Myelin Sheath Of Axons Research Articles

Omeprazole Suppresses Oxaliplatin-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

(1) Background: Oxaliplatin is used as first-line chemotherapy not only for colorectal cancer but also for gastric and pancreatic cancers. However, it induces peripheral neuropathy with high frequency as an adverse event, and there is no effective preventive or therapeutic method. (2) Methods: The effects of omeprazole, a proton pump inhibitor (PPI), on oxaliplatin-induced peripheral neuropathy (OIPN) was investigated using an in vivo model and a real-world database. (3) Results: In a rat model, oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical hypersensitivity accompanied by sciatic nerve axonal degeneration and myelin sheath disorder. Repeated injection of omeprazole (5–20 mg/kg, i.p., five times per week for 4 weeks) ameliorated these behavioral and pathological abnormalities. Moreover, omeprazole did not affect the tumor growth inhibition of oxaliplatin in tumor bearing mice. Furthermore, clinical database analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) suggests that the group using omeprazole has a lower reporting rate of peripheral neuropathy of oxaliplatin-treated patients than the group not using (3.06% vs. 6.48%, p < 0.001, reporting odds ratio 0.44, 95% confidence interval 0.32–0.61). (4) Conclusions: These results show the preventing effect of omeprazole on OIPN.

In utero alcohol exposure impairs vessel-associated positioning and differentiation of oligodendrocytes in the developing neocortex

Prenatal alcohol exposure (PAE) is a major cause of nongenetic mental retardation and can lead to fetal alcohol syndrome (FAS), the most severe manifestation of fetal alcohol spectrum disorder (FASD). FASD infants present behavioral disabilities resulting from neurodevelopmental defects. Both grey and white matter lesions have been characterized and are associated with apoptotic death and/or ectopic migration profiles. In the last decade, it was shown that PAE impairs brain angiogenesis, and the radial organization of cortical microvessels is lost. Concurrently, several studies have reported that tangential migration of oligodendrocyte precursors (OPCs) originating from ganglionic eminences is vascular associated. Because numerous migrating oligodendrocytes enter the developing neocortex, the present study aimed to determine whether migrating OPCs interacted with radial cortical microvessels and whether alcohol-induced vascular impairments were associated with altered positioning and differentiation of cortical oligodendrocytes. Using a 3D morphometric analysis, the results revealed that in both human and mouse cortices, 15 to 40% of Olig2-positive cells were in close association with radial cortical microvessels, respectively. Despite perinatal vascular disorganization, PAE did not modify the vessel association of Olig2-positive cells but impaired their positioning between deep and superficial cortical layers. At the molecular level, PAE markedly but transiently reduced the expression of CNPase and MBP, two differentiation markers of immature and mature oligodendrocytes. In particular, PAE inverted their distribution profiles in cortical layers V and VI and reduced the thickness of the myelin sheath of efferent axons. These perinatal oligo-vascular defects were associated with motor disabilities that persisted in adults. Altogether, the present study provides the first evidence that Olig2-positive cells entering the neocortex are associated with radial microvessels. PAE disorganized the cortical microvasculature and delayed the positioning and differentiation of oligodendrocytes. Although most of these oligovascular defects occurred in perinatal life, the offspring developed long-term motor troubles. Altogether, these data suggest that alcohol-induced oligo-vascular impairments contribute to the neurodevelopmental issues described in FASD.

93. The Effects of Subnormothermic Plasma and Red Blood Cell Based Perfusion on the Function and Viability of Limb Allografts

