Myelin Sheath Degeneration Research Articles

Morphometric, immunohistochemical and ultrastructural examination of age-related structural alterations in optic nerve

Aims: As individuals age, there is a known decline in visual function attributed to a reduction in the optic nerve fibers and myelin sheath degeneration. Studies present conflicting findings on whether aging affects axonal integrity in the human optic nerve. This study aims to investigate degenerative changes in the aging rat optic nerve. Methods: The investigation involved 36 Wistar albino rats. The rats were divided into six groups: the newborn, prepubertal, pubertal, junior, adult, and elderly groups. This study investigated optic nerve axon counts, axon diameters, levels of glial fibrillary acidic protein immunoreactivity (GFAP-IR) and nerve growth factor immunoreactivity (NGF-IR), as well as findings from light microscopy (LM) and electron microscopy (EM) in these groups. Results: This study observed age-related alterations in rat optic nerves, including increased diameter, irregular axon count fluctuations (both increases and decreases), elevated astrocyte count, and a simultaneous decline in oligodendrocyte count. Additionally, it was observed that NGF-IR was predominantly at the membrane level in newborns and moderately in the cytoplasm, whereas in older ages, it was evident at both cellular and axonal levels furthermore, it was observed that GFAP-IR increased with age. However, in LM and EM examinations, axonal loss and rarefaction, accumulation of osmiophilic substances, splitting of the myelin sheath, vacuolization, axonal retraction were observed. Conclusion: In this study, it was found that one of the causes of age-related vision loss is the advanced degenerative changes in the optic nerve and it was concluded that the remaining small-diameter myelinated nerve fibers may partially compensate for the sense of vision. Our study reveals that age-related degenerative changes in the central nervous system resemble those in multiple sclerosis (MS), suggesting a potential contribution to MS pathogenesis.

Bisphenol-F and Bisphenol-S (BPF and BPS) Impair the Stemness of Neural Stem Cells and Neuronal Fate Decision in the Hippocampus Leading to Cognitive Dysfunctions.

Neurogenesis occurs throughout life in the hippocampus of the brain, and many environmental toxicants inhibit neural stem cell (NSC) function and neuronal generation. Bisphenol-A (BPA), an endocrine disrupter used for surface coating of plastic products causes injury in the developing and adult brain; thus, many countries have banned its usage in plastic consumer products. BPA analogs/alternatives such as bisphenol-F (BPF) and bisphenol-S (BPS) may also cause neurotoxicity; however, their effects on neurogenesis are still not known. We studied the effects of BPF and BPS exposure from gestational day 6 to postnatal day 21 on neurogenesis. We found that exposure to non-cytotoxic concentrations of BPF and BPS significantly decreased the number/size of neurospheres, BrdU+ (proliferating NSC marker)and MAP-2+ (neuronal marker) cells and GFAP+ astrocytes in the hippocampus NSC culture, suggesting reduced NSC stemness and self-renewal and neuronal differentiation and increased gliogenesis. These analogs also reduced the number of BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells in the hippocampus of the rat brain, suggesting decreased NSC proliferation and impaired maturation of newborn neurons. BPF and BPS treatment increases BrdU/cleaved caspase-3+ cells and Bax-2 and cleaved caspase protein levels, leading to increased apoptosis in hippocampal NSCs. Transmission electron microscopy studies suggest that BPF and BPS also caused degeneration of neuronal myelin sheath, altered mitochondrial morphology, and reduced number of synapses in the hippocampus leading to altered cognitive functions. These results suggest that BPF and BPS exposure decreased the NSC pool, inhibited neurogenesis, induced apoptosis of NSCs, caused myelin degeneration/synapse degeneration, and impaired learning and memory in rats.

The Effects and Mechanism of Scutellaria baicalensis Georgi Stems and Leaves Flavonoids on Myelin Sheath Degeneration Induced by Composite Aβ in Rats.

