Lentinan alleviates sciatic nerve injury by promoting autophagy to remove myelin fragments.

Lentinan, a natural drug with wide-ranging pharmacological activities, can regulate autophagy-the process through which Schwann cells (SCs) eliminate myelin fragments after peripheral nerve injury (PNI). However, the effect of lentinan after PNI and the role of accelerated myelin debris removal via autophagy in this process are unclear. This study examined the effect of lentinan on rat sciatic nerve repair following crush injury and the underlying mechanisms. After the successful establishment of the sciatic nerve compression injury model, group-specific treatments were performed. The treatment group received 20 mg/kg lentinan via intraperitoneal injection, while the model group was treated with normal saline. The recovery in each group was then evaluated. Further, a rat SC line (RSC96) was cultured in medium with/without lentinan after supplementation with homogenous myelin fractions to evaluate the removal of myelin particles. Our results showed that lentinan promotes autophagic flux in vivo via the AMPK/mTOR signaling pathway, accelerates the clearance of myelin debris by SCs, and inhibits neuronal apoptosis, thereby promoting neurological recovery. Similarly, in vitro experiments showed that lentinan promotes the phagocytosis of myelin debris by SCs. In conclusion, our results suggest that lentinan primarily promotes nerve regeneration by accelerating the autophagic clearance of myelin debris in SCs, and this process is likely regulated by the AMPK/mTOR signaling pathway. Therefore, this study provides compelling evidence that lentinan may be a cost-effective and natural treatment agent for PNI.

Erythrocyte Plasma Membrane Lipid Composition Mirrors That of Neurons and Glial Cells in Murine Experimental In Vitro and In Vivo Inflammation.

Lipid membrane turnover and myelin repair play a central role in diseases and lesions of the central nervous system (CNS). The aim of the present study was to analyze lipid composition changes due to inflammatory conditions. We measured the fatty acid (FA) composition in erythrocytes (RBCs) and spinal cord tissue (gas chromatography) derived from mice affected by experimental allergic encephalomyelitis (EAE) in acute and remission phases; cholesterol membrane content (Filipin) and GM1 membrane assembly (CT-B) in EAE mouse RBCs, and in cultured neurons, oligodendroglial cells and macrophages exposed to inflammatory challenges. During the EAE acute phase, the RBC membrane showed a reduction in polyunsaturated FAs (PUFAs) and an increase in saturated FAs (SFAs) and the omega-6/omega-3 ratios, followed by a restoration to control levels in the remission phase in parallel with an increase in monounsaturated fatty acid residues. A decrease in PUFAs was also shown in the spinal cord. CT-B staining decreased and Filipin staining increased in RBCs during acute EAE, as well as in cultured macrophages, neurons and oligodendrocyte precursor cells exposed to inflammatory challenges. This regulation in lipid content suggests an increased cell membrane rigidity during the inflammatory phase of EAE and supports the investigation of peripheral cell membrane lipids as possible biomarkers for CNS lipid membrane concentration and assembly.

Inhibiting nighttime melatonin and boosting cortisol increase patrolling monocytes, phagocytosis, and myelination in a murine model of multiple sclerosis.

Conflicting results on melatonin synthesis in multiple sclerosis (MS) have been reported due to variabilities in patient lifestyles, which are not considered when supplementing melatonin. Since melatonin acts through its receptors, we identified melatonin receptors in oligodendrocytes (OLs) in the corpus callosum, where demyelination occurs; the subventricular zone, where neural stem/progenitor cells (NSPCs) are located; and the choroid plexus, which functions as a blood-cerebrospinal fluid barrier. Moreover, using chimeric mice, resident macrophages were found to express melatonin receptors, whereas bone marrow-derived macrophages lost this expression in the demyelinated brain. Next, we showed that cuprizone-fed mice, which is an MS model, tended to have increased melatonin levels. While we used different approaches to alter the circadian rhythm of melatonin and cortisol, only the constant light approach increased NSPC proliferation and differentiation to oligodendrocyte precursor cells (OPCs), OPCs maturation to OLs and recruitment to the site of demyelination, the number of patrolling monocytes, and phagocytosis. In contrast, constant darkness and exogenous melatonin exacerbated these events and amplified monocyte infiltration. Therefore, melatonin should not be considered a universal remedy, as is currently claimed. Our data emphasize the importance of monitoring melatonin/cortisol oscillations in each MS patient by considering diet and lifestyle to avoid melatonin overdose.

