remyelination Dotaz Zobrazit nápovědu
Remyelination is a naturally occurring response to demyelination and has a central role in the pathophysiology of multiple sclerosis and traumatic brain injury. Recently we demonstrated that a novel MRI technique entitled Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n (RAFFn) achieved exceptional sensitivity in detecting the demyelination processes induced by lysophosphatidylcholine (LPC) in rat brain. In the present work, our aim was to test whether RAFF4, along with magnetization transfer (MT) and diffusion tensor imaging (DTI), would be capable of detecting the changes in the myelin content and microstructure caused by modifications of myelin sheets around axons or by gliosis during the remyelination phase after LPC-induced demyelination in the corpus callosum of rats. We collected MRI data with RAFF4, MT and DTI at 3 days after injection (demyelination stage) and at 38 days after injection (remyelination stage) of LPC (n = 12) or vehicle (n = 9). Cell density and myelin content were assessed by histology. All MRI metrics detected differences between LPC-injected and control groups of animals in the demyelination stage, on day 3. In the remyelination phase (day 38), RAFF4, MT parameters, fractional anisotropy, and axial diffusivity detected signs of a partial recovery consistent with the remyelination evident in histology. Radial diffusivity had undergone a further increase from day 3 to 38 and mean diffusivity revealed a complete recovery correlating with the histological assessment of cell density attributed to gliosis. The combination of RAFF4, MT and DTI has the potential to differentiate between normal, demyelinated and remyelinated axons and gliosis and thus it may be able to provide a more detailed assessment of white matter pathologies in several neurological diseases.
- Klíčová slova
- MRI, demyelination, diffusion, myelin, remyelination, rotating frame relaxation,
- Publikační typ
- časopisecké články MeSH
[This corrects the article DOI: 10.3389/fnins.2021.625167.].
- Klíčová slova
- MRI, demyelination, diffusion, myelin, remyelination, rotating frame relaxation,
- Publikační typ
- tisková chyba MeSH
Traumatic injuries to peripheral nerves are frequent, however, specific pharmacological treatments are currently lacking. Curcumin has antioxidant, anti-inflammatory and neuroprotective properties but high oral doses are required for therapeutic use, particularly due to its low bioavailability. The aim of the present study was to investigate the effects of local and continuous treatment using low curcumin doses on functional recovery and nerve regeneration after rat sciatic nerve crush (SNC). Curcumin was administered by osmotic pumps with a catheter delivering the drug at the injury site (0.2 mg/day for 4 weeks). Functionally, early improvements in mechanical sensitivity, finger spacing of the injured paw, skilful walking and grip strength were observed in curcumin-treated animals. The curcumin treatment increased expression of compact myelin proteins (MPZ and PMP22), myelin sheath thickness and, correspondingly, increased motor and sensitive nerve conduction velocity. Microscopic analysis of gastrocnemius muscle indicated a curcumin-induced decrease in neurogenic lesions. Curcumin treatment reduced the production of reactive oxygen species (ROS) (which were notably produced by macrophages), lipid peroxidation and increased expression of transcription factor Nrf2. In silico analyses indicated that curcumin combines all the characteristics required to be an efficient lipid peroxidation inhibitor at the heart of biological membranes, hence protecting their degradation due to ROS. This antioxidant capacity is likely to contribute to the beneficial effects of curcumin after SNC injury. These results demonstrate that, when administrated locally, low doses of curcumin represent a promising therapy for peripheral nerve regeneration.
- Klíčová slova
- Curcumin, Myelin, Oxidative stress, Sciatic nerve crush,
- MeSH
- antioxidancia farmakologie MeSH
- drtivá poranění farmakoterapie patologie patofyziologie MeSH
- faktor 2 související s NF-E2 metabolismus MeSH
- kosterní svaly účinky léků patologie patofyziologie MeSH
- kultivované buňky MeSH
- kurkumin farmakologie MeSH
- náhodné rozdělení MeSH
- nervové vedení účinky léků MeSH
- nervus ischiadicus účinky léků zranění patologie patofyziologie MeSH
- neuroprotektivní látky farmakologie MeSH
- obnova funkce účinky léků fyziologie MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- potkani Sprague-Dawley MeSH
- remyelinizace účinky léků fyziologie MeSH
- simulace molekulární dynamiky MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antioxidancia MeSH
- faktor 2 související s NF-E2 MeSH
- kurkumin MeSH
- neuroprotektivní látky MeSH
- Nfe2l2 protein, rat MeSH Prohlížeč
- MeSH
- elektronová mikroskopie MeSH
- krysa rodu Rattus MeSH
- míšní nervy fyziologie MeSH
- nervová vlákna myelinizovaná fyziologie ultrastruktura MeSH
- nervus suralis fyziologie ultrastruktura MeSH
- regenerace nervu * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths-the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair. METHODS: Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy. RESULTS: Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells. CONCLUSIONS: The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.