Alzheimer's disease is a degenerative disease of the central nervous system, and its characteristic pathological changes are closely associated with Aβ deposition and neurofibrillary tangles. Many studies have found that malignant changes in the myelin sheath and oligodendrocyte (OL) are accompanied by the occurrence and development of AD. Therefore, any method that can resist myelin sheath and OL disorders may be a potential strategy for AD. To investigate the effects and mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on the myelin sheath degeneration induced by Aβ25-35 combined with AlC13 and RHTGF-β1 (composite Aβ) in rats. A rat AD model was established by intracerebroventricular injection of composite Aβ. The Morris water maze was used to screen the memory impairment rat model. The successful model rats were divided into the model group and the 35, 70, and 140 mg/kg SSFS groups. The myelin sheath changes in the cerebral cortex were observed with an electron microscope. The expression of the oligodendrocyte- specific protein claudin 11 was detected with immunohistochemistry. The protein expression levels of myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG) and myelin basic protein (MBP), sphingomyelin synthase-1 (SMS1), and sphingomyelinase-2 (SMPD2) were assayed by Western blotting. The intracerebroventricular injection of composite Aβ caused degeneration of the myelin sheath structure and was accompanied by the decreased claudin 11, MOG, MAG, MBP, and SMS1, and increased SMPD2 protein expression in the cerebral cortex. However, 35, 70, and 140 mg/kg SSFs can differentially ameliorate the above abnormal changes induced by composite Aβ. SSFs can alleviate myelin sheath degeneration and increase the protein expression of claudin 11, MOG, MAG, and MBP, and the effective mechanism may be related to the positive regulation of SMS1 and SMPD2 activities.

Enhanced oxidative phosphorylation, re-organized intracellular signaling, and epigenetic de-silencing as revealed by oligodendrocyte translatome analysis after contusive spinal cord injury

Reducing the loss of oligodendrocytes (OLs) is a major goal for neuroprotection after spinal cord injury (SCI). Therefore, the OL translatome was determined in Ribotag:Plp1-CreERT2 mice at 2, 10, and 42 days after moderate contusive T9 SCI. At 2 and 42 days, mitochondrial respiration- or actin cytoskeleton/cell junction/cell adhesion mRNAs were upregulated or downregulated, respectively. The latter effect suggests myelin sheath loss/morphological simplification which is consistent with downregulation of cholesterol biosynthesis transcripts on days 10 and 42. Various regulators of pro-survival-, cell death-, and/or oxidative stress response pathways showed peak expression acutely, on day 2. Many acutely upregulated OL genes are part of the repressive SUZ12/PRC2 operon suggesting that epigenetic de-silencing contributes to SCI effects on OL gene expression. Acute OL upregulation of the iron oxidoreductase Steap3 was confirmed at the protein level and replicated in cultured OLs treated with the mitochondrial uncoupler FCCP. Hence, STEAP3 upregulation may mark mitochondrial dysfunction. Taken together, in SCI-challenged OLs, acute and subchronic enhancement of mitochondrial respiration may be driven by axonal loss and subsequent myelin sheath degeneration. Acutely, the OL switch to oxidative phosphorylation may lead to oxidative stress that is further amplified by upregulation of such enzymes as STEAP3.

MiR-148b-3p suppresses the proliferation and migration of Schwann cells by targeting USP6 following sciatic nerve injury

ABSTRACT Background Peripheral nerve injury is a common disorder associated with damaged axons and distal myelin sheath degeneration, and Schwann cells play a paramount role in peripheral nerve regeneration. This study aims to explore the role of microRNA miR-148b-3p on Schwann cells after peripheral nerve injury. Methods Sciatic nerve transection was conducted in rat as the model of peripheral nerve injury. The expression level of miR-148b-3p and Ubiquitin Specific Peptidase 6 (USP6) was detected by qRT-PCR and Western blot at diverse time points after nerve transection. Cell migration and proliferation were determined in primary Schwann cells isolated from rat. The functional interaction of miR-148b-3p and USP6 mRNA was validated by dual-luciferase reporter assay. Results In the animal model of sciatic nerve injury, miR-148b-3p expression level in the proximal nerve stump showed downregulation after nerve transection procedure, while USP6 expression level was elevated. The overexpression of miR-148b-3p inhibited the proliferation and migration of primary Schwann cells, while suppressing miR-148b-3p showed the opposite effect. USP6 mRNA was identified as a target of miR-148b-3p, which was found to mediate the effect of miR-148b-3p. USP6 silencing suppressed the migration and proliferation in primary Schwann cells. Conclusion Our data demonstrated the functional role of miR-148b-3p/USP6 axis in regulating the migration and proliferation of Schwann cells following peripheral nerve injury. miR-148b-3p showed downregulation and its target USP6 was upregulated after nerve transection procedure. Targeting miR-148b-3p/USP6 axis may provide a novel opportunity for peripheral nerve repair.