Effect of Hyperbaric oxygen on myelin injury and repair after hypoxic-ischemic brain damage in adult rat.

INTRODUCTION: Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of death and neurological disability with limited options for treatment in neonates, children and adults worldwide. The pathogenesis and treatment of white matter (WM) injury in adult patients with HIE remains largely elusive. METHODS: Sixty male Sprague-Dawley rats were randomly divided into control group, sham-operated group (HBO treatment 6 days after sham operation), and Hypoxia-ischemia (HI) induced brain damage group (receiving left carotid arteries ligation + hypoxia treatment), 1.5ATA hyperbaric oxygen group (HI + 1.5ATA HBOT) and 2.5ATA HBOT group (HI + 2.5ATA HBOT). All the rats were evaluated by water maze before operation, and 6 days after operation, and the function of learning and memory was evaluated; Demyelination in the hippocampus and prefrontal cortex was observed by Luxol fast blue staining (LFB) and MBP immunostaining; the number of Myelin Oligodendrocyte Glycoprotein (MOG),glial fibrillary acidic protein (GFAP), ionic calcium-binding adaptor (Iba-1) and NG2 positive cells in the hippocampus and prefrontal cortex were determined by immunofluorescence staining. The expression of interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor (TNF-α), Hypoxia Inducible Factor 1 Subunit Alpha (HIF1-α) and Superoxide dismutase (SOD) in brain and serum of rats were measured by Western Blot method and Enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with those in the normal control group and sham-operated group, in the HI group, the learning and memory abilities of rats were significantly decreased (P < 0.05), the intensity of LFB and MBP immunostaining in hippocampus and prefrontal cortex was significantly decreased (P < 0.05); the number of MOG positive oligodendrocytes (OLs) significantly decreased (P < 0.05), whereas the number of Iba-1, GFAP, NG2 positive microglias, astrocytes and oligodendrocyte precursors (OPCs) was increased (P < 0.05); the level of IL-1ß, IL-6, TNF-α and HIF-1a in brain and serum were significantly increased (P < 0.05), whereas SOD was significantly decreased in brain and increased in serum. Compared with those in the HI group, in both 1.5ATA and 2.5ATA HBOT group, the learning and memory abilities were significantly increased (P < 0.05); the intensity of LFB and MBP immunostaining in the hippocampus and prefrontal cortex was significantly increased (P < 0.05); the number of MOG positive OLs significantly increased (P < 0.05); the number of Iba-1, GFAP, NG2 positive microglias, astrocytes and OPCs was decreased (P < 0.05); the level of IL-1ß, IL-6, TNF-α and HIF-1a in brain and serum were significantly decreased (P < 0.05); the level of SOD was significantly increased in brain and decreased in serum. Morever, compared with those in the 1.5ATA group, 2.5ATA provided better treatment results (P < 0.05). CONCLUSION: In the present study, we demonstrated the mechanism of different pressure HBOT on HI induced brain injury from three levels: (1) On a tissue level, HBOT protects against HI induced myelin injury; (2) On a cellular level, HBOT attenuates HI-induced OL loss, suppresss the reactive activation of astrocyte and microglia, and may promote OPC to differentiate into OL; (3) On a molecular level, HBOT inhibites neuroinflammation, and balances oxidative damage and antioxidant capacity. Among the above effects, 2.5ATA HBOT is better than 1.5ATA HBOT. Ongoing research will continue to seek out the signalling pathways and molecules mechanisms on different pressure of HBOT-related myelin protection, and possibly expand suitable HBOT use in adult HIE clinically.