Purpose: Vascularized composite allotranplantation (VCA) is an evolving area of modern transplantation medicine to reconstruct composite tissue defects such as abdominal wall, face, and limb. One of the challenges in VCA is the narrow window of tolerable ischemia time which limits the number of available donors and imposes a single center transplantation approach. Current standard of care, static cold storage, is only effective for short periods and may result in severe tissue damage and acute rejection when prolonged. Ex-situ perfusion has the potential to overcome these challenges by extending allowable pre-transplantation ischemia time. However, optimum perfusate composition, preservation temperature, and hemodynamic parameters of perfusion are still debated. Over the past decade, the benefits of addition of fresh plasma in hemorrhagic shock resuscitation and attenuation of subsequent reperfusion injury have been recognized. Whether these observations are due to high or low molecular weight (HMW and LMW, respectively) plasma proteins require further investigation. This study investigated the effects of the addition of plasma on the viability of perfused limb allografts with prolonged ischemia time. Methods: All limb transplantations were performed orthotopically between male Lewis rats (200-250 g). In group 1, amputated limbs were transplanted immediately to determine the effects of surgical trauma. In group 2, amputated limbs were preserved at 4°C simulating the clinical standard of care. In other groups, amputated limbs were perfused for 6 hours at 20° to 22°C using one of the following perfusates groups and transplanted to another recipient (in less than 90 minutes): RBC only (G3), RBC + whole plasma (G4), RBC + LMW plasma (G5), RBC + HMW plasma (G6). At 3 months post-transplantation, surviving recipients had end-point assessment using electromyography where compound muscle action potentials (CMAP) and extensor digitorum longus (EDL) muscle force generation were compared to contralateral healthy limb. Muscle and nerve histology samples were collected at the end of EMG testing. Results: Recipients in the group perfused with RBC and HMW plasma proteins had severe reperfusion injury and did not survive beyond 3 days. Among surviving recipients, the addition of whole plasma did not appear to improve amplitude and latency on gastrocnemius and EDL muscles compared to immediately transplanted limbs. Groups perfused with RBC only and RBC with LMW plasma demonstrated excellent amplitude and latencies on both muscle groups, with no significant difference compared to immediately transplanted limbs (p>0.05). The EDL muscle in these groups also generated similar tetanic and twitch forces compared to the immediate transplantation group (p>0.05). Conclusion: Ex-situ perfusion at 20° to 22°C for 6 hours using RBC and LMW plasma appears to protect both fast and slow twitch muscles, and improve axonal regeneration and myelin sheath thickness to a degree comparable with the immediately transplanted group.

Quality of life of patients with multiple sclerosis receiving medical care at Palestinian Ministry of Health Directorates in the West Bank, occupied Palestinian territory, and associated factors: a cross-sectional survey

BackgroundMultiple sclerosis is a neurological disease in which the immune system attacks the myelin sheath of axons, leading to symptoms that include loss of function, fatigue, blindness, and loss of balance. It is more common in women than in men. The disease has detrimental effects on patients’ health-related quality of life (QOL), physically, socially, and emotionally. This study assessed the QOL of patients with multiple sclerosis receiving medical care at Palestinian Ministry of Health directorates. MethodsIn this cross-sectional study, we approached all patients with multiple sclerosis receiving medical care in Ministry of Health clinics in all districts of the West Bank. In total, 150 patients were willing to participate. Participants were aged between 20 and 65 years and receiving treatment in ten directorates in the West Bank. We collected data from patients when they visited the clinics to collect medicines. The multiple sclerosis quality of life-54 (MSQOL-54) instrument is a self-administered questionnaire that is divided into two sections, the first comprising questions on basic demographic and socioeconomic characteristics, and the second focusing on the patient's QOL by assessing physical, mental, and emotional health factors. The MSQOL-54 scale scores were created using the Likert method by averaging items within the scales, then row scores were linearly transformed into 0–100 scales. The physical health composite score encompassed physical function health perceptions, energy and fatigue, and role limitations (relating to physical pain, sexual function, social function, and health distress). The mental health composite score encompassed health distress, overall QOL, emotional wellbeing, and role limitations (relating to emotional and cognitive function). These constructed variables were multiplied by the weight given to each variable to give the subtotal for each composite. Univariate analyses were initially performed using frequencies for categorical variables. Mean and SD were calculated for continuous variables. FindingsPatients had a mean age of 35 years (SD 10·90), and 103 (69%) were women. 43 (29%) lived in the north of the West Bank, 68 (45%) lived in the middle, and 39 (26%) in the south. 78 (52%) had a university degree, and 101 (67%) were married. 114 (76%) had a monthly income equal to the average wage in the occupied Palestinian territory. 77 (51%) were unemployed and 82 (55%) lived in cities. 109 (73%) were diagnosed with multiple sclerosis in the first year of the appearance of symptoms, and 127 (85%) took medication regularly. 76 (51%) benefitted from medication. 149 (99%) were diagnosed as having relapsing remitting multiple sclerosis. The overall mean QOL score was 58·71 (SD 22·06). For role limitation, the mean QOL scores relating to physical and emotional problems were 32 (SD 39·51) and 32 (40·11), to physical function was 35·8 (20·82), to emotional wellbeing was 45·94 (17·88), to fatigue was 40·74 (17·91), to health perception was 42·86 (21·80), and to health distress was 3·19 (1·38). The mean physical and mental health composite scores were 40·94 (38·97) and 39·91 (36·67), respectively. Similar physical and mental components of the QOL scores were found in patients with multiple sclerosis in studies from Bosnia and Herzegovina, Slovenia, and Italy. InterpretationThis study highlights the importance of assessing the QOL of patients with multiple sclerosis in the occupied Palestinian territory. All patients had low physical and mental health-related QOL scores. For the participants in this study, the most affected components of QOL were those related to role limitations due to physical and emotional problems, physical function, emotional wellbeing, fatigue, and health perception. Health distress was found to be the most powerful predictor of QOL of patients with multiple sclerosis. The results could potentially assist the Palestinian Ministry of Health in developing plans to improve the QOL of patients with multiple sclerosis. FundingNone.

