CDP-choline to promote remyelination in multiple sclerosis: the need for a clinical trial

Abstract

Multiple sclerosis is a multifactorial chronic inflammatory disease of the central nervous system that leads to demyelination and neuronal cell death, resulting in functional disability. Remyelination is the natural repair process of demyelination, but it is often incomplete or fails in multiple sclerosis. Available therapies reduce the inflammatory state and prevent clinical relapses