Multi-omics analysis revealed the role of CYP1A2 in the induction of mechanical allodynia in type 1 diabetes.

Background: Mechanical allodynia (MA) is one of the leading clinical symptoms of painful diabetic peripheral neuropathy (PDPN), which is a primary reason for non-traumatic amputations, foot ulceration, and gait abnormalities in patients with diabetes. However, the pathogenic mechanisms of MA have not yet been fully elucidated, and there is no effective treatment. This study aims to study the potential pathogenetic mechanisms of MA and to provide targets for the therapy of MA. Methods: A single intraperitoneal injection of streptozotocin induced type 1 diabetes in rat models. Subsequently, rats were divided into the control group, the diabetic group without MA, and the diabetic group with MA based on weekly behavioral assays. The differentially expressed lipids in the sciatic nerve of each group were detected using untargeted lipidomics, and the differentially expressed genes in the sciatic nerve of each group were detected by transcriptomics. The pathogenesis of MA was predicted using integrated analysis and validated by immunofluorescence staining and transmission electron microscopy. Results: Untargeted lipidomics revealed the accumulation of a more severe lipid in MA rats. Transcriptomics results suggested that differentially expressed genes in MA rats were primarily related to lipid droplets and myelin sheath. Integrated analysis results indicated that the downregulation of Cytochrome P450 1A2 (CYP1A2) expression was closely linked to lipid metabolism disorders. Immunofluorescence staining demonstrated that down-regulation of CYP1A2 expression occurred in MA rats. Transmission electron microscopy results showed that more severe lipid droplet accumulation and myelin sheath degeneration occurred in MA rats. Conclusion: Our findings imply that the downregulation of CYP1A2 expression leads to disorders of lipid metabolism and further leads to lipid droplet accumulation and myelin sheath degeneration, which might ultimately lead to the development of MA. Therefore, our study contributes to promoting the understanding of the molecular mechanisms of MA and providing potential targets for the clinical treatment of MA.

Ferroptosis in the pathogenesis of brain tumors

The field of research on ferroptosis has seen an explosive growth in the past few years since the term was coined in 2012. This review highlights the current state of knowledge on the developmental mechanism of this unique mode of cell death, induced by iron-dependent phospholipid peroxidation, which is regulated by a variety of cellular metabolic events, including redox homeostasis. The xCT system, an amino acid antiporter that supports the synthesis of glutathione (GSH) and oxidation protection, is among these factors. The risk of iron accumulation in neurons, astrocytes, oligodendrocytes, microglia, and Schwann cells and the development of oxidative stress are discussed. Ferroptosis triggers a cascade of events including activation of inflammation, oxidation of neurotransmitters, impaired neuronal communication, myelin sheath degeneration, astrocyte dysregulation, dementia, and cell death. On the other hand, the exceptional vulnerability of cancer cells originating from the nervous tissue to ferroptosis is estimated. The evidence is given for the initiation of ferroptosis in tumor cells as a factor inhibiting the growth and promoting the death of these cells. Particular attention is paid to the pharmacological modulation of ferroptosis through its induction and inhibition for the treatment of drug-resistant cancers. The choice of targets for the induction of ferroptosis in cancer cells is discussed. Glutathione peroxidase 4 and xCT amino acid antiporter are recognized as the most preferred targets and the antitumor potential of their inhibition and side effects are evaluated.

Protective effect of anakinra on audiovestibular function in a murine model of endolymphatic hydrops.

