited Commentary

Diagnostic Value of Serum Levels of GFAP, pNF-H, and NSE Compared With Clinical Findings in Severity Assessment of Human Traumatic Spinal Cord Injury.

An analytical cohort study. This study aimed to evaluate severity of traumatic spinal cord injury (SCI) based on the serum levels of phosphorylated form of heavy subunit of neurofilament (pNF-H), neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), which are axonal, neural cell body, and glial cell injury markers, respectively. Prior studies have reported elevated serum levels of pNF-H, NSE, and GFAP as biomarkers for the detection of traumatic SCI in animals. However, in this study, these biomarkers were studied in humans and with an extended level of timing. The study included 35 patients with SCI with a mean age of 36.5 years. All patients were evaluated using the American Spinal Injury Association Impairment Scale, followed by examinations including radiography and spinal computed tomography for determining the injury level. Serum levels of NSE, pNF-H, and GFAP were determined using enzyme-linked immunosorbent assay. The mean serum level of GFAP was significantly higher in patients with SCI than in the control group. Mean serum levels of pNF-H and NSE were significantly higher during 24 and 48 hours after injury in patients with SCI than in the control group. The serum level of GFAP was appropriate for estimating the severity of SCI in the first 24 hours after injury. Our findings suggest that increased serum levels of GFAP, NSE, and pNF-H can be used for the diagnosis and degree of SCI severity in trauma patients. During 48 hours after injury, estimation of serum levels of pNF-H, NSE, and GFAP, combined with neurological testing, could predict the presence of SCI and severity prior to spinal computed tomography and surgical or conservative interventions. 2.