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Aims: Spinal cord injury (SCI) can cause a variety of cells apoptosis, neurodegeneration, and eventually permanent paralysis. This study aimed to examine whether transplanting human umbilical cord mesenchymal stem cells (hucMSCs) can promote locomotor function recovery, reduce apoptosis and inhibit demyelination in SCI models., Main Methods: Rats were allocated into Sham group (spinal cord exposure only), SCI + PBS group (spinal cord impact plus phosphate-buffered saline (PBS) injections), SCI + hucMSCs group (spinal cord impact plus hucMSCs injections) groups. Behavioral tests, Basso-Beattie-Bresnahan locomotion scores (BBB scores), were carried out at 0, 3, 7, 14, 21, 28 days after SCI surgery. Hematoxylin-eosin staining observed spinal cord morphology. Nissl staining detected the number of nissl bodies. Myelin basic protein (MBP) and oligodendrocyte (CNPase) were examed by immunohistochemical staining. The apoptosis of oligodendrocyte and neurons were detected by immunofluorescence., Results: The 28-day behavioral test showed that the BBB score of rats in the SCI + hucMSCs group increased significantly, comparing to the SCI + PBS group. The numbers of nissl bodies and myelin sheath in the damaged area of SCI + hucMSCs group were also significantly increased compared to the SCI + PBS group. HucMSCs transplanting decreased the expression of protein level of Caspase-3 and Bax and increased the Bcl-2, MBP and CNPase, rescued the apoptosis of neurons and the oligodendrocyte., Conclusion: These results showed that hucMSCs can improve motor function, tissue repairing and reducing apoptosis in SCI rats., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The evidence associating diet and risk of multiple sclerosis (MS) is inconclusive., Objectives: The aim of this study was to investigate associations between a Mediterranean diet and risk of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS., Methods: We used data from the 2003-2006 Ausimmune Study, an Australian multicenter, case-control study examining environmental risk factors for FCD, with participants matched on age, sex, and study region (282 cases, 558 controls; 18-59 y old; 78% female). The alternate Mediterranean diet score (aMED) was calculated based on data from a food-frequency questionnaire. We created a modified version of the aMED (aMED-Red) where ∼1 daily serving (65 g) of unprocessed red meat received 1 point. All other components remained the same as aMED. Conditional logistic regression (254 cases, 451 controls) was used to test associations between aMED and aMED-Red scores and categories and risk of FCD, adjusting for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, education, total energy intake, and dietary underreporting., Results: There was no statistically significant association between aMED and risk of FCD [per 1-SD increase in aMED score: adjusted odds ratio (aOR): 0.89; 95% CI: 0.75, 1.06; P = 0.181]. There was evidence of a nonlinear relation between aMED-Red and risk of FCD when a quadratic term was used (P = 0.016). Compared with the lowest category of aMED-Red, higher categories were significantly associated with reduced risk of FCD, corresponding to a 37% (aOR: 0.63; 95% CI: 0.41, 0.98; P = 0.039), 52% (aOR: 0.48; 95% CI: 0.28, 0.83; P = 0.009), and 42% (aOR: 0.58; 95% CI: 0.35, 0.96; P = 0.034) reduced risk of FCD in categories 2, 3, and 4, respectively., Conclusions: A Mediterranean diet, including unprocessed red meat, was associated with reduced risk of FCD in this Australian adult population. The addition of unprocessed red meat to a Mediterranean diet may be beneficial for those at high risk of MS., (Copyright © American Society for Nutrition 2019.)

