One possible explanation stems from the fact that CDP-choline =! acetylcholine. The 2015 paper published in Brain suggests that the mechanism by which CDP-choline promotes proliferation of oligodendrocytes is via the second messenger diacyl glycerol (DAG), which is essential for protein kinase C (PKC) activation. In this study, all PKC inhibitors blocked the effect of CDP-choline on oligodendrocyte proliferation.
Often in biology it seems that one signaling molecule will elicit opposite effects as a kind of negative feedback loop. E.g., thyroid hormone release increases the metabolism of many cells of the body, but also suppresses thyroid-stimulating hormone (TSH), reducing thyroid release. Analogously, one could imagine that CDP-choline would promote oligodendrocyte proliferation, while at the same time acetylcholinergic activation of the muscarinic receptors would arrest proliferation. (This is all highly speculative, but at least it's a start).
Effects of CDP-choline on OPC proliferation in vitro. CDP-choline increased the proliferation rate of OPCs in cell culture experiments as measured by BrdU incorporation (A, n = 4). In B exemplary stained proliferating OPC (green BrdU, red A2B5) are shown after incubation with CDP-choline compared to controls (nuclei were counterstained with DAPI). Inhibition of the enzyme phospholipase C (PLC), which is required for the activation of the enzyme diacyglyceride (DAG), reversed the additional proliferative effects induced by CDP-choline (C, n = 4). Phosphatidylcholine (end product in the CDP-choline pathway) did not induce any effects on OPC proliferation (D, n = 5). DAG is essential for the activation of protein kinase C (PKC) and three different inhibitors (Bis = bisindolylmaleimide IV: Calph = calphostin C: Chelery = chelerythrine chloride) were tested with CDP-choline in OPC cultures. All PKC inhibitors completely reversed the additional proliferative effects of CDP-choline (E, n = 5). Bars represent mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001. The schematic overview (F) shows that CDP-choline is converted directly with DAG to phosphatidylcholine and CMP (cytidine-mono-phosphate) in a reaction catalyzed by CPT (1,2-diacylglycerol cholinephosphotransferase). DAG is a product of the hydrolysis of PIP2 (phosphatidylinositol 4,5-bisphosphate) by the membrane-bound enzyme PLC (phospholipase C) and is an essential physiological activator of protein kinase C. Our results show that the inhibition of PLC and thereby DAG reverses the CDP-choline effect on proliferation. DAG is essential for protein kinase C activation and it can be suggested that CDP-choline exerts its effects on proliferation via DAG and thus via protein kinase C activation, as we could show that inhibition of PKC activity reversed the CDP-choline effects on proliferation and phosphatidylcholine had no effects on proliferation. PIP2 = phosphatidylinositol 4,5-bisphosphate.