Ménière's disease (MD), a common disease in the inner ear, is characterized by an increase in endolymph in the cochlear duct and vestibular labyrinth. The pathophysiology of the condition appears to be the immune response. Studies have shown that basal levels of the IL-1β increased in some MD patients. Here, we used a murine model of endolymphatic hydrops (EH) to study the effect of anakinra on auditory and vestibular function. Mice were intraperitoneal injected with anakinra or saline before LPS by postauricular injection. Weight and disease severity were measured, histologic changes in auditory were assessed, and inflammation state was evaluated. We found that anakinra therapy reduced LPS-induced EH, alleviated LPS-induced hearing loss and vestibular dysfunction, and inhibited the expression of the inflammatory cytokines and macrophage infiltration in the cochlea of mice. We further demonstrated that anakinra ameliorated the disorganization and degeneration of myelin sheath, and reduced the neuron damage in cochlea of EH mice. Consequently, anakinra contributes to a promising therapeutic approach to MD, by restricting EH, alleviating auditory and vestibular function, inhibiting inflammation of the inner ear and protecting the cochlear nerve. Further investigations are needed to assess the potential therapeutic benefits of anakinra in patients with MD.

Stress-induced myelin damage in the hippocampal formation in a rat model of depression

BackgroundAccording to previous studies, myelin damage may be involved in the occurrence of depression. However, to date, no study has quantitatively investigated the changes in myelinated fibers and myelin sheaths in the hippocampal formation (HF) and hippocampal subfields in the context of depression. Methods: Male Sprague-Dawley (SD) rats (aged 4–5 weeks) were evenly divided into the control group and chronic unpredictable stress (CUS) group. Behavioral tests were performed, and then changes in myelinated fibers and myelin ultrastructure in hippocampal subfields in depression model rats were investigated using modern stereological methods and transmission electron microscopy techniques. Results: After a four-week CUS protocol, CUS rats showed depressive-like and anxiety-like behaviors. The total length and total volume of myelinated fibers were reduced in the CA1 region and DG in the CUS group compared with the control group. The total volumes of myelin sheaths and axons in the CA1 region but not in the DG were significantly lower in the CUS group than in the control group. The decrease in the total length of myelinated nerve fibers in the CA1 region in CUS rats was mainly due to a decrease in the length of myelinated fibers with a myelin sheath thickness of 0.15 μm–0.20 μm. Limitations: The exact relationship between the degeneration of myelin sheaths and depression-like, anxiety-like behaviors needs to be further investigated. Conclusions: CUS induces depression- and anxiety-like behaviors, and the demyelination in the CA1 region induced by 4 weeks of CUS might be an important structural basis for these behaviors.

White matter-associated microglia: New players in brain aging and neurodegenerative diseases

There has been growing interest in brain aging and rejuvenation. It is well known that brain aging is one of the leading causes of neurodegenerative diseases, such as Alzheimer’s disease, but brain aging alone can cause cognitive decline. Microglia are thought to act as ‘conductors’ of white matter aging by modulating diverse glial cells and phagocytosing white matter-derived myelin debris. A recent study identified a specific subpopulation of microglia in the white matter of aged mice, termed white matter-associated microglia (WAM). Additionally, senescent microglia show impaired phagocytic function and altered lipid metabolism, which cause accumulation of lipid metabolites and eventually lead to myelin sheath degeneration. These results suggest that senescent WAM could be pivotal players in axonal loss during brain aging. The aim of this review is to assess the current state of knowledge on brain aging, with an emphasis on the roles of the white matter and microglia, and suggest potential approaches for rejuvenating the aged brain.

Microsecond molecular dynamics studies of cholesterol-mediated myelin sheath degeneration in early Alzheimer's disease.

Cholesterol-mediated perturbations of membrane structural integrity are key early events in the molecular pathogenesis of Alzheimer's disease (AD). In AD, protein misfolding (proteopathy) and pro-inflammatory conditions (immunopathy) culminate in neuronal death, a process enabled by altered membrane biophysical properties which render neurons more susceptible to proteopathic and immunopathic cytotoxicities. Since cholesterol is a principal neuronal membrane lipid, normal cholesterol homeostasis is central to membrane health; also, since increased cholesterol composition is especially present in neuronal myelin sheath (i.e. brain "white matter"), recent studies have not surprisingly revealed that white matter atrophy precedes the conventional biomarkers of AD (amyloid plaques, tau tangles). Employing extensive microsecond all-atom molecular dynamics simulations, we investigated biophysical and mechanical properties of myelin sheath membrane as a function of cholesterol mole fraction (χCHL). Impaired χCHL modulates multiple bilayer properties, including surface area per lipid (APL), chain order, number and mass density profiles, area compressibility and bending moduli, bilayer thickness, lipid tilt angles, H-bonding interactions and tail interdigitation. The increased orientational ordering of both palmitoyl and oleoyl chains in model healthy myelin sheath (HMS) membranes illustrates the condensing effect of cholesterol. With an increase in χCHL, number density profiles of water tend to attain bulk water number density more quickly, indicating shrinkage in the interfacial region with increasing χCHL. The average tilt value is 11.5° for the C10-C13 angle in cholesterol and 64.2° for the P-N angle in POPC lipids in HMS. These calculations provide a molecular-level understanding of myelin sheath susceptibility to pathology as an early event in the pathogenesis of AD.

