Search

Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution.

One main pathological hallmark of multiple sclerosis (MS) is demyelination. Novel therapies which enhance myelin repair are urgently needed. Insulin and insulin-like growth factor 1 (IGF-1) have strong functional relationships. Here, we addressed the potential capacity of IGF-1 and insulin to enhance remyelination in an animal demyelination model in vivo. We found that chronic intrathecal infusion of IGF-1 enhanced remyelination after lysolecithin-induced demyelination in the spinal cord of young and aged rats. Aged rats showed a weaker innate remyelination capacity and are therefore a good model for progressive MS which is defined by chronic demyelination. In contrast to IGF-1, Insulin had no effect on remyelination in either age group. Our findings highlight the potential use of IGF-1 as remyelinating therapy for MS, particularly the progressive stage in which chronic demyelination is the hallmark.

Most of the current therapies, as well as many of the clinical trials, for multiple sclerosis (MS) target the inflammatory autoimmune processes, but less than 20% of all clinical trials investigate potential therapies for the chronic progressive disease stage of MS. The latter is responsible for the steadily increasing disability in many patients, and there is an urgent need for novel therapies that protect nervous system tissue and enhance axonal growth and/or remyelination. As outlined in this review, solid pre-clinical data suggest neutralization of the neurite outgrowth inhibitor Nogo-A as a potential new way to achieve both axonal and myelin repair. Several phase I clinical studies with anti-Nogo-A antibodies have been conducted in different disease paradigms including MS and spinal cord injury. Data from spinal cord injury and amyotrophic lateral sclerosis (ALS) trials accredit a good safety profile of high doses of anti-Nogo-A antibodies administered intravenously or intrathecally. An antibody against a Nogo receptor subunit, leucine rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1), was recently shown to improve outcome in patients with acute optic neuritis in a phase II study. Nogo-A-suppressing antibodies could be novel drug candidates for the relapsing as well as the progressive MS disease stage. In this review, we summarize the available pre-clinical and clinical evidence on Nogo-A and elucidate the potential of Nogo-A-antibodies as a therapy for progressive MS.

Aims The search for novel drugs that enhance myelin repair in entities such as multiple sclerosis has top priority in neurological research, not least because remyelination can hinder further neurodegeneration in neuro-inflammatory conditions. Recently, several new compounds with the potential to boost remyelination have been identified using high-throughput in vitro screening methods. However, assessing their potential to enhance remyelination in vivo using plastic embedded semi-thin sections or electron microscopy, even though being the gold standard for assessing remyelination, is toxic, extremely time-consuming, and expensive. Methods We screened available myelin dyes for a staining candidate which offers a faster and easier alternative to visualize remyelination in cryo-sections. Results We identified sudan black as a candidate with excellent myelin resolution and we show that our adapted sudan black staining can demonstrate myelin repair in rodent spinal cord cryosections as reliable as in semithin sections, but much faster, easier, less toxic and less expensive. Besides that, it can resolve the small myelinated axons in the corpus callosum. The staining can yet readily be combined with immunostainings which can be challenging in semithin sections. We validated the method in human spinal cord tissue as well as in experimental demyelination of the rat spinal cord by a lysolecithin time course experiment. As proof-of-principle, we demonstrate that sudan black is able to reliably detect the remyelination enhancing properties of benztropine. Conclusion Our adapted sudan black staining can be used to rapidly and non-toxically screen for remyelinating therapies in demyelinating diseases. This article is protected by copyright. All rights reserved.