- Klíčová slova
- Multiple sclerosis, Neuroregeneration, Oligodendrocyte, Remyelination, Teriflunomide,
- MeSH
- buněčná diferenciace MeSH
- hydroxybutyráty metabolismus farmakologie MeSH
- krotonáty farmakologie terapeutické užití MeSH
- myelinová pochva * metabolismus MeSH
- oligodendroglie * metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- hydroxybutyráty MeSH
- krotonáty MeSH
- teriflunomide MeSH Prohlížeč
PURPOSE OF REVIEW: To discuss recent changes in the multiple sclerosis (MS) treatment algorithm and to present therapies currently in MS clinical trials. RECENT FINDINGS: High efficacy disease modifying therapies are optimally beneficial when used in the early, inflammatory phase of MS. Bruton's tyrosine kinase has emerged as an important therapeutic target for both relapsing and progressive forms of MS. Multiple therapies targeting remyelination failed to provide conclusive evidence of broad therapeutic benefit; however, more targeted approaches offer hope that myelin repair might be achieved resulting in specific clinical improvements. Strategies targeting chronic Epstein-Barr virus infection and dysbiosis of the gut microbiome are the first to link microbial risk factors for MS and therapeutic interventions. SUMMARY: A striking number of diverse treatments under investigation bodes well for development of better and more effective therapies in MS.
- MeSH
- algoritmy MeSH
- infekce virem Epsteina-Barrové * MeSH
- lidé MeSH
- remyelinizace * MeSH
- roztroušená skleróza * farmakoterapie MeSH
- virus Epsteinův-Barrové MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that attacks mainly young people. It leads to the progressive deterioration of the neurological status. Histopatologically, this disease is characterized by appearance of multiple foci of the demyelination in white matter of the CNS, with various grade of an axonal loss. The current treatment is targeted on moderating the inflammatory process and symptomatic therapy. In spite of all this therapy, the course of the disease often progresses. The tissue of the CNS in mammalians, including humans, is able to provide some degree of spontaneous remyelination. Unfortunatelly the extent of this process is not sufficient for the complete restoration. The support of remyelination by using the cell manipulations is the aim of many experimental studies. Theoretically, it is possible to achieve remyelination either by exogenous induction of remyelination from endogenous sources (precursor cells) or by the real transplantation of myelin-forming cells intrafocally, intracerebroventricularly or into the blood stream. In this work, we present the brief view on the recent state of this topic. We present the list of the cell types, useable for cell transplantations and the summary of the growth factors influencing the behaviour of the oligodendroglial precursors. We are considering the hampers in usage of the cell therapy of demyelinating disorders in clinics.
CONTEXT: Methanol poisoning induces acute optic neuropathy with possible long-term visual damage. OBJECTIVE: To study the dynamics and key determinants of visual pathway functional changes during 4 years after acute methanol poisoning. METHODS: A total of 42 patients with confirmed methanol poisoning (mean age 45.7 ± 4.4 years) were examined 4.9 ± 0.6, 25.0 ± 0.6, and 49.9 ± 0.5 months after discharge. The following tests were performed: visual evoked potential (VEP), retinal nerve fiber layer (RNFL) measurement, brain magnetic resonance imaging (MRI), complete ocular examination, biochemical tests, and apolipoprotein E (ApoE) genotyping. RESULTS: Abnormal VEP P1 latency was registered in 18/42 right eyes (OD) and 21/42 left eyes (OS), abnormal N1P1 amplitude in 10/42 OD and OS. Mean P1 latency shortening during the follow-up was 15.0 ± 2.0 ms for 36/42 (86%) OD and 14.9 ± 2.4 ms for 35/42 (83%) OS, with maximum shortening up to 35.0 ms. No significant change of mean N1P1 amplitude was registered during follow-up. A further decrease in N1P1 amplitude ≥1.0 mcV in at least one eye was observed in 17 of 36 patients (47%) with measurable amplitude (mean decrease -1.11 ± 0.83 (OD)/-2.37 ± 0.66 (OS) mcV versus -0.06 ± 0.56 (OD)/-0.83 ± 0.64 (OS) mcV in the study population; both p < .001). ApoE4 allele carriers had lower global and temporal RNFL thickness and longer initial P1 latency compared to the non-carriers (all p < .05). The odds ratio for abnormal visual function was 8.92 (3.00-36.50; 95%CI) for ApoE4 allele carriers (p < .001). The presence of ApoE4 allele was further associated with brain necrotic lesions (r = 0.384; p = .013) and brain hemorrhages (r = 0.395; p = .011). CONCLUSIONS: Improvement of optic nerve conductivity occurred in more than 80% of patients, but evoked potential amplitude tended to decrease during the 4 years of observation. ApoE4 allele carriers demonstrated lower RNFL thickness, longer P1 latency, and more frequent methanol-induced brain damage compared to non-carriers.
