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 endocrine
glands, 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.