Do we need this after a stroke? Have we demyelinated neurons in the brain? What does your doctor know about this and what is the protocol to fix it? Scream at your doctor if you have to get her attention about actually fixing you up to 100% recovery.
Remyelination promoting therapies in multiple sclerosis animal models: a systematic review and meta-analysis
Abstract
An
unmet but urgent medical need is the development of myelin repair
promoting therapies for Multiple Sclerosis (MS). Many such therapies
have been pre-clinically tested using different models of toxic
demyelination such as cuprizone, ethidium bromide, or lysolecithin and
some of the therapies already entered clinical trials. However, keeping
track on all these possible new therapies and their efficacy has become
difficult with the increasing number of studies. In this study, we aimed
at summarizing the current evidence on such therapies through a
systematic review and at providing an estimate of the effects of tested
interventions by a meta-analysis. We show that 88 different therapies
have been pre-clinically tested for remyelination. 25 of them (28%)
entered clinical trials. Our meta-analysis also identifies 16 promising
therapies which did not enter a clinical trial for MS so far, among them
Pigment epithelium-derived factor, Plateled derived growth factor, and
Tocopherol derivate TFA-12.We also show that failure in bench to bedside
translation from certain therapies may in part be attributable to poor
study quality. By addressing these problems, clinical translation might
be smoother and possibly animal numbers could be reduced.
Introduction
Multiple Sclerosis (MS) is a chronic demyelinating disease1. With the only exception of Ocrelizumab2,
which has a modest impact on disease progression, none of the 16 FDA
approved MS therapies are able to stop or at least to decelerate the
progressively increasing disability of affected patients3.
One well-acknowledged approach to prevent disease progression is via a
boost of myelin repair. Remyelination not only restores efficient
electric conduction along axons but, because the myelin sheaths have
trophic functions for the axons4, also reduces neurodegeneration, which closely correlates with clinical disability5.
The intense search for strategies to enhance myelin regeneration to hinder further neurodegeneration and to increase clinical function of patients, is as well reflected by the large number of pre-clinical studies assessing potential remyelinating strategies. Commonly used experimental systems to study potential remyelinating therapies include neuro-inflammatory animal models such as experimental autoimmune encephalomyelitis (EAE)6 or virus-induced demyelination/inflammation7 as well as toxin-induced demyelination models with cuprizone8, lysolecithin, ethidium bromide, and complement/anti-galactocerebroside antibodies9 being the most commonly used agents of the latter group10. All of these models have strengths and limitations; whereas neuro-inflammatory models reproduce well the disseminated and inflammatory features of MS, toxin-induced demyelination models are more suited to dissect specific mechanisms of myelin decline and regeneration with a clear temporal separation of these processes and without concomitant inflammation10,11.
Cuprizone is a systemic copper-chelating agent. Upon feeding, it leads to demyelination of distinct brain regions, among them the corpus callosum. Cuprizone has a highly reproducible timeline of de- and remyelination and enables long-term demyelination when fed for a prolonged time window. The exact mechanism of cuprizone-induced demyelination is unknown10,12. Compared to Cuprizone, lysolecithin has the disadvantage of needing an invasive injection to a pre-defined CNS-position. Nevertheless, it is also highly predictive under temporal aspects. Moreover, any CNS area can be targeted selectively with this detergent13. Ethidium bromide leads to much larger areas of demyelination and degrades all nucleated cells within the injection area (including astrocytes and microglia cells)9. The local injection of Anti-galactocerebroside antibodies/complement is rarely used as toxic demyelination model. The time to complete remyelination is shorter in this model but involves a greater demyelinating area than lysolecithin10.
Many putative therapies have been identified using these toxic demyelination models, from which some already entered clinical trials. We aimed at summarizing all the already pre-clinically tested putative remyelinating therapies via a systematic review and meta-analysis in order to assess which remyelinating therapies can be promising and could be tested in clinical trials. We also investigate the efficacy of the therapies in these experimental animal models that have already entered clinical trials. We focused our analysis on the four in vivo toxic demyelination models cuprizone, lysolecithin, ethidium bromide, and complement/anti-galactocerebroside antibodies. These models might be more suited to assess potential therapies aiming at halting disease progression of progressive MS in contrast to neuro-inflammatory models, in which potential immune-modulatory effects of therapies could confound efficacy11. The results of our review should provide a framework for future clinical trials investigating putative remyelinating interventions for MS, in particular during the chronic phase of the disease when remyelination failure determines disability progression.
The intense search for strategies to enhance myelin regeneration to hinder further neurodegeneration and to increase clinical function of patients, is as well reflected by the large number of pre-clinical studies assessing potential remyelinating strategies. Commonly used experimental systems to study potential remyelinating therapies include neuro-inflammatory animal models such as experimental autoimmune encephalomyelitis (EAE)6 or virus-induced demyelination/inflammation7 as well as toxin-induced demyelination models with cuprizone8, lysolecithin, ethidium bromide, and complement/anti-galactocerebroside antibodies9 being the most commonly used agents of the latter group10. All of these models have strengths and limitations; whereas neuro-inflammatory models reproduce well the disseminated and inflammatory features of MS, toxin-induced demyelination models are more suited to dissect specific mechanisms of myelin decline and regeneration with a clear temporal separation of these processes and without concomitant inflammation10,11.
Cuprizone is a systemic copper-chelating agent. Upon feeding, it leads to demyelination of distinct brain regions, among them the corpus callosum. Cuprizone has a highly reproducible timeline of de- and remyelination and enables long-term demyelination when fed for a prolonged time window. The exact mechanism of cuprizone-induced demyelination is unknown10,12. Compared to Cuprizone, lysolecithin has the disadvantage of needing an invasive injection to a pre-defined CNS-position. Nevertheless, it is also highly predictive under temporal aspects. Moreover, any CNS area can be targeted selectively with this detergent13. Ethidium bromide leads to much larger areas of demyelination and degrades all nucleated cells within the injection area (including astrocytes and microglia cells)9. The local injection of Anti-galactocerebroside antibodies/complement is rarely used as toxic demyelination model. The time to complete remyelination is shorter in this model but involves a greater demyelinating area than lysolecithin10.
Many putative therapies have been identified using these toxic demyelination models, from which some already entered clinical trials. We aimed at summarizing all the already pre-clinically tested putative remyelinating therapies via a systematic review and meta-analysis in order to assess which remyelinating therapies can be promising and could be tested in clinical trials. We also investigate the efficacy of the therapies in these experimental animal models that have already entered clinical trials. We focused our analysis on the four in vivo toxic demyelination models cuprizone, lysolecithin, ethidium bromide, and complement/anti-galactocerebroside antibodies. These models might be more suited to assess potential therapies aiming at halting disease progression of progressive MS in contrast to neuro-inflammatory models, in which potential immune-modulatory effects of therapies could confound efficacy11. The results of our review should provide a framework for future clinical trials investigating putative remyelinating interventions for MS, in particular during the chronic phase of the disease when remyelination failure determines disability progression.
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