Lapatinib alleviates TOCP-induced axonal damage in the spinal cord of mouse

Neuregulin-1 (NRG1), a family of EGF-like factors that activates ErbB receptors, can regulate the proliferation, migration, and myelinating of Schwann cells. We previously reported that NRG1/ErbB signal is responsible for organophosphate (OP)-induced delayed neuropathy (OPIDN) in hens, a susceptive animal model to neuropathic organophosphorous compounds. Our previous study discovered that a neuropathic OP, tri-o-cresyl phosphate (TOCP) activated NRG1/ErbB signaling pathway in both spinal cord and sciatic nerves of hens during the formation of OPIDN and lapatinib, a non-selective antagonist of ErbB1 and ErbB2 receptors, alleviated the toxicity. In this study, we intended to further look into the potential role of NRG1 in the pathogenesis of TOCP-induced axon damage in spinal cord and sciatic nerves and whether lapatinib could also rescue this damage in mice, an OPIDN-resistant animal model. The results revealed that no obvious toxic signs were observed after single TOCP exposure. However, slight histopathological wreck in lumbar spinal cord and sciatic nerves was found following TOCP intoxication, and the damage in sciatic nerves was characterized by axon degeneration of myelin sheath but not the loss of neural skeleton. Only histopathological damage induced by TOCP in spinal cord could be prevented by lapatinib. The translational expression of NRG1/ErbB signaling molecules was analyzed by both in vivo and in vitro studies. In general, NRG1/ErbB pathway was activated by TOCP while combined treatment with lapatinib attenuated TOCP-induced NRG1/ErbB signaling cascade. The results implied that NRG1/ErbB system may predominately play functional role in spinal cord (central nervous system) but not in sciatic nerves (peripheral nervous system) of mouse subjected to neurotoxic OP, which was confirmed by the study in vitro that lapatinib was not able to attenuate TOCP-induced neurotoxicity in rodent Schwann cell line RSC 96 cells.

Human Umbilical Cord Mesenchymal Stem Cells-Secreted TSG-6 Is Anti-Inflammatory and Promote Tissue Repair After Spinal Cord Injury

Spinal cord injury (SCI) causes patients paralysis and hard to recover. The therapeutic effects of current clinical drugs are accompanied by side effects. In recent years, stem cell therapy has attracted the attention of researchers. Human umbilical cord mesenchymal stem cells (hucMSCs) have been widely used in various diseases due to their excellent paracrine function. TNF-stimulated gene 6 (TSG-6), a secretion factor of stem cells, may play an important role in hucMSCs in the treatment of SCI. So we conducted an experiment to explore its effect. We first observed that the expression of TSG-6 increased in SCI rats after injected with hucMSCs. Then, we used siRNA to knowdown the expression of TSG-6. We treated SCI rats with TSG-6-knockdown hucMSCs. Without TSG-6 expression, hucMSCs treatment made the tissue recovery worse and the number of Nissl bodies less. Meanwhile, neutrophils infiltrated more in the damaged parts. Our research also proved that TSG-6 may help demyelination recovering and alleviate astrocytes gathering in the injury sites. Our study revealed that hucMSCs secreted TSG-6 may decrease the degeneration of myelin sheath, reduce inflammation, decrease neuron loss and promote tissue repair. These results provided a new therapeutic factor for the treatment of SCI.