Vitamin D Promotes Remyelination by Suppressing c-Myc and Inducing Oligodendrocyte Precursor Cell Differentiation after Traumatic Spinal Cord Injury.

Demyelination due to oligodendrocytes loss occurs after traumatic spinal cord injury (TSCI). Several studies have suggested the therapeutic potential of vitamin D (VitD) in demyelinating diseases. However, experimental evidence in the context of TSCI is limited, particularly in the presence of prior VitD-deficiency. In the present study, a contusion and a transection TSCI rat model were used, representing mild and severe injury, respectively. Motor recovery was assessed in rats with normal VitD level or with VitD-deficiency after 8 weeks' treatment post-TSCI (Cholecalciferol, 500 IU/kg/day). The impact on myelin integrity was examined by transmission electron microscopy and studied in vitro using primary culture of oligodendrocytes. We found that VitD treatment post-TSCI effectively improved hindlimb movement in rats with normal VitD level irrespective of injury severity. However, cord-transected rats with prior deficiency did not seem to benefit from VitD supplementation. Our data further suggested that having sufficient VitD was essential for persevering myelin integrity after injury. VitD rescued oligodendrocytes from apoptotic cell death in vitro and enhanced their myelinating ability towards dorsal root axons. Enhanced myelination was mediated by increased oligodendrocyte precursor cells (OPCs) differentiation into oligodendrocytes in concert with c-Myc downregulation and suppressed OPCs proliferation. Our study provides novel insights into the functioning of VitD as a regulator of OPCs differentiation as well as strong preclinical evidence supporting future clinical testing of VitD for TSCI.

Ginsenoside Rg1 promotes remyelination and functional recovery in demyelinating disease by enhancing oligodendrocyte precursor cells-mediated myelin repair.

BACKGROUND: Inefficient differentiation of oligodendrocyte precursor cells (OPCs) is one of the significant pathological obstacles of myelin repair and provides an essential therapeutic target against behavioral dysfunction in various neurodegenerative diseases, especially in secondary progressive multiple sclerosis (SPMS). Ginsenoside Rg1 (Rg1) has traditionally been recognized as a protector of neuronal damages, preventing its degeneration. PURPOSE: We investigated the effects of Rg1 on myelin regeneration-mediated by OPCs and its therapeutic significance in SPMS. METHODS: A cuprizone (CPZ) model was established and then administered with Rg1 specific for evaluations of functional recovery and remyelination. In vitro, the primary mouse OPCs were isolated and cultured for examining their ability of myelin repair. Furthermore, a chronic experimental autoimmune encephalomyelitis (EAE) model was utilized to assess the therapeutic value on SPMS. RESULTS: We found that Rg1 promoted functional recovery of the demyelinated mice, including spatial memory, motor function, and anxiety-like behavior. Histologically, Rg1 enhanced myelin-genesis as proven by myelin staining and microstructures of myelin observed by transmission electron microscope. Furthermore, Rg1 significantly increased Olig2+ oligodendrocyte lineage cells in callosum, implying that the pro-remyelination effect of Rg1 was closely correlated to the enhanced differentiation of OPCs. We further demonstrated that Rg1 increased the survival and proliferation of OPCs as well as induced maturation in oligodendrocytes (OLs). Molecular analysis showed that Rg1 transduced the pro-differentiation signaling programmed by the GSK3ß/ß-Catenin pathway. Notably, relying on its pro-remyelination effects, Rg1 ameliorated severity and histopathology of EAE disease. CONCLUSION: By paving the way for OPCs differentiation, Rg1 could maintain the integrity of myelin and is a promising candidate for functional recovery in demyelinating diseases.

Differential Effect of Iron and Myelin on Susceptibility MRI in the Substantia Nigra.

