Mesenchymal Stem Cells for Treatment of CNS Injury

Brain and spinal cord injuries present significant therapeutic challenges. The treatments available for these conditions are largely ineffective, partly due to limitations in directly targeting the therapeutic agents to sites of pathology within the central nervous system (CNS). The use of stem cells to treat these conditions presents a novel therapeutic strategy. A variety of stem cell treatments have been examined in animal models of CNS trauma. Many of these studies have used stem cells as a cell-replacement strategy. These investigations have also highlighted the significant limitations of this approach. Another potential strategy for stem cell therapy utilises stem cells as a delivery mechanism for therapeutic molecules. This review surveys the literature relevant to the potential of mesenchymal stem cells for delivery of therapeutic agents in CNS trauma in humans

How does Nogo receptor influence demyelination and remyelination in the context of multiple sclerosis?

Multiple sclerosis (MS) can progress with neurodegeneration as a consequence of chronic inflammatory mechanisms that drive neural cell loss and/or neuroaxonal dystrophy in the central nervous system. Immune-mediated mechanisms can accumulate myelin debris in the disease extracellular milieu during chronic-active demyelination that can limit neurorepair/plasticity and experimental evidence suggests that potentiated removal of myelin debris can promote neurorepair in models of MS. The myelin-associated inhibitory factors (MAIFs) are integral contributors to neurodegenerative processes in models of trauma and experimental MS-like disease that can be targeted to promote neurorepair. This review highlights the molecular and cellular mechanisms that drive neurodegeneration as a consequence of chronic-active inflammation and outlines plausible therapeutic approaches to antagonize the MAIFs during the evolution of neuroinflammatory lesions. Moreover, investigative lines for translation of targeted therapies against these myelin inhibitors are defined with an emphasis on the chief MAIF, Nogo-A, that may demonstrate clinical efficacy of neurorepair during progressive MS

Interleukin-18 alters protein expressions of neurodegenerative diseases-linked proteins in human SH-SY5Y neuron-like cells

Peer reviewe

Oligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions

Oligodendrocytes are supporting glial cells that ensure the metabolism and homeostasis of neurons with specific synaptic axoglial interactions in the central nervous system. These require key myelinating glial trophic signals important for growth and metabolism. Thyroid hormone (TH) is one such trophic signal that regulates oligodendrocyte maturation, myelination, and oligodendroglial synaptic dynamics via either genomic or nongenomic pathways. The intracellular and extracellular transport of TH is facilitated by a specific transmembrane transporter known as the monocarboxylate transporter 8 (MCT8). Dysfunction of the MCT8 due to mutation, inhibition, or downregulation during brain development leads to inherited hypomyelination, which manifests as psychomotor retardation in the X-linked inherited Allan-Herndon-Dudley syndrome (AHDS). In particular, oligodendroglial-specific MCT8 deficiency may restrict the intracellular T3 availability, culminating in deficient metabolic communication between the oligodendrocytes and the neurons they ensheath, potentially promulgating neurodegenerative adult diseases such as multiple sclerosis (MS). Based on the therapeutic effects exhibited by TH in various preclinical studies, particularly related to its remyelinating potential, TH has now entered the initial stages of a clinical trial to test the therapeutic efficacy in relapsing-remitting MS patients (NCT02506751). However, TH analogs, such as DITPA or Triac, may well serve as future therapeutic options to rescue mature oligodendrocytes and/or promote oligodendrocyte precursor cell differentiation in an environment of MCT8 deficiency within the CNS. This review outlines the therapeutic strategies to overcome the differentiation blockade of oligodendrocyte precursors and maintain mature axoglial interactions in TH-deprived conditions

Axonal degeneration in multiple sclerosis:can we predict and prevent permanent disability?

Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages. While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS. Specialized imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS). A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies. The clinical translation of a combined Na(+) and Ca(2+) channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS. In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS

Hematopoietic stem cell transplantation for multiple sclerosis:Is it a clinical reality?

Hematopoietic stem cell transplantation (HSCT) is a treatment paradigm that has long been utilized for cancers of the blood and bone marrow but has gained some traction as a treatment paradigm for multiple sclerosis (MS). Success in the treatment of patients with this approach has been reported primarily when strict inclusion criteria are imposed that have eventuated a more precise understanding of MS pathophysiology, thereby governing trial design. Moreover, enhancing the yield and purity of hematopoietic stem cells during isolation along with the utility of appropriate conditioning agents has provided a clearer foundation for clinical translation studies. To support this approach, preclinical data derived from animal models of MS, experimental autoimmune encephalomyelitis, have provided clear identification of multipotent stem cells that can reconstitute the immune system to override the autoimmune attack of the central nervous system. In this review, we will discuss the rationale of HSCT to treat MS by providing the benefits and complications of the clinically relevant protocols, the varying graft types, and conditioning regimens. However, we emphasize that future trials based on HSCT should be focused on specific therapeutic strategies to target and limit ongoing neurodegeneration and demyelination in progressive MS, in the hope that such treatment may serve a greater catchment of patient cohorts with potentially enhanced efficiency and lower toxicity. Despite these future ambitions, a proposed international multicenter, randomized clinical trial of HSCT should be governed by the best standard care of treatment, whereby MS patients are selected upon strict clinical course criteria and long-term follow-up studies of patients from international registries are imposed to advocate HSCT as a therapeutic option in the management of MS

The Beta-Amyloid Protein of Alzheimer’s Disease: Communication Breakdown by Modifying the Neuronal Cytoskeleton

Alzheimer’s disease (AD) is one of the most prevalent severe neurological disorders afflicting our aged population. Cognitive decline, a major symptom exhibited by AD patients, is associated with neuritic dystrophy, a degenerative growth state of neurites. The molecular mechanisms governing neuritic dystrophy remain unclear. Mounting evidence indicates that the AD-causative agent, β-amyloid protein (Aβ), induces neuritic dystrophy. Indeed, neuritic dystrophy is commonly found decorating Aβ-rich amyloid plaques (APs) in the AD brain. Furthermore, disruption and degeneration of the neuronal microtubule system in neurons forming dystrophic neurites may occur as a consequence of Aβ-mediated downstream signaling. This review defines potential molecular pathways, which may be modulated subsequent to Aβ-dependent interactions with the neuronal membrane as a consequence of increasing amyloid burden in the brain