Cyclin‐dependent kinase 7 contributes to myelin maintenance in the adult central nervous system and promotes myelin gene expression

Mechanisms regulating oligodendrocyte differentiation, developmental myelination and myelin maintenance in adulthood are complex and still not completely described. Their understanding is crucial for the development of new protective or therapeutic strategies in demyelinating pathologies such as multiple sclerosis. In this perspective, we have investigated the role of Cyclin-dependent kinase 7 (Cdk7), a kinase involved in cell-cycle progression and transcription regulation, in the oligodendroglial lineage. We generated a conditional knock-out mouse model in which Cdk7 is invalidated in post-mitotic oligodendrocytes. At the end of developmental myelination, the number and diameter of myelinated axons, as well as the myelin structure, thickness and protein composition, were normal. However, in young adult and in aged mice, there was a higher number of small caliber myelinated axons associated with a decreased mean axonal diameter, myelin sheaths of large caliber axons were thinner, and the level of some major myelin-associated proteins was reduced. These defects were accompanied by the appearance of an abnormal clasping phenotype. We also used an in vitro oligodendroglial model and showed that Cdk7 pharmacological inhibition led to an altered myelination-associated morphological modification combined with a decreased expression of myelin-specific genes. Altogether, we identified novel functions for Cdk7 in CNS myelination.

Three-dimensional bioprinting sodium alginate/gelatin scaffold combined with neural stem cells and oligodendrocytes markedly promoting nerve regeneration after spinal cord injury.

Accumulating research has indicated that the transplantation of combined stem cells and scaffolds is an effective method for spinal cord injury (SCI). The development of three-dimensional (3D) bioprinting technology can make the 3D scaffolds combined with cells more accurate and effective for SCI treatment. However, unmyelinated newborn nerve fibers have no nerve signaling conduction, hampering recovery of motor function. In this study, we designed and printed a type of sodium alginate/gelatin scaffold loaded with neural stem cells and oligodendrocytes, which were involved in the formation of the myelin sheaths of neural cell axons. In order to observe the effectiveness of this 3D bioprinting scaffold, we transplanted it into the completely transected rat spinal cord, and then immunofluorescence staining, hematoxylin–eosin staining and behavioral assessment were performed. The results showed that this 3D bioprinting scaffold markedly improved the hindlimb motor function and promoted nerve regeneration. These findings suggested that this novel 3D bioprinting scaffold was a good carrier for cells transplantation, thereby enhancing spinal cord repair following injury.

Cannabinoid and endocannabinoid system: a promising therapeutic intervention for multiple sclerosis.