Background The heterogeneous composition of substantia nigra (SN), including iron, nigrosome-1 substructure, and myelinated white matter, complicates the interpretation of MRI signals. Purpose To investigate R2* and quantitative susceptibility mapping (QSM) in the SN subdivisions of participants with Parkinson disease and healthy control subjects. Materials and Methods In this prospective study conducted from November 2018 to November 2019, participants with Parkinson disease and sex-matched healthy control subjects underwent 3-T MRI. R2* and QSM values were measured and compared in the anterior SN and posterior SN at the rostral (superior) and caudal (inferior) levels. Postmortem MRI and histology correlation of midbrain tissues was evaluated to investigate the effect of myelin and iron in the SN on R2* and QSM values. Results Forty individuals were evaluated: 20 healthy control subjects (mean age, 61 years ± 3 [standard deviation]; 10 men) and 20 participants with Parkinson disease (mean age, 61 years ± 4; 10 men). The R2* values of participants with Parkinson disease were higher in all subdivisions of the SN compared with R2* values in healthy control subjects (all P < .05). For QSM, no evidence of a difference was found in the rostral posterior SN (healthy control subjects, 54.1 ppb ± 21.0; Parkinson disease, 62.2 ppb ± 19.8; P = .49). The combination of rostral R2* and caudal QSM values resulted in an area under the receiver operating characteristic curve of 0.84. R2* values showed higher correlation with QSM values at the caudal level than at the rostral level within each group (all P < .001). Postmortem investigation demonstrated that R2* and QSM values showed weak correlation in the myelin-rich areas (r = 0.22 and r = 0.36, P < .001) and strong correlation in myelin-scanty areas (r ranged from approximately 0.52 to approximately 0.78, P < .001) in the SN. Conclusion Considering the iron and myelin distribution in the substantia nigra subdivisions, the subdivisional analysis of substantia nigra using R2* and quantitative susceptibility mapping might aid in specifically differentiating individuals with Parkinson disease from healthy control subjects. © RSNA, 2021 Online supplemental material is available for this article.

Electroacupuncture Inhibits Myelin Sheath Injury in the Internal Capsule After Focal Cerebral Infarction in Rats Through the Nogo-A/NgR Signaling Pathway.

BACKGROUND Ischemic stroke is usually accompanied by white matter damage. The effect of electroacupuncture (EA) on ameliorating white matter damage is still unclear. The purpose of this study was to explore the precise mechanism of EA in treating ischemic white matter. MATERIAL AND METHODS In this study, 40 Sprague-Dawley rats were randomly divided into 4 groups: normal group, the sham-operated group, model group, and EA group. The stroke model was established by right middle cerebral artery occlusion, and EA was performed 24 h after the operation for 30 min per day. After 14 days of treatment, brain tissue samples were collected. Hematoxylin and eosin and Luxol fast blue staining were used to observe the changes of white matter damage in the internal capsule (IC). The expression levels of myelin basic protein (MBP), Nogo-A, and Nogo-A receptor (NgR) were detected by immunohistochemistry and western blot. RESULTS Compared with the sham-operated group, the model group had decreased expression of MBP and significantly increased expression of Nogo-A and NgR (P<0.05). Compared with the model group, the IC damage was alleviated in the EA group. Immunohistochemistry and western blot analysis showed that EA significantly increased the expression of MBP in white matter (P<0.05) and downregulated the expression levels of Nogo-A and NgR (P<0.05). CONCLUSIONS The results of this study indicate that EA can inhibit the expression of Nogo-A/NgR and promote myelin sheath regeneration.

CNS Hypomyelination Disrupts Axonal Conduction and Behavior in Larval Zebrafish.