Animal models of scopolamine-induced amnesia are widely used to study underlying mechanisms and treatment of cognitive impairment in neurodegenerative diseases such as Alzheimer's disease (AD). Previous studies have identified that melatonin improves cognitive dysfunction in animal models. In this study, using a mouse model of scopolamine-induced amnesia, we assessed spatial and short-term memory functions for 4 weeks, investigated the expression of myelin-basic protein (MBP) in the dentate gyrus, and examined whether melatonin and scopolamine cotreatment could keep cognitive function and MBP expression. In addition, to study functions of melatonin for keeping cognitive function and MBP expression, we examined expressions of brain-derived neurotrophic factor (BDNF) and tropomycin receptor kinase B (TrkB) in the mouse dentate gyrus. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally treated for 2 and 4 weeks. Two and 4 weeks after scopolamine treatment, mice showed significant cognitive impairment; however, melatonin and scopolamine cotreatment recovered cognitive impairment. Two and 4 weeks of scopolamine treatment, the density of MBP immunoreactive myelinated nerve fibers was significantly decreased in the dentate gyrus; however, scopolamine and melatonin cotreatment significantly increased the scopolamine-induced reduction of MBP expression in the dentate gyrus. Furthermore, the cotreatment of scopolamine and melatonin significantly increased the scopolamine-induced decrease of BDNF and TrKB immunoreactivity in the dentate gyrus. Taken together, our results indicate that melatonin treatment exerts anti-amnesic effect and restores the scopolamine-induced reduction of MBP expression through increasing BDNF and TrkB expressions in the mouse dentate gyrus., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The osmotic demyelination syndrome (ODS) is a serious neurologic condition that occurs in the setting of rapid correction of hyponatremia. It presents with protean manifestations, from encephalopathy to the "locked-in" syndrome. ODS can complicate liver transplantation (LT), and its incidence may increase with the inclusion of serum sodium as a factor in the Mayo End-Stage Liver Disease score. A comprehensive understanding of risk factors for the development of ODS in the setting of LT, along with recommendations to mitigate the risk of ODS, are necessary. The literature to date on ODS in the setting of LT was reviewed. Major risk factors for the development of ODS include severe pretransplant hyponatremia (serum sodium [SNa] < 125 mEq/L), the magnitude of change in SNa pre- versus posttransplant, higher positive intraoperative fluid balance, and the presence of postoperative hemorrhagic complications. Strategies to reduce the risk of ODS include correcting hyponatremia pretransplant via fluid restriction and/or ensuring an appropriate rate of increase from the preoperative SNa via close attention to fluid and electrolyte management both during and after surgery. Multidisciplinary management involving transplant hepatology, nephrology, neurology, surgery, and anesthesiology/critical care is key to performing LT safely in patients with hyponatremia., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Inflammation, demyelination, oligodendrocyte (OLG) death, and axonal degeneration are primary characteristics of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). OLGs generate myelin sheaths that surround axons, while damage to OLGs leads to demyelination and neurological functional deficit. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to effectively ameliorate clinical signs in EAE. Its therapeutic mechanism has, however, not been completely elucidated. In the present study, we found that MAT retarded the disease process, attenuated the clinical severity of EAE rats, ameliorated inflammation and demyelination, and suppressed the apoptosis of OLGs in the central nervous system (CNS) of EAE rats. In addition, MAT markedly blocked increased expression of the proNGF-p75(NTR) death signaling complex, which is known to mediate OLG death in EAE animals. At the same time, MAT also prevented a decrease in the levels of NGF and its receptor TrkA, which together mediate the cell survival pathway and differentiation of OLGs. ProNGF, NGF, and the downstream effector proteins play an important role in the growth, differentiation, and apoptosis of OLGs as well as the reparative response to neuronal damage. These findings thus indicate that MAT improves clinical severity of EAE in part by reducing OLG apoptosis via restoring the ratios of proNGF:NGF and the respective receptors p75(NTR):TrkA in vivo. Taken together, these results suggest that MAT may be a promising agent for MS treatment based on its protective effect on OLGs., (Copyright © 2015. Published by Elsevier Inc.)

Background: Astrocytes play an important role in the growth and survival of developing neurons by secreting neurotrophic factors., Objective: The goal of this study was to investigate how low-intensity pulsed ultrasound (LIPUS) stimulation directly affects brain astrocyte function., Methods: Here, we report that LIPUS stimulation increased protein levels of BDNF, GDNF, VEGF, and GLUT1 in rat brain astrocytes as measured by western blot analysis. Histological outcomes including demyelination and apoptosis were examined in rats after administration of aluminum chloride (AlCl3)., Results: At the mechanistic level, integrin inhibitor (RGD peptide) attenuated the LIPUS-induced neurotrophic factor expression. The data suggest that neurotrophic factor protein levels may be promoted by LIPUS through activation of integrin receptor signaling. In addition, LIPUS stimulation protected cells against aluminum toxicity as demonstrated by an increase in the median lethal dose for AlCl3 from 3.77 to 6.25 mM. In in vivo histological evaluations, LIPUS significantly reduced cerebral damages in terms of myelin loss and apoptosis induced by AlCl3., Conclusions: The results of this study demonstrate that transcranial LIPUS is capable of enhancing the protein levels of neurotrophic factors, which could have neuroprotective effects against neurodegenerative diseases., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline. Previous reports have suggested that, in some cases, urea can also be used to correct hyponatremia. Correction of severe hyponatremia with urea has never been compared to treatment with a vaptan or hypertonic saline with regard to the risk of brain complications in the event of a too rapid rise in serum sodium. Here, we compared the neurological outcome of hyponatremic rats corrected rapidly with urea, lixivaptan, and hypertonic saline. Despite similar increase in serum sodium obtained by the three drugs, treatment with lixivaptan or hypertonic saline resulted in a higher mortality than treatment with urea. Histological analysis showed that treatment with urea resulted in less pathological change of experimental osmotic demyelination than was induced by hypertonic saline or lixivaptan. This included breakdown of the blood-brain barrier, microglial activation, astrocyte demise, and demyelination. Thus, overcorrection of hyponatremia with urea resulted in significantly lower mortality and neurological impairment than the overcorrection caused by lixivaptan or hypertonic saline.

Overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome (ODS). Minocycline protects ODS associated with overly rapid correction of chronic hyponatremia with hypertonic saline infusion in rats. In clinical practice, inadvertent rapid correction frequently occurs due to water diuresis, when vasopressin action suddenly ceases. In addition, vasopressin receptor antagonists have been applied to treat hyponatremia. Here the susceptibility to and pathology of ODS were evaluated using rat models developed to represent rapid correction of chronic hyponatremia in the clinical setting. The protective effect of minocycline against ODS was assessed. Chronic hyponatremia was rapidly corrected by 1 (T1) or 10 mg/kg (T10) of tolvaptan, removal of desmopressin infusion pumps (RP), or administration of hypertonic saline. The severity of neurological impairment in the T1 group was significantly milder than in other groups and brain hemorrhage was found only in the T10 and desmopressin infusion removal groups. Minocycline inhibited demyelination in the T1 group. Further, immunohistochemistry showed loss of aquaporin-4 (AQP4) in astrocytes before demyelination developed. Interestingly, serum AQP4 levels were associated with neurological impairments. Thus, minocycline can prevent ODS caused by overly rapid correction of hyponatremia due to water diuresis associated with vasopressin action suppression. Increased serum AQP4 levels may be a predictive marker for ODS.

White matter is frequently involved in ischemic stroke, and progressive ischemic white matter injuries are associated with various neurologic dysfunctions in the elderly population. Demyelination and oligodendrocyte (OL) loss are prominent features of ischemic white matter injury. Endothelin-1 injection into the internal capsule resulted in a localized demyelinating lesion in mice, where loss of OL lineage cells and inflammatory cell infiltration were observed accompanied by upregulation of toll-like receptor 2 (TLR2). Intriguingly, the extent of demyelinating pathology was markedly larger in TLR2 deficient mice than that of wild-type (WT) mice. TLR2 deficient mice showed enhanced OL death and decreased phosphorylation of ERK1/2 compared with WT animals. Cultured OLs from TLR2 deficient mice were more vulnerable to oxygen-glucose deprivation than WT OLs. Applying TLR2 agonists Pam3CSK4 or Zymosan after oxygen-glucose deprivation substantially rescued WT OL death with augmentation of ERK1/2 phosphorylation. Treatment with Pam3CSK4 also reduced the extent of endothelin-1 induced ischemic demyelination in vivo. Our data indicate TLR2 may provide endogenous protective effects on ischemic demyelination and OL degeneration., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: The purpose of this study was to investigate whether the flavonoid quercetin can prevent alterations in the behavioral tests and of cholinergic neurotransmission in rats submitted to the ethidium bromide (EB) experimental demyelination model during events of demyelination and remyelination., Main Methods: Wistar rats were randomly distributed into four groups (20 animals per group): Control (pontine saline injection and treatment with ethanol), Querc (pontine saline injection and treatment with quercetin), EB (pontine 0.1% EB injection and treatment with ethanol), and EB+Querc (pontine 0.1% EB injection and treatment with quercetin). The groups Querc and Querc+EB were treated once daily with quercetin (50mg/kg) diluted in 25% ethanol solution (1ml/kg) and the animals of the control and EB groups were treated once daily with 25% ethanol solution (1ml/kg). Two stages were observed: phase of demyelination (peak on day 7) and phase of remyelination (peak on day 21 post-injection). Behavioral tests (beam walking, foot fault and inclined plane test), acetylcholinesterase (AChE) activity and lipid peroxidation in pons, cerebellum, hippocampus, hypothalamus, striatum and cerebral cortex were measured., Key Findings: The quercetin promoted earlier locomotor recovery, suggesting that there was demyelination prevention or further remyelination velocity as well as it was able to prevent the inhibition of AChE activity and the increase of lipidic peroxidation, suggesting that this compound can protect cholinergic neurotransmission., Significance: These results may contribute to a better understanding of the neuroprotective role of quercetin and the importance of an antioxidant diet in humans to provide benefits in neurodegenerative diseases such as MS., (Copyright © 2014. Published by Elsevier Inc.)