Multiple sclerosis (MS) is a chronic and complex neurodegenerative disease, distinguished by the presence of lesions in the central nervous system (CNS) due to exacerbated immunological responses that inflict oligodendrocytes and the myelin sheath of axons. In recent years, studies have focused on targeted therapeutics for MS that emphasize the role of G protein-coupled receptors (GPCRs), specifically cannabinoids receptors. Clinical studies have suggested the therapeutic potential of cannabinoids derived from Cannabis sativa in relieving pain, tremors and spasticity. Cannabinoids also appear to prevent exaggerated immune responses in CNS due to compromised blood-brain barrier. Both, endocannabinoid system (ECS) modulators and cannabinoid ligands actively promote oligodendrocyte survival by regulating signaling, migration and myelination of nerve cells. The cannabinoid receptors 1 (CB1) and 2 (CB2) of ECS are the main ones in focus for therapeutic intervention of MS. Various CB1/CB2 receptors agonists have been experimentally studied which showed anti-inflammatory properties and are considered to be effective as potential therapeutics for MS. In this review, we focused on the exacerbated immune attack on nerve cells and the role of the cannabinoids and its interaction with the ECS in CNS during MS pathology.

Modulating Gut Microbiota: An Emerging Approach in the Prevention and Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a progressive neuromuscular disorder characterized by demyelination of neurons of the central nervous system (CNS). The pathogenesis of the disorder is described as an autoimmune attack targeting the myelin sheath of nerve cell axons in the CNS. Available treatments only reduce the risk of relapse, prolonging the remissions of neurological symptoms and halt the progression of the disorder. Among the new ways of targeting neurological disorders, including MS, there is modulation of gut microbiota since the link between gut microbiota has been rethought within the term gut-brain axis. Gut microbiota is known to help the body with essential functions such as vitamin production and positive regulation of immune, inflammatory, and metabolic pathways. High consumption of saturated fatty acids, gluten, salt, alcohol, artificial sweeteners, or antibiotics is the responsible factor for causing gut dysbiosis. The latter can lead to dysregulation of immune and inflammatory pathways, which eventually results in leaky gut syndrome, systemic inflammation, autoimmune reactions, and increased susceptibility to infections. In modern medicine, scientists have mostly focused on the modulation of gut microbiota in the development of novel and effective therapeutic strategies for numerous disorders, with probiotics and prebiotics being the most widely studied in this regard. Several pieces of evidence from preclinical and clinical studies have supported the positive impact of probiotic and/or prebiotic intake on gut microbiota and MS. This review aims to link gut dysbiosis with the development/progression of MS, and the potential of modulation of gut microbiota in the therapeutics of the disease.

Melatonin Ameliorates Axonal Hypomyelination of Periventricular White Matter by Transforming A1 to A2 Astrocyte via JAK2/STAT3 Pathway in Septic Neonatal Rats.

BackgroundAstrocyte A1/A2 phenotypes may play differential role in the pathogenesis of periventricular white matter (PWM) damage in septic postnatal rats. This study aimed to determine whether melatonin (MEL) would improve the axonal hypomyelination through shifting A1 astrocytes towards A2.MethodsOne-day-old Sprague–Dawley rats were divided into control, LPS, and LPS+MEL groups. Immunofluorescence was performed to detect C1q, IL-1α, TNF-α, IBA1, GFAP, MAG, C3 and S100A10 immunoreactivity in the PWM of neonatal rats. Electron microscopy was conducted to observe alterations of axonal myelin sheath in the PWM; moreover, myelin protein expression was assessed using in situ hybridization. The effects of MEL on neurological function were evaluated by behavioral tests. In vitro, A1 astrocytes were induced by IL-1α, C1q and TNF-α, and following which the effect of MEL on C3 and S100A10 expression was determined by Western blot and immunofluorescence.ResultsAt 1 and 3 days after LPS injection, IBA1+ microglia in the PWM were significantly increased in cell numbers which generated excess amounts of IL-1α, TNF-α, and C1q. The number of A1 astrocytes was significantly increased at 7–28d after LPS injection. In rats given MEL treatment, the number of A1 astrocytes was significantly decreased, but that of A2 astrocytes, PLP+, MBP+ and MAG+ cells was increased. By electron microscopy, ultrastructural features of axonal hypomyelination were attenuated by MEL. Furthermore, MEL improved neurological dysfunction as evaluated by different neurological tests. In vitro, MEL decreased the C3 significantly, and upregulated expression of S100A10 in primary astrocytes subjected to IL-1α, TNF-α and C1q treatment. Importantly, JAK2/STAT3 signaling pathway was found to be involved in modulation of A1/A2 phenotype transformation.ConclusionMEL effectively alleviates PWMD of septic neonatal rats, which is most likely through modulating astrocyte phenotypic transformation from A1 to A2 via the MT1/JAK2/STAT3 pathway.