Myelination is essential for central nervous system (CNS) formation, health and function. As a model organism, larval zebrafish have been extensively employed to investigate the molecular and cellular basis of CNS myelination, because of their genetic tractability and suitability for non-invasive live cell imaging. However, it has not been assessed to what extent CNS myelination affects neural circuit function in zebrafish larvae, prohibiting the integration of molecular and cellular analyses of myelination with concomitant network maturation. To test whether larval zebrafish might serve as a suitable platform with which to study the effects of CNS myelination and its dysregulation on circuit function, we generated zebrafish myelin regulatory factor (myrf) mutants with CNS-specific hypomyelination and investigated how this affected their axonal conduction properties and behavior. We found that myrf mutant larvae exhibited increased latency to perform startle responses following defined acoustic stimuli. Furthermore, we found that hypomyelinated animals often selected an impaired response to acoustic stimuli, exhibiting a bias toward reorientation behavior instead of the stimulus-appropriate startle response. To begin to study how myelination affected the underlying circuitry, we established electrophysiological protocols to assess various conduction properties along single axons. We found that the hypomyelinated myrf mutants exhibited reduced action potential conduction velocity and an impaired ability to sustain high-frequency action potential firing. This study indicates that larval zebrafish can be used to bridge molecular and cellular investigation of CNS myelination with multiscale assessment of neural circuit function.SIGNIFICANCE STATEMENT Myelination of CNS axons is essential for their health and function, and it is now clear that myelination is a dynamic life-long process subject to modulation by neuronal activity. However, it remains unclear precisely how changes to myelination affects animal behavior and underlying action potential conduction along axons in intact neural circuits. In recent years, zebrafish have been employed to study cellular and molecular mechanisms of myelination, because of their relatively simple, optically transparent, experimentally tractable vertebrate nervous system. Here we find that changes to myelination alter the behavior of young zebrafish and action potential conduction along individual axons, providing a platform to integrate molecular, cellular, and circuit level analyses of myelination using this model.

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.

Postnatal Iron Supplementation with Ferrous Sulfate vs. Ferrous Bis-Glycinate Chelate: Effects on Iron Metabolism, Growth, and Central Nervous System Development in Sprague Dawley Rat Pups.

Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.

The Effect of Chronic Ethanol Exposure and Thiamine Deficiency on Myelin-related Genes in the Cortex and the Cerebellum.

BACKGROUND: Long-term alcohol consumption has been linked to structural and functional brain abnormalities. Furthermore, with persistent exposure to ethanol (EtOH), nutrient deficiencies often develop. Thiamine deficiency is a key contributor to alcohol-related brain damage and is suspected to contribute to white matter pathology. The expression of genes encoding myelin proteins in several cortical brain regions is altered with EtOH exposure. However, there is limited research regarding the impact of thiamine deficiency on myelin dysfunction. METHODS: A rat model was used to assess the impact of moderate chronic EtOH exposure (CET; 20% EtOH in drinking water for 1 or 6 months), pyrithiamine-induced thiamine deficiency treatment (PTD), both conditions combined (CET-PTD), or CET with thiamine injections (CET + T) on myelin-related gene expression (Olig1, Olig2, MBP, MAG, and MOG) in the frontal and parietal cortices and the cerebellum. RESULTS: The CET-PTD treatments caused the greatest suppression in myelin-related genes in the cortex. Specifically, the parietal cortex was the region that was most susceptible to PTD-CET-induced alterations in myelin-related genes. In addition, PTD treatment, with and without CET, caused minor fluctuations in the expression of several myelin-related genes in the frontal cortex. In contrast, CET alone and PTD alone suppressed several myelin-related genes in the cerebellum. Regardless of the region, there was significant recovery of myelin-related genes with extended abstinence and/or thiamine restoration. CONCLUSION: Moderate chronic EtOH alone had a minor effect on the suppression of myelin-related genes in the cortex; however, when combined with thiamine deficiency, the reduction was amplified. There was a suppression of myelin-related genes following long-term EtOH and thiamine deficiency in the cerebellum. However, the suppression in the myelin-related genes mostly occurred 24 h after EtOH removal or following thiamine restoration; within 3 weeks of abstinence or thiamine recovery, gene expression rebounded.