Myelin detection in fluorescence microscopy images using machine learning

BackgroundThe myelin sheath produced by glial cells insulates the axons, and supports the function of the nervous system. Myelin sheath degeneration causes neurodegenerative disorders, such as multiple sclerosis (MS). There are no therapies for MS that promote remyelination. Drug discovery frequently involves screening thousands of compounds. However, this is not feasible for remyelination drugs, since myelin quantification is a manual labor-intensive endeavor. Therefore, the development of assistive software for expedited myelin detection is instrumental for MS drug discovery by enabling high-content image-based drug screens. New methodIn this study, we developed a machine learning based expedited myelin detection approach in fluorescence microscopy images. Multi-channel three-dimensional microscopy images of a mouse stem cell-based myelination assay were labeled by experts. A spectro-spatial feature extraction method was introduced to represent local dependencies of voxels both in spatial and spectral domains. Feature extraction yielded two data set of over forty-seven thousand annotated images in total. ResultsMyelin detection performances of 23 different supervised machine learning techniques including a customized-convolutional neural network (CNN), were assessed using various train/test split ratios of the data sets. The highest accuracy values of 98.84±0.09% and 98.46±0.11% were achieved by Boosted Trees and customized-CNN, respectively. Comparison with existing methodsOur approach can detect myelin in a common experimental setup. Myelin extending in any orientation in 3 dimensions is segmented from 3 channel z-stack fluorescence images. ConclusionsOur results suggest that the proposed expedited myelin detection approach is a feasible and robust method for remyelination drug screening.

Fluoride-Induced Expression of Neuroinflammatory Markers and Neurophysiological Regulation in the Brain of Wistar Rat Model.

Excess fluoride intake has been linked with various pathological conditions. The objective of the present study was to understand the role of fluoride in neurotoxic, neuroinflammatory, and neurodegenerative changes in the brain tissue of Wistar rats. Wistar rats were fed with water containing 20-100ppm (ppm) sodium fluoride (NaF). An array of neurotransmitters (acetylcholine, dopamine, epinephrine, norepinephrine, serotonin, histamine, and glutamate) expression levels were estimated with respect to different fluoride concentrations. Additionally, its effect on the expression levels of specific neuroinflammatory markers (iNOS, COX-2, TNF-α, PKC, VEGF, and HSP-70) in brain tissues of Wister rats was assessed. An increase in NaF concentration resulted in increased fluoride deposition in the brain which in turn caused increase levels of epinephrine, histamine, serotonin, and glutamate and decreased levels of norepinephrine, acetylcholine, and dopamine in a dose-dependent manner. Tissue fluoride levels of the hippocampus, neocortex, cerebellum, spinal cord, and sciatic nerve increased significantly in fluoride fed rats. Transmission electron microscopy in the experimental animals revealed axon deterioration, myelin sheath degeneration, and dark cells with scanty cytoplasm in the spinal cord and sciatic nerve. Additionally, vacuolated swollen mitochondria were observed in the neocortex, hippocampus, and cerebellum. Results suggest excess fluoride intake modulates a set of biological marker and promote neuroinflammatory and neurodegenerative condition in Wister rats. Therefore, we conclude that the accumulation of NaF alters the neurological function which leads to neurodegenerative disorders.

Notch pathway up-regulation via curcumin mitigates bisphenol-A (BPA) induced alterations in hippocampal oligodendrogenesis

CNS myelination process involves proliferation and differentiation of oligodendrocyte progenitor cells (OPCs). Defective myelination causes onset of neurological disorders. Bisphenol-A (BPA), a component of plastic items, exerts adverse effects on human health. Our previous studies indicated that BPA impairs neurogenesis and myelination process stimulating cognitive dysfunctions. But, the underlying mechanism(s) of BPA induced de-myelination and probable neuroprotection by curcumin remains elusive. We found that curcumin protected BPA mediated adverse effects on oligosphere growth kinetics. Curcumin significantly improved proliferation and differentiation of OPCs upon BPA exposure both in-vitro and in-vivo. Curcumin enhanced the mRNA expression and protein levels of myelination markers in BPA treated rat hippocampus. Curcumin improved myelination potential via increasing β-III tubulin-/MBP+ cells (neuron-oligodendrocyte co-culture) and augmented fluoromyelin intensity and neurofilament/MBP+ neurons in vivo. In silico docking studies suggested Notch pathway genes (Notch-1, Hes-1 and Mib-1) as potential targets of BPA and curcumin. Curcumin reversed BPA mediated myelination inhibition via increasing the Notch pathway gene expression. Genetic and pharmacological Notch pathway inhibition by DAPT and Notch-1 siRNA exhibited decreased curcumin mediated neuroprotection. Curcumin improved BPA mediated myelin sheath degeneration and neurobehavioral impairments. Altogether, results suggest that curcumin protected BPA induced de-myelination and behavioural deficits through Notch pathway activation.