Regeneration of the peripheral motor nerves and myelin sheath following hyperglycemic induction and recovery

The peripheral nervous system is made up of motor and sensory neurons that allow the brain to sense and respond to the environment. Diabetes mellitus is a chronic metabolic condition that often results in damage to these nerves. Patients with diabetic peripheral neuropathy (DPN) present with numbness, paresthesia, and/or muscle weakness. Because the pathophysiology underlying DPN is not yet clear, treatment is limited to pain management. In the Clark lab, we have shown that incubation of larval zebrafish for five days in 60 mM glucose concentration negatively affects axon length and myelin sheath coverage. Due to the known regenerative capabilities of zebrafish, we hypothesize that after removing the larvae from hyperglycemic conditions, peripheral motor axons and myelin sheath will begin to regenerate. Tg(NBT:DsRed) and Tg(mbp:caaxEGFP) larval zebrafish were incubated in 120 mM glucose solution (treatment), or egg water (control), for seven days beginning five days postfertilization. Incubation time was increased from 5 to 7 days to allow for a more robust phenotype while maintaining survivability. To allow for regeneration, zebrafish were placed in normal egg water for an additional ten days, and control fish were kept in egg water for an equal amount of time. Motor axon length of zebrafish following 7-day incubation glucose solution was significantly shorter than controls of the same age (12dpf), p<0.0001****. Following the 10-day recovery period, there was no significant difference between the 22dpf control group and the 22dpf treatment group, p = 0.1489, suggesting that the motor axons regenerated back to original length. Similarly, the length of the myelin sheath at 12dpf was significantly shorter in the treatment group compared to controls, p<0.0001****. Following recovery, there was no significant difference in myelin sheath length between treatment and control groups at 22dpf, p = 0.8801. This suggests that both the motor axons and myelin sheath were able to regenerate to lengths similar to controls following a 10-day recovery period. Future experiments conducting drug screens on compounds known to impact regeneration may elucidate signaling pathways in the regeneration process. This discovery would guide further research into potential therapeutics for DPN, and may even be manipulated for allow for regeneration in the central nervous system.

Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis.

In remitting–relapsing multiple sclerosis (RR-MS), relapses are driven by autoreactive immune cells that enter the brain and spinal cord and damage myelin sheaths of axons in white and grey matter, whereas during remissions myelin is repaired by activated oligodendroglial cells. Disease-modifying therapies (DMTs) may either retard/attenuate myelin damage or promote/enhance/speed up myelin repair. Almost all currently approved DMTs inhibit myelin damage and are considerably toxic. Enhancement of myelin repair is considered an unmet medical need of MS patients. Citicoline, known for many years as a nootropic and neuroprotective drug and recently pronounced food supplement, has been found to be significantly efficacious in two complementary rodent models of MS, experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced myelin toxicity. Moreover, citicoline treatment improves visual evoked potentials (VEPs) in glaucoma patients, which is relevant because VEP monitoring is frequently used as an indicator of remyelination in MS. Although over-the-counter availability of citicoline may impede its formal translation to the clinic of MS, evaluation of its efficacy for supporting remyelination in this disease is strongly indicated.