Olive Leaf Polyphenols Attenuate the Clinical Course of Experimental Autoimmune Encephalomyelitis and Provide Neuroprotection by Reducing Oxidative Stress, Regulating Microglia and SIRT1, and Preserving Myelin Integrity.

Numerous evidences suggest that plant polyphenols may have therapeutic benefits in regulating oxidative stress and providing neuroprotection in many neurodegenerative diseases, including multiple sclerosis (MS). However, these mechanisms are not yet completely understood. In this study, we investigated the effect of olive leaf polyphenols on oxidative stress through oxidation marker level and activity (TBARS, SOD, and GPX) and their protein expression (SOD1, SOD2, and GPX1), as well as the protein expression of Sirtuin 1 (SIRT1) and microglia markers (Iba-1, CD206, and iNOS) and myelin integrity (proteolipid protein expression) in the brain of rats with induced experimental autoimmune encephalomyelitis (EAE) and subjected to olive leaf therapy. Experiments were performed in male EAE DA rats, which were randomly divided into 2 main groups: EAE groups treated with the therapy of olive leaf (EAE+TOL) and untreated EAE control groups. The EAE treated groups consumed olive leaf tea instead of drinking water (ad libitum) from the beginning to the end of the experiment. In addition, olive leaf extract was injected intraperitoneally (i.p.) for the 10 continuous days and started on the 8th day after EAE induction. The clinical course was monitored in both groups until the 30th day after EAE induction. Our results demonstrated that TOL attenuated the clinical course of EAE; reduced the oxidative stress (by decreasing the concentration of MDA); upregulated antioxidant enzymes (SOD1, SOD2, and GPX1), SIRT1 (overall and microglial), and anti-inflammatory M2 microglia; downregulated proinflammatory M1 type; and preserved myelin integrity. These data support the idea that TOL may be an effective therapeutic approach for treating MS and other neurodegenerative diseases.

Electroacupuncture promotes axonal regrowth by attenuating the myelin-associated inhibitors-induced RhoA/ROCK pathway in cerebral ischemia/reperfusion rats.

The limited capacity of central nerve regeneration after cerebral ischemia has been the focus of attention in the field. Electroacupuncture (EA) is an effective therapy for functional rehabilitation after cerebral stroke. However, the underlying mechanism is still unclear. This study explored whether EA can improve the inhibitory microenvironment, attenuate RhoA/ROCK-mediated neurite regrowth inhibitory pathways, andpromote the expression of neuroplasticity proteins, thus exerting a protective role in cerebral ischemia/reperfusion (I/R) injury. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by 7 days of reperfusion, and they received EA or fasudil once daily for 7 days. The Garcia JH score, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and transmission electron microscopy (TEM) were used to assess neural injury. The protein and mRNA levels of myelin-associated inhibitors (MAIs), RhoA/ROCK pathway-related molecules and neuroplasticity-related proteins were examined to explore the effect of EA on rats with cerebral I/R injury. We found that EA significantly decreased the infarct size and improved neurological function and hippocampal ultrastructure in the rats with cerebral ischemia/reperfusion (I/R) injury. EA ameliorates the inhibition of axonal regrowth and provides a protective role in functional rehabilitation after cerebral stroke by downregulating the MAI-induced RhoA/ROCK signaling pathway and by promoting the expression of GAP43 and BDNF to protect against cerebral I/R injury. Our findings provide a better understanding of the molecular mechanism underlying EA as an effective therapy for ischemic stroke.

Methods for quantitative susceptibility and R2* mapping in whole post-mortem brains at 7T applied to amyotrophic lateral sclerosis.