Chronic demyelinated lesions and subsequent functional impairment are resulted from eventual failure of remyelination process as seen in multiple sclerosis. Activation of adenosine A1 receptor is reported to be effective on neural stem cells (NSCs) proliferation and oligodendrocytes differentiation. Therefore, this study attempted to investigate the effect of A1 receptor agonist N6-cyclohexyladenosine (CHA), on lysolecithin (LPC) induced demyelination and remyelination in rat optic chiasm. The experiments were carried out on male Wistar rats using visual evoked potential recording, myelin staining by Luxol fast blue and histological evaluation of demyelinated and remyelinated axons within the area of lesion. CHA was administrated i.c.v. during demyelination or remyelination phases. As revealed by myelin staining, the most extent of demyelination occurred at 7th day post-lesion (dpl 7), but gradually myelination was restored toward control during days 14-28. VEP P1-latency and P1-N1 amplitude showed widespread demyelination on dpl 7 and 14 which consequently was reversed during days 14-28 post lesion. I.c.v. treatment of animals with CHA during demyelination phase (days 0-13) reduced the extent of demyelination. During remyelination phase (days 14-28), CHA was able to increase remyelination in both electrophysiological and histopathological studies. The effects of CHA seem to be due to its protective effect on myelinating cells and its regenerative effect through potentiating endogenous neural progenitors., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The green tea component epigallocatechin-3-gallate (EGCG) may be beneficial in autoimmune diseases; however, the underlying mechanisms are not well understood. In this study, we determined the effect of EGCG on the development of experimental autoimmune encephalomyelitis, an animal model for human multiple sclerosis, and the underlying mechanisms. Female C57BL/6 mice were fed EGCG (0%, 0.15%, 0.3%, and 0.6% in diet) for 30 days and then immunized with specific antigen myelin oligodendrocyte glycoprotein 35-55. EGCG dose dependently attenuated clinical symptoms and pathological features (leukocyte infiltration and demyelination) in the central nervous system and inhibited antigen-specific T-cell proliferation and delayed-type hypersensitivity skin response. We further showed that EGCG reduced production of interferon-γ, IL-17, IL-6, IL-1β, and tumor necrosis factor-α; decreased types 1 and 17 helper T cells (Th1 and Th17, respectively); and increased regulatory T-cell populations in lymph nodes, the spleen, and the central nervous system. Moreover, EGCG inhibited expression of transcription factors T-box expressed in T cells and retinoid-related orphan receptor-γt, the specific transcription factor for Th1 and Th17 differentiation, respectively; the plasma levels of intercellular adhesion molecule 1; and CCR6 expression in CD4(+) T cells. These results indicate that EGCG may attenuate experimental autoimmune encephalomyelitis autoimmune response by inhibiting immune cell infiltration and modulating the balance among pro- and anti-autoimmune CD4(+) T-cell subsets. Thus, we identified a novel mechanism that underlies EGCG's beneficial effect in autoimmune disease., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Systemic infection can influence the course in many diseases of the central nervous system (CNS) such as multiple sclerosis (MS), yet the relationship between infection outside the CNS and potential damage and/or protection within the CNS is still not understood. Activation of microglia is a characteristic feature of most CNS autoimmune disorders, including MS, and both protective and degenerative functions of microglia have been proposed. Hence, we analyzed the effects of a systemic inflammatory reaction induced by peripheral treatment with lipopolysaccharide (LPS) on microglial reaction and cuprizone induced de- and remyelination. We found that LPS administration delayed demyelination, which was linked with inhibition of microglial proliferation and reduced numbers of activated microglia. The phenotype of microglia changed as an increase of Toll-like receptor 4 was found. During remyelination, LPS treatment delayed the onset of myelin protein re-expression, but later there was a beneficial effect via an increase of proliferating oligodendrocyte precursor cells (OPC) and mature oligodendrocytes. Moreover, the expression of ciliary neurotrophic factor was increased in response to LPS, a growth factor known to mediate OPC proliferation. Additional experiments showed that the time window to induce LPS effects was limited and associated with the presence of microglia. In conclusion, LPS delayed demyelination and caused beneficial effects on remyelination via increasing the proliferation of OPC. These differences seem to be an effect of LPS induced microglial modulation and indicate that exposure to certain infectious agents within a given time window may be beneficial in promoting tissue repair., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The osmotic demyelination syndrome (ODS) has been a recognized complication of the rapid correction of hyponatremia for decades. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium. This finding suggests that the pathogenesis of ODS may be more complex and involve the inability of brain cells to respond to rapid changes in osmolality of the interstitial (extracellular) compartment of the brain, leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas. Features of the syndrome include quadriparesis and neurocognitive changes in the presence of characteristic lesions found on magnetic resonance imaging of the brain. Although slow correction of hyponatremia seems to be the best way to prevent development of the syndrome, there are new data that suggest reintroduction of hyponatremia in those patients who have undergone inadvertent rapid correction of the serum sodium and corticosteroids may play a role in prevention of ODS.