Study of neuropathological effect of Triortho Cresyl Phosphate in Midbrain of Hen

The objective of our study was to investigate the neuropathological effects in hens after administration of triortho cresyl phosphate , The experiment was summarized as the following: one hundred eighty hens were divided into 2 main groups, the first group was acute neurotoxicity done on 60 hen divided equally into control and treatment which received single-dose 600mg/kg orally for 18 days. The second group was subchronic toxicity done on 120 chicken that in turn divided equally into 4 subgroups, these are (untreated control, 2, 4, and 8 mg/kg daily) for 100 days. Neurotoxicity of triortho cresyl phosphate in hen of the midbrain in acute and one handred days. Subchronic studies showed mainly changes in the synapses characterized by disorganization, the presence of dark, degenerated mitochondria stained in synapses and ramifications. In some occasion's myelinated nerve, fibers showed evidence of degenerate myelin with vacuolation and spheroid body formation. In addition, myelin changes were characterized the formation of laminated bodies, also auto phagocytosis of degenerate myelin. Furthermore, the presence of degenerate mitochondria in the axoplasm of axon and in the cytoplasm of neurons. The degeneration of mitochondria characterized by loss of formation of laminated bodies in severe cases even deposits of calcium materials in the lamellated degenerate mitochondria. In conclusion, the presence of degenerated lamellate calcified mitochondria could be a strong indication that triortho-cresyl phosphate, does not cause only degenerated myelin sheath of axon but also cause degeneration of mitochondria.

HIV-Infected Patients: Cross Site-Specific Hydrolysis of H3 and H4 Histones and Myelin Basic Protein with Antibodies against These Three Proteins.

Histones play important roles in chromatin functioning and gene transcription, but in the intercellular space, they are harmful since they stimulate systemic inflammatory and toxic responses. Electrophoretically homogeneous IgGs against myelin basic protein (MBP), as well as H3 and H4 histones, were isolated from sera of HIV-infected patients. In contrast to known classical proteases, these IgGs split exclusively only histones and MBP but no other control proteins. Among 13 sites of hydrolysis of H3 by IgGs against H3 and 14 sites for anti-MBP IgGs, only two sites of the hydrolysis were the same. Between seven cleavage sites of H4 with IgGs against H4 and 9 sites of this histone hydrolysis by antibodies against MBP, only three sites were the same. The sites of hydrolysis of H3 (and H4) with abzymes against these histones and against MBP were different, but several expended protein clusters containing hydrolysis sites are partially overlapped. The existence of enzymatic cross-reactivity of abzymes against H3 and H4 and MBP represents a great menace to humans since due to cell apoptosis, histones constantly occur in human blood. They can hydrolyze MBP of the myelin sheath of axons and play a negative role in the pathogenesis of HIV-infected patients.

HIV-Infected Patients: Cross Site-Specific Hydrolysis of H2a and H2b Histones and Myelin Basic Protein with Antibodies against These Three Proteins.

Anti-DNA antibodies are usually produced against histone-DNA complexes appearing during cell apoptosis, while histones are known as damage-associated molecules. A myelin sheath of axons contains myelin basic protein (MBP) playing an important role in the pathogenesis of autoimmune diseases. Antibodies with enzymatic activities (abzymes) are distinctive features of some autoimmune and viral diseases. Abzymes against different proteins can usually only hydrolyze these specific proteins. Using sequential chromatographies of homogeneous IgG preparations from sera of HIV-infected patients on columns with immobilized MBP, H2a, and H2b histones, the anti-MBP, anti-H2a, and anti-H2b antibodies were obtained. It was first shown that IgGs against H2a and H2b effectively hydrolyze these histones and MBP, while anti-MBP split MBP, H2a, and H2b, but no other control proteins. Using the MALDI mass spectrometry, the cleavage sites of H2a, H2b, and MBP by abzymes against these three proteins were found. Among 14 sites of hydrolysis of H2a by IgGs against H2a and 10 sites by anti-MBP IgGs, only one site of hydrolysis was the same for these abzymes. Eleven cleavage sites of H2b with IgGs against H2b and 10 sites of its hydrolysis with antibodies against MBP were different. Anti-H2a, anti-H2b, and anti-MBP abzymes are unpredictable examples of IgGs possessing not only cross-complexation but also catalytic cross-reactivity, which may be a common phenomenon for such abzymes in patients with different autoimmune diseases. The existence of cross-reactivity of abzymes against H2a and H2b histones and MBP represent a great danger to humans since, in contrast with MBP, histones due to cell apoptosis constantly occur in human blood. Anti-H2a, anti-H2b, and anti-MBP can attack and hydrolyze myelin basic protein of the myelin sheath of axons and plays a negative role in the pathogenesis of several pathologies.

