Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models

Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients. Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination. As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation. However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure. Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent). To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination. Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination. We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-013-1112-y) contains supplementary material, which is available to authorized users

Targeted Ablation of Oligodendrocytes Triggers Axonal Damage

Glial dysfunction has been implicated in a number of neurodegenerative diseases. In this study we investigated the consequences of glial and oligodendrocyte ablation on neuronal integrity and survival in Drosophila and adult mice, respectively. Targeted genetic ablation of glia was achieved in the adult Drosophila nervous system using the GAL80-GAL4 system. In mice, oligodendrocytes were depleted by the injection of diphtheria toxin in MOGi-Cre/iDTR double transgenic animals. Acute depletion of oligodendrocytes induced axonal injury, but did not cause neuronal cell death in mice. Ablation of glia in adult flies triggered neuronal apoptosis and resulted in a marked reduction in motor performance and lifespan. Our study shows that the targeted depletion of glia triggers secondary neurotoxicity and underscores the central contribution of glia to neuronal homeostasis. The models used in this study provide valuable systems for the investigation of therapeutic strategies to prevent axonal or neuronal damage

Promoting remyelination in multiple sclerosis-recent advances

We review the current state of knowledge of remyelination in multiple sclerosis (MS), concentrating on advances in the understanding of the pathology and the regenerative response, and we summarise progress on the development of new therapies to enhance remyelination aimed at reducing progressive accumulation of disability in MS. We discuss key target pathways identified in experimental models, as although most identified targets have not yet progressed to the stage of being tested in human clinical trials, they may provide treatment strategies for demyelinating diseases in the future. Finally, we discuss some of the problems associated with testing this class of drugs, where they might fit into the therapeutic arsenal and the gaps in our knowledge

Comparative study of 0.1% hyaluronic acid versus 0.5% carboxymethylcellulose in patients with dry eye associated with moderate keratitis or keratoconjunctivitis

Dorothea Groß,1 Marc Childs,2 Jean-Marie Piaton3 1Ursapharm Arzneimittel GmbH, Saarbrücken, Germany; 2Laboratoires Delbert, Paris, 3Ophthalmologic Practice, Domont, France Background: Eye drops containing 0.1% hyaluronic acid (HA) and 0.5% carboxymethylcellulose (CMC) applied one drop three times a day per affected eye were compared in patients with moderate keratitis or keratoconjunctivitis related to dry eye disease (DED). Patients and methods: This was a prospective, randomized, multicenter, Phase IIIB noninferiority study, with a single-masked phase in parallel mode with two groups over 84 days. The primary efficacy outcome was change in ocular surface (OS) staining between day 0 (D0) and day 35 (D35). The conjunctiva and cornea were stained with lissamine green and fluorescein. Secondary efficacy measures at day 84 (D84) were OS-staining score (SS), ocular comfort index, tear-film breakup time and how patients and investigators rated treatment efficacy and safety. Results: At D35, 0.1% HA achieved a 46.6% reduction in OS-SS (-2.03±1.35 points, n=39 patients) and 0.5% CMC treatment, followed by a 34.9% reduction (-1.61±1.69 points, n=38 patients) compared to D0. At D84, the SS difference to D0 improved by -2.58±1.45 points (-59.2%) for 0.1% HA and -2.59±2.27 points (-54.4%) for 0.5% CMC. Ocular comfort-index scores improved, with significantly lower (better) values for stinging and itching on D84 for 0.1% HA. Patients assessed treatment with 0.1% HA as significantly better than 0.5% CMC (Likert scale, 4.82 vs 3.97; P=0.018). Four adverse events (AEs) occurred in four of 41 patients (9.8%) treated with 0.1% HA, and three AEs in two of 39 patients (5.1%) treated with 0.5% CMC. No serious AEs were noted. Conclusion: DED signs and symptoms of DED significantly improved with both eye drops. OS staining improved >54% at D84. Treatment was well tolerated, with only minor AEs <10%. 0.1% HA and 0.5% CMC were equally safe and effective. Significant and nonsignificant results were constantly in favor of 0.1% HA. Keywords: hyaluronate, carboxymethylcellulose, eye drops, fluorescein, lissamine gree

External dacryocystorhinostomy: do we really need to repair the posterior flap?

Purpose: This study aims to compare a simplified technique of external dacryocystorhinostomy (DCR), where the posterior flap is excised, with the more traditional approach of double flap repair. Methods: A prospective, comparative, single surgeon, single centre clinical trial was conducted of eighty-three patients who received external DCR, with either anterior and posterior flap anastomosis (Group A), or anterior flap anastomosis and excision of the posterior flap (Group B), in a tertiary referral hospital in Nepal. Patients with nasolacrimal duct obstruction and epiphora were assigned to one of two groups. Follow up was a minimum of 6 months for inclusion in the study. Success was defined objectively by irrigation of the puncta without regurgitation and subjectively by the absence of epiphora or discharge. Results: The overall success rate of external DCR was 89.2%, after a mean follow up of 13.5 ± 2.2 months. There was no difference in success between the two groups (p-value = 0.73), with 90.7% success in Group A and 87.5% in Group B. The frequency of complications was not statistically different between Groups A and B (p-value = 0.79). Conclusions: Excision of the posterior flap and anastomosis of only the anterior flap is not disadvantageous to the outcomes of external DCR surgery when compared with the more traditional approach of anastomosis of both flaps. We believe this simplified procedure can be implemented as the standard technique for external DCR, particularly in developing nations such as Nepal

Neuroprotection and repair in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease that is considered by many people to have an autoimmune aetiology. In recent years, new data emerging from histopathology, imaging and other studies have expanded our understanding of the disease and may change the way in which it is treated. Conceptual shifts have included: first, an appreciation of the extent to which the neuron and its axon are affected in MS, and second, elucidation of how the neurobiology of axon–glial and, particularly, axon–myelin interaction may influence disease progression. In this article, we review advances in both areas, focusing on the molecular mechanisms underlying axonal loss in acute inflammation and in chronic demyelination, and discussing how the restoration of myelin sheaths via the regenerative process of remyelination might prevent axon degeneration. An understanding of these processes could lead to better strategies for the prevention and treatment of axonal loss, which will ultimately benefit patients with MS