Susceptibility weighted magnetic resonance imaging (MRI) is sensitive to the local concentration of iron and myelin. Here, we describe a robust image processing pipeline for quantitative susceptibility mapping (QSM) and R2* mapping of fixed post-mortem, whole-brain data. Using this pipeline, we compare the resulting quantitative maps in brains from patients with amyotrophic lateral sclerosis (ALS) and controls, with validation against iron and myelin histology. Twelve post-mortem brains were scanned with a multi-echo gradient echo sequence at 7T, from which susceptibility and R2* maps were generated. Semi-quantitative histological analysis for ferritin (the principal iron storage protein) and myelin proteolipid protein was performed in the primary motor, anterior cingulate and visual cortices. Magnetic susceptibility and R2* values in primary motor cortex were higher in ALS compared to control brains. Magnetic susceptibility and R2* showed positive correlations with both myelin and ferritin estimates from histology. Four out of nine ALS brains exhibited clearly visible hyperintense susceptibility and R2* values in the primary motor cortex. Our results demonstrate the potential for MRI-histology studies in whole, fixed post-mortem brains to investigate the biophysical source of susceptibility weighted MRI signals in neurodegenerative diseases like ALS.

Combination of Quercetin, Hirudin and Cinnamaldehyde Promotes Schwann Cell Differentiation and Myelination against High Glucose by Inhibiting ERK Signaling Pathway.

OBJECTIVE: To investigate the therapeutic and synergistic effects of QHC (combination of quercetin (Q), hirudin (H) and cinnamaldehyd (C)) on Schwann cell differentiation and myelination against high glucose (HG) induced injury. METHODS: Primary-culture Schwann cells exposed to HG (50 mmol/L) for 72 h and Schwann cell-dorsal root ganglion (DRG) neuron cocultures exposed to HG (50 mmol/L) for 7 days were employed as in vitro model of diabetic neuropathy. The cells were randomly divided into 10 groups: control (CON, 25 mmol/L glucose), HG (50 mmol/L glucose), HG plus 10 µmol/L quercetin (Q), HG plus 0.04 IU/mL hirudin (H), HG plus 100 nmol/L cinnamaldehyd (C), HG plus 10 µmol/L quercetin and 0.04 IU/mL hirudin (QH), HG plus 10 µmol/L quercetin and 50 nmol/L cinnamaldehyd (QC), HG plus 0.04 IU/mL hirudin and 50 nmol/L cinnamaldehyd (HC), HG plus 10 µmol/L quercetin, 0.04 IU/mL hirudin and 50 nmol/L cinnamaldehyd (QHC) or 10 µmol/L U0126. Cell differentiation was evaluated by periaxin immunofluorescence staining. The protein expression levels of myelin protein zero (P0), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), extracellular signal-regulated kinase (ERK), p-ERK, p-c-Jun, c-Jun, notch intracellular domain (NICD) and the mRNA expression levels of P0, MBP, MAG, Krox-20, Notch1 and Jagged1 were detected by Western blotting and real-time quantitative PCR analysis. The secretion of ciliary neurotrophic factor (CNTF) was determined by enzyme-linked immunosorbent assay (ELISA). The number and length of the myelin segments were evaluated by MBP immunofluorescence staining. The expression and the location of p-ERK in cocultures were detected by MAG and p-ERK immunofluorescence double staining. RESULTS: Co-treatment with Q, C, H and their combination promoted Schwann cell differentiation, increased CNTF secretion, up-regulated the protein and mRNA expressions of myelin, and increased the number and length of the myelin segments (P<0.01 or P<0.05). In particular, the combination therapy of Q, H and C was superior to the respective monotherapy (P<0.01). Combination therapy of QHC exhibited higher inhibitory activities for ERK signaling related molecules than each monomer or the combination of the two monomers (P<0.01). CONCLUSION: QHC combination yielded synergy in promoting Schwann cell differentiation and myelination and the protective effect may involve in the inhibition of ERK signaling pathway, providing scientific evidence for better understanding of combination of Q, H and C in clinical applications.

Dietary influence on central nervous system myelin production, injury, and regeneration.