JAK-1/STAT-3 pathway mediated role in aging cerebellar cortex degenerative changes of albino wistar rats

BackgroundGlial fibrillary acidic protein (GFAP) is considered an important component of cerebellar astrocyte cytoskeleton. Previous studies had shown that the amount of GFAP may increase in all aging brain zones reflecting underlying gliosis. JAK-STAT system carry signals to deoxyribonucleic acid (DNA) affecting genes transcription. Different zones of the human brain accumulate Alzheimer's Disease (AD) pathological markers but cerebellum is proved to be the least affected zone. AimThe aim of the present research is to explore the impact of JAK-1/STAT-3 pathway on aging process of rats' cerebellar cortex. MethodSixty albino Wistar rats were divided into 12 M, 24 M and 32 M groups aged twelve, twenty-four and thirty-two months respectively. After one week of acclimatization, cerebella were dissected under general anesthesia and collected for histopathological examination, western blotting and biochemical examination. ResultsDegenerative changes were noticed in the cerebellum in addition to a significant decrease of thickness of all cerebellar layers thickness except granular layer in both 24 M and 32 M groups which also showed moderate and sever GFAP immunoreaction respectively. In 24M-group purkinje cells showed irregular nuclear envelope with disturbed mitochondrial cristae while in 32M-group, purkinje cells showed a greater extent of nuclear envelop irregularity and myelin sheath of granular cells axons appeared splitted. 12 M, 24 M and 32 M groups showed mild, moderate and sever caspase-3 immunoreaction. There was a significant decrease in JAK-1, STAT-3 and GSH expression in 24 M and 32 M groups while SOCS-3, TNF-α and MDA expression increased in the same groups which denotes the occurrence of cerebellar inflammatory pathway linked to aging. ConclusionJAK-1 and STAT-3 activity increase or SOCS-3 activity decrease can protect against cerebellar insult associated with aging cerebellum.

Certification procedures used by the Biological Stain Commission for eriochrome cyanine R (C.I. 43820, Mordant blue 3)

ABSTRACTEriochrome cyanine R (C.I. 43820, Mordant blue 3), also known as chromoxane cyanine R and solochrome cyanine R, has been used as a biological stain since 1957. In conjunction with ferric ions, it provides selective blue coloration of the nuclei of cells in methods procedurally similar to commonly used progressive or regressive hemalum (aluminum-hematoxylin) stains. Eriochrome cyanine R also is used to stain the myelin sheaths of axons in nerve tissue; the results are visually similar to those in sections stained with luxol fast blue MBS (C.I. 74180, solvent blue 38) with selective blue coloration of myelin and erythrocytes. Eriochrome cyanine R is an article of commerce with many uses in industrial coloration and analytical chemistry; it can be used instead of either hematoxylin or luxol fast blue MBS, especially in the event of a shortage of either of the latter compounds. The Biological Stain Commission (BSC) will certify batches of eriochrome cyanine R that meet the criteria set out in this document. The criteria include satisfactory UV/visible spectra at pH 4 and pH 12 − 13, a dye content not less than 40% and not greater than 52% (calculated as the color acid; equivalent to 46 − 59% of the trisodium salt), and satisfactory performance in three staining methods: regressive for nuclei, progressive for nuclei and regressive for myelin.

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma.

Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM.

Could non-invasive brain-stimulation prevent neuronal degeneration upon ion channel re-distribution and ion accumulation after demyelination?