- Klíčová slova
- Toxic optic neuropathy, apolipoprotein E, chronic axonal neurodegeneration, long-term visual sequelae, methanol poisoning, remyelination, visual evoked potential,
- MeSH
- apolipoprotein E4 genetika MeSH
- časové faktory MeSH
- dospělí MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- methanol otrava MeSH
- následné studie MeSH
- nemoci zrakového nervu chemicky indukované diagnóza genetika patofyziologie MeSH
- nervus opticus účinky léků patofyziologie MeSH
- poruchy zraku chemicky indukované diagnóza genetika patofyziologie MeSH
- prognóza MeSH
- prospektivní studie MeSH
- reakční čas MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- zrak účinky léků genetika MeSH
- zrakové evokované potenciály MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- apolipoprotein E4 MeSH
- methanol MeSH
Spinal cord injury (SCI) is a devastating condition that usually results in sudden and long-lasting locomotor and sensory neuron degeneration below the lesion site. During the last two decades, the search for new therapies has been revolutionized with the improved knowledge of stem cell (SC) biology. SCs therapy offers several attractive strategies for spinal cord repair. The transplantation of SCs promotes remyelination, neurite outgrowth and axonal elongation, and activates resident or transplanted progenitor cells across the lesion cavity. However, optimized growth and differentiation protocols along with reliable safety assays should be established prior to the clinical application of SCs. Additionally, the ideal method of SCs labeling for efficient cell tracking after SCI remains a challenging issue that requires further investigation. This review summarizes the current findings on the SCs-based therapeutic strategies, and compares different SCs labeling approaches for SCI.
- Klíčová slova
- spinal cord injury, stem cell labeling, stem cells,
- MeSH
- buněčný tracking metody MeSH
- lidé MeSH
- nervové kmenové buňky cytologie transplantace MeSH
- neurogeneze MeSH
- poranění míchy diagnostické zobrazování patologie terapie MeSH
- regenerace nervu MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Siponimod (Mayzent®), a sphingosine 1-phosphate receptor (S1PR) modulator which prevents lymphocyte egress from lymphoid tissues, is approved for the treatment of relapsing-remitting and active secondary progressive multiple sclerosis. It can cross the blood-brain barrier (BBB) and selectively binds to S1PR1 and S1PR5 expressed by several cell populations of the central nervous system (CNS) including microglia. In multiple sclerosis, microglia are a key CNS cell population moving back and forth in a continuum of beneficial and deleterious states. On the one hand, they can contribute to neurorepair by clearing myelin debris, which is a prerequisite for remyelination and neuroprotection. On the other hand, they also participate in autoimmune inflammation and axonal degeneration by producing pro-inflammatory cytokines and molecules. In this study, we demonstrate that siponimod can modulate the microglial reaction to lipopolysaccharide-induced pro-inflammatory activation.
- Klíčová slova
- modulation, multiple sclerosis, neurodegeneration, polarization, sphingosine 1-phosphate receptor signalling,
- MeSH
- azetidiny * farmakologie metabolismus MeSH
- benzylové sloučeniny farmakologie MeSH
- lidé MeSH
- mikroglie metabolismus MeSH
- roztroušená skleróza * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- azetidiny * MeSH
- benzylové sloučeniny MeSH
- siponimod MeSH Prohlížeč