Nanoscience in Multiple Sclerosis

Multiple Sclerosis (MS) - the most common autoimmune disease of the central nervous system – is traditionally diagnosed by methods mainly using magnetic resonance techniques to detect the lesions. Use of nanoparticles as the contrast agents can help in better diagnosis of the damaged cells. Iron nanoparticles are used in various advanced techniques like superparamagnetic iron oxide nanoparticles (SPIONs) and ultra-small SPIONs (USPIONs). The major challenge in treatment of MS is the delivery of the drug into the brain, crossing the blood brain barrier (BBB). Nanoparticles like liposomes, nanoshells, dendrimers, nanogels, micelles have potential applications in the same. Presently, no significant treatment is devoid of side effects like fever, headache and fatigue, Use of nanoscience in MS in drug delivery and treatment can help solve the prevailing inadequacies. Administered quantum dots conjugated with self-antigens act on lymph nodes and spleen. These assemblies produce regulatory T-cells which prevent degeneration of myelin sheath. New studies study modifications to produce inflammation-resistant myelin by inducing response in lymph nodes during T-cell priming. This review aims to briefly describe the application of nanotechnology in diagnosis, drug delivery and treatment of MS.

Changes in expression of microRNA-221 and phosphatase and tension protein homologue in nerve stump after peripheral nerve injury

To study the expressions of microRNA-221 (miR-221) and the protein of phosphatase and tension protein homologue (PTEN) in the proximal and distal stumps after sciatic nerve injury in rats and their correlation with the repair of peripheral nerve injury, so as to provide a new target for clinical diagnosis of peripheral nerve injury. Ninety-six male Sprague-Dawley rats of SPF grade were selected to establish sciatic nerve injury models. Twenty-four rats were sacrificed at 0 (immediately after operation), 1, 4, and 7 days after operation. The proximal and distal sciatic nerve fragments were taken under aseptic conditions. The expression of miR-221 was detected by real-time fluorescent quantitative PCR, and the expression of PTEN protein was detected by Western blot and immunofluorescent staining. The relationship between miR-221 and PTEN was verified by dual-luciferase reporter gene. At the same time, the ultrastructure of nerve stump was observed by transmission electron microscopy. The results of real-time fluorescent quantitative PCR, Western blot, and immunofluorescence staining showed that the relative expression of miR-221 in the proximal and distal stumps increased gradually with time, and the relative expression of PTEN protein decreased gradually, and the differences between different time points after operation were significant ( P<0.05). At 1, 4, and 7 days after operation, the relative expression of miR-221 in proximal stump was significantly higher than that in distal stump, and the relative expression of PTEN protein in proximal stump was significantly lower than that in distal stump ( P<0.05). Dual-luciferase reporter gene suggested that PTEN was the target for miR-221. Transmission electron microscopy observation showed that the normal morphological structure was observed at 0 day after operation, and the proliferation of Schwann cells and degeneration of axons and myelin sheaths gradually increased with time. There was no significant difference between proximal and distal stumps at 1 day after operation. At 4 and 7 days, Schwann cells proliferated more in proximal stump than in distal stump, and the degeneration of axons and myelin sheaths was less. After sciatic nerve injury in rats, the up-regulation of the miR-221 expression targets the down-regulation of PTEN expression, which results in the difference of expression levels of miR-221 and PTEN in proximal and distal stumps. This phenomenon may play a role in promoting nerve repair after peripheral nerve injury.