Fast and efficient transmission of electrical signals in the nervous system is mediated through myelinated nerve fibers. In neuronal diseases such as multiple sclerosis, the conduction properties of axons are disturbed by the removal of the myelin sheath, leaving nerve cells at a higher risk of degenerating. In some cases, the protective myelin sheath of axons can be rebuilt by remyelination through oligodendroglial cells. In any case, however, changes in the ion channel organization occur and may help to restore impulse conduction after demyelination. On the other hand, changes in ion channel distribution may increase the energy demand of axons, thereby increasing the probability of axonal degeneration. Many attempts have been made or discussed in recent years to increase remyelination of affected axons in demyelinating diseases such as multiple sclerosis. These approaches range from pharmacological treatments that reduce inflammatory processes or block ion channels to the modulation of neuronal activity through electrical cortical stimulation. However, these treatments either affect the entire organism (pharmacological) or exert a very local effect (electrodes). Current results show that neuronal activity is a strong regulator of oligodendroglial development. To bridge the gap between global and very local treatments, non-invasive transcranial magnetic stimulation could be considered. Transcranial magnetic stimulation is externally applied to brain areas and experiments with repetitive transcranial magnetic stimulation show that the neuronal activity can be modulated depending on the stimulation parameters in both humans and animals. In this review, we discuss the possibilities of influencing ion channel distribution and increasing neuronal activity by transcranial magnetic stimulation as well as the effect of this modulation on oligodendroglial cells and their capacity to remyelinate previously demyelinated axons. Although the physiological mechanisms underlying the effects of transcranial magnetic stimulation clearly need further investigations, repetitive transcranial magnetic stimulation may be a promising approach for non-invasive neuronal modulation aiming at enhancing remyelination and thus reducing neurodegeneration.

Severity of the autoimmune encephalomyelitis symptoms in mouse model by inhibition of LAT-1 transporters

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the dynamic immune system acting against the myelin sheath of neuronal axons in the abluminal (brain-facing) side of the central nervous system. This immune system is greatly influenced by the free amino acid environment from the luminal (blood-facing) side. Whether the luminal and abluminal free amino acid balance influences EAE disease progression is still unclear. Changes in free amino acid levels on both sides of the blood–brain barrier were observed with or without blocking of the l-amino acid transporter (LAT-1) during EAE disease progression. Brain tissue, plasma, splenocytes samples were used to measure free amino acid by LC–MS/MS. Samples were also used to measure cytokines by ELISA and numbers of immune cells by flow cytometry. In the chronic stage of EAE progression, clinical scores of LAT-1-inhibited EAE mice were higher than those of normal EAE mice. Significantly elevated T-cell counts, MMP-9 activity, and IL-6 levels were found in the LAT-1-inhibited EAE group. Inhibition of LAT-1 with 2-amino-2-norbornanecarboxylic acid (BCH) treatment resulted in decreased leucine concentration in splenocytes and increased leucine levels in plasma. The leucine levels on the abluminal side of LAT-1-inhibited EAE mice were also significantly higher than those of control mice but not those of EAE mice. The increased leucine concentration present at the luminal side crossed the blood brain barrier (BBB) and fueled inflammation with concurrent disease severity in the abluminal side of EAE mice.

Invasion of microglia/macrophages and granulocytes into the Mauthner axon myelin sheath following spinal cord injury of the adult goldfish, Carassius auratus.

Rapid activation of resident glia occurs after spinal cord injury. Somewhat later, innate and adaptive immune responses occur with the invasion of peripheral immune cells into the wound site. The activation of resident and peripheral immune cells has been postulated to play harmful as well as beneficial roles in the regenerative process. Mauthner cells, large identifiable neurons located in the hindbrain of most fish and amphibians, provided the opportunity to study the morphological relationship between reactive cells and Mauthner axons (M-axons) severed by spinal cord crush or by selective axotomy. After crossing in the hindbrain, the M-axons of adult goldfish, Carassius auratus, extend the length of the spinal cord. Following injury, the M-axon undergoes retrograde degeneration within its myelin sheath creating an axon-free zone (proximal dieback zone). Reactive cells invade the wound site, enter the axon-free dieback zone and are observed in the vicinity of the retracted M-axon tip as early as 3 hr postinjury. Transmission electron microscopy allowed the detection of microglia/macrophages and granulocytes, some of which appear to be neutrophil-like, at each of these locations. We believe that this is the first report of the invasion of such cells within the myelin sheath of an identifiable axon in the vertebrate central nervous system (CNS). We speculate that microglia/macrophages and granulocytes that are attracted within a few hours to the damaged M-axon are part of an inflammatory response that allows phagocytosis of debris and plays a role in the regenerative process. Our results provide the baseline from which to utilize immunohistochemical and genetic approaches to elucidate the role of non-neuronal cells in the regenerative process of a single axon in the vertebrate CNS.