Background & Aims: Although many patients with multiple sclerosis (MS) use special diets, the data available at present are insufficient to assess any potential benefit of diet modification. Cuprizone induced demyelination is a commonly used animal model for demyelination in the central nervous system., Methods: The present study was designed to analyse behaviour and activity due to demyelination in mice fed with 0.2% cuprizone on three different diets. The diets consisted of (1) salmon fillets rich in marine n-3 polyunsaturated fatty acids (PUFAs), (2) cod liver oil rich in marine n-3 PUFAs, or (3) a control diet containing soybean oil rich in n-6 PUFAs. After 5 weeks of continuous cuprizone treatment, animal activity was assessed with the elevated plus maze (EPM) test. After 6 weeks the brains were fixated in paraformaldehyde and stained with luxol fast blue (LFB)., Results: There was significantly less demyelination in the salmon-cuprizone group than in the two other cuprizone-treatment groups (P<0.0005). The salmon-cuprizone mice had less weight loss (P<0.001) and showed more visits in both open and closed arms of the elevated plus maze than the other cuprizone-treated groups (P<0.0001). In addition they had more entries in the open arms than both the cod liver oil-cuprizone (P<0.02) and the soybean oil-cuprizone-treated mice (P<0.0001)., Conclusions: A diet containing salmon seems to protect against behavioural changes induced by demyelination in the cuprizone model, indicating that a fish diet could have a protective effect in demyelinating diseases.

Erythropoietin (EPO) is an endogenous cytokine with antiapoptotic, antiinflammatory, and neurotrophic properties. Apart from being produced by the kidney, liver, and spleen in response to hypoxia, EPO is highly expressed in the brain during development and after neuropathological insults. The observation that receptors for EPO are present on brain capillaries and glial capillary end-feet has suggested that circulating (plasma) EPO may be transferred into the brain. This review summarizes the increasing number of studies indicating that peripherally administered recombinant human (rHu) EPO crosses the blood-brain barrier. Moreover, several of these studies have shown that peripherally administered rHuEPO can protect against the damage caused by a diversity of neuropathological conditions such as (a) stroke, (b) head and spinal cord trauma, (c) inflammatory and demyelinating conditions, (d) toxin-induced epileptic seizures, and (e) retinal ischemia. While all these studies are based on experiments in animal models, the effectiveness of rHuEPO in ischemic stroke in human patients has recently been suggested in a proof-of-concept trial, which is also discussed.

Brain myelinolysis occurs after correction of chronic hyponatremia in rats when the magnitude of increase in serum sodium (delta SNa) exceeds 20 to 25 mEq/liter/24 hr (the critical threshold for brain). We tested the hypothesis that after a sustained excessive correction, brain lesions (BL) could be prevented by subsequently decreasing the serum sodium below the critical threshold for brain through the administration of hypotonic fluids. After three days of severe (< 115 mEq/liter) chronic (3 days) hyponatremia, 55 rats were submitted to an excessive correction (delta SNa > 25 mEq/liter) by a single i.p. infusion of hypertonic saline (NaCl). This osmotic stress was maintained during 12 hours before the serum sodium decrease was initiated. Thirty-two rats reached the twelfth post-correction hour without symptoms. In group 1 after a large (delta SNa 32 mEq/liter) and sustained (12 hr) osmotic stress, the natremia was rapidly (2 hr) decreased by the administration of oral tap water and, at the end of the first 24 hours, the magnitude of correction was maintained below 20 mEq/liter/24 hr. All the rats fared well in this group and were free of neurologic symptoms. Mild BL were noticed in only 20% of them. On the contrary, in controls (no hypotonic fluids administration at the twelfth hour) whose serum sodium was left overcorrected, all the rats became symptomatic and 57% of them died rapidly. Brain damage developed in 100% of the surviving rats. In group 2, despite hypotonic fluids administration, the serum sodium decreased insufficiently and the correction was > 20 mEq/liter at the end of the first 24 hours (delta SNa 25 mEq/liter).(ABSTRACT TRUNCATED AT 250 WORDS)