Oligodendrocytes not only produce myelin to facilitate nerve impulse conduction, but are also essential metabolic partners of the axon. Oligodendrocyte loss and myelin destruction, as occurs in multiple sclerosis (MS), leaves axons vulnerable to degeneration and permanent neurological deficits ensue. Many studies now propose that lifestyle factors such as diet may impact demyelinating conditions, including MS. Most prior reviews have focused on the regulatory role of diet in the inflammatory events that drive MS pathogenesis, however the potential for dietary factors to modulate oligodendrocyte biology, myelin injury and myelin regeneration remain poorly understood. Here we review the current evidence from clinical and animal model studies regarding the impact of diet or dietary factors on myelin integrity and other pathogenic features of MS. Some limited evidence exists that certain foods may decrease risk or influence the progression of MS, such as increased intake of fish or polyunsaturated fatty acids, caloric restriction and fasting-mimicking diets. In addition, evidence suggests adolescent obesity or insufficient vitamin D levels increase the risk for developing MS. However, no clear or consistent evidence exists that dietary components exacerbate disease progression. Cumulatively, current evidence highlights the need for more extensive clinical trials to validate dietary effects on MS and to identify diets or supplements that may be beneficial as food-based strategies in the management of MS alone or in combination with conventional disease modifying therapies.

Synthetic α-Tocopherol, Compared with Natural α-Tocopherol, Downregulates Myelin Genes in Cerebella of Adolescent Ttpa-null Mice.

BACKGROUND: Vitamin E (α-tocopherol; α-T) deficiency causes spinocerebellar ataxia. α-T supplementation improves neurological symptoms, but little is known about the differential bioactivities of natural versus synthetic α-T during early life. OBJECTIVE: We assessed the effects of dietary α-T dose and source on tissue α-T accumulation and gene expression in adolescent α-tocopherol transfer protein-null (Ttpa-/-) mice. METHODS: Three-week-old male Ttpa-/- mice (n  = 7/group) were fed 1 of 4 AIN-93G-based diets for 4 wk: vitamin E deficient (VED; below α-T limit of detection); natural α-T, 600 mg/kg diet (NAT); synthetic α-T, 816 mg/kg diet (SYN); or high synthetic α-T, 1200 mg/kg diet (HSYN). Male Ttpa+/+ littermates fed AIN-93G [75 mg synthetic α-T (CON)] served as controls (n  = 7). At 7 wk of age, tissue α-T concentrations and stereoisomer profiles were measured for all groups. RNA-sequencing was performed on cerebella of Ttpa-/- groups. RESULTS: Ttpa-/- mice fed VED had undetectable brain α-T concentrations. Cerebral cortex α-T concentrations were greater in Ttpa-/- mice fed NAT (9.1 ± 0.7 nmol/g), SYN (10.8 ± 1.0 nmol/g), and HSYN (13.9 ± 1.6 nmol/g) compared with the VED group but were significantly lower than in Ttpa+/+ mice fed CON (24.6 ± 1.2 nmol/g) (P < 0.001). RRR-α-T was the predominant stereoisomer in brains of Ttpa+/+ mice (∼40%) and Ttpa-/- mice fed NAT (∼94%). α-T stereoisomer composition was similar in brains of Ttpa-/- mice fed SYN and HSYN (2R: ∼53%; 2S: ∼47%). Very few of the 16,774 genes measured were differentially expressed. However, compared with the NAT diet, HSYN significantly downregulated 20 myelin genes, including 2 transcription factors: SRY-box transcription factor 10 (Sox10) and myelin regulatory factor (Myrf), and several downstream target genes (false discovery rate <0.05). CONCLUSIONS: High-dose synthetic α-T compared with natural α-T alters myelin gene expression in the adolescent mouse cerebellum, which could lead to morphological and functional abnormalities later in life.

Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity.

Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.

Chronic exposure to high fat diet triggers myelin disruption and interleukin-33 upregulation in hypothalamus.

BACKGROUND: Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3-6 months to induce chronic obesity. RESULTS: The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. CONCLUSIONS: Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.