Another remyelination target

Abiraman K, Pol SU, O’Bara MA, Chen GD, Khaku ZM, Wang J, Thorn D, Vedia BH, Ekwegbalu EC, Li JX, Salvi RJ, Sim FJ Anti-muscarinic adjunct therapy accelerates functional human oligodendrocyte repair. J Neurosci. 2015;35(8):3676-88

Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC-specific receptors. Among these, we identified CHRM3, a M3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140a(+)O4(+) cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors

In this study they looked for switch factors that affect oligododencrocyte maturation. They found cholinergic/ acetylcholine receptor M3, also known as the muscarinic 3, is a muscarinic acetylcholine receptor. It is encoded by the human gene CHRM3. The M3 muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrineglands, the exocrine glands, lungs, pancreas and the brain. In the CNS, they induce emesis (Vomiting). Muscarinic M3receptors are expressed in regions of the brain that regulate insulin homeostasis, such as the hypothalamus and dorsal vagal complex of the brainstem. In general, they cause smooth muscle contraction and increased glandular secretions. They blocked this receptor with Solifenacin is a competitive cholinergic receptor antagonist. The binding of acetylcholine to these receptors, particularly the M3 receptor subtype, plays a critical role in the contraction of smooth muscle. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half life, a once-a-day dose can offer 24-hour control of the urinary bladder smooth muscle tone. So whilst it may promote remyelination it may also give you unwanted bladder problems if you can’t void, it could make it worse. This is a problem with the targets of remyelination so far found, except perhaps LINGO-1, is that thetargets also have other functions in the body and therefore their blockade may have side-effects.
On the plus-side maybe another treatment. It is interesting that we now have over five trials on going and not one single pre-clinical study has been done to determine, whether these treatments can affect chronic demyelinated and scarred lesions as opposed to newly demyelinated lesions. This may impact on the type of trial done.  

Likewise do we need to treat long term or will a short course do the trick.

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    • I can't wait to see the results.

      I was at a meeting last week and someone voiced the concern that the dose used to induce remyelination in animals was much higher than the human dose. I don't have the paper and the trial information to hand to comment on this.

      Another potential cause for concern is whether the immune response is being dealt with. We shall see. The anti-LINGO-1 trial missed its primary endpoint just, was this because they were a bit too slow in recruiting people onto the study or because 99.9% of the drug they inject is useless because it doesn't get into the optic nerve. If they have treated quicker more antibody would have entered the CNS because of blood brain barrier breakdown

    • I understand your position MD. I would love the study of the anti- lingo 1 shows good results as remyelination , but it seems that things are going very slow …

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