Neurotoxic responses in brain of catla catla exposed to cypermethrin: A semiquantitative multibiomarker evaluation

Abstract Fish being in direct and continuous contact with water serve as ecologically relevant indicator of health of aquatic environment. Cypermethrin (CYP) 2 , a pyrethroid pesticide is a potent neurotoxicant which induces adverse effects on non – target organisms, particularly fish. Present study was designed to evaluate in vivo effects of CYP on acetyl cholinesterase (AChE) activity, histopathology and ultra structure in brain of Catla catla. Fish was exposed to two sub-lethal concentrations of the pesticide (0.124 µg/L and 0.41 µg/L) for 45 days. Analysis of the brain tissue was done at an interval of 15, 30 and 45 days. Significant concentration and time dependent inhibition of AChE activity, and degree of tissue change (DTC 3 ) with respect to control was observed in brain after the toxicant treatment. Light microscopy revealed several histoarchitectural lesions such as necrosis, oedema, vacuolization, spongiosis and gliosis. Transmission electron microscographs of the control fish depicted neurons surrounded by supporting neuroglial tissue. Mild to moderate cellular changes such as shrinkage of axoplasm, irregular nucleus and fragmented rough endoplasmic reticulum was observed after 15 days of exposure to the pesticide. Most severe cytological alterations noticed after prolonged exposure to the toxicant at higher concentration were degeneration and decompaction of myelin sheath, swollen, vacuolated mitochondria with fragmented cristae, and neuroglia featuring degenerated cells. Necrotic changes such as neuronal shrinkage, disintegration of plasma membrane and condensed chromatin, suggested apoptosis induction. The prevalence of partial or complete cristolysis in mitochondria indicates that oxidative phosphorylation was severely compromised. The observed biochemical & cellular changes reflect the neurotoxic potential of cypermethrin at environmentally relevant sub-lethal concentration to Catla catla.

Impaired Myelination in the Aging Primate Brain: Quantification using a Combination of Novel Label‐Free Spectral Confocal Reflectance (SCoRe) Microscopy and Fluorescent Immunohistochemistry (IHC)

IntroductionNormal aging in the rhesus monkey is characterized by cognitive decline in learning, memory, and executive function. Monkeys are free of frank neurodegenerative diseases like Alzheimer's, and cortical neurons do not degenerate. Instead, age‐related myelin pathology accumulates and correlates with cognitive decline. Hence, quantifying myelination and assessing individual myelin sheaths is paramount to the study of normal aging. One of the challenges in understanding white matter pathology is the absence of suitable methods to measure myelin dynamics in the primate brain. While electron microscopy has identified ballooning degeneration and loss of myelin sheaths at the ultrastructural level, it has limited applicability to examination of large brain regions and requires unique fixation procedures that make other analyses difficult. Similarly, traditional myelin stains are very difficult to quantify and regular immunohistochemical markers fail to show the pathology directly. As an alternative, we investigated using the novel, label‐free microscopy method SCoRe (spectral confocal reflectance microscopy) in combination with IHC markers of normal myelin to measure myelin integrity in the aging primate brain.MethodsUsing SCoRe and IHC in brain tissue of 10 behaviorally tested adult rhesus monkeys (5 young and 5 old), we examined myelination in the cingulum bundle and cingulate gyrus of the frontal lobe, two regions previously identified for their involvement in cognitive functions compromised in aging. SCoRe was used to visualize individual myelinated axons in combination with a paranodal marker (anti‐Caspr) and axonal marker (anti‐neurofilament H—NFH). Specific measurements were made of the internode length of myelinated axons (anti‐Caspr + SCoRe) and percent of myelinated fibers (anti‐NFH + SCoRe). We also assessed remyelination efforts using a novel, selective antibody (BCAS1) marking actively myelinating oligodendrocytes (anti‐BCAS + anti‐CC1).ResultsWe found that the percentage of myelinated fibers decreases in the aging brain, which is consistent with previous findings in mouse, non‐human primate, and human. We also report an age‐related decrease in internode length and an increase in paranodes that support previous electron microscopy studies in the non‐human primate brain. Additionally, there is a decrease in the number of actively myelinating oligodendrocytes in the aging brain, corroborating previous data showing impaired remyelination with age.ConclusionsThese results demonstrate that we can use label‐free confocal microscopy techniques combined with IHC to quantify age‐related changes in myelin in the brain. Furthermore, these results suggest that myelin disturbances may be exacerbated (or caused) by a decrease in actively myelinating oligodendrocytes and provide an area for further research into the mechanisms of white matter pathology. This combination of techniques should be widely applicable in the study of white matter pathology that develops in health and disease.Support or Funding Information[Supported by NIH Grants R01‐AG04364 and R21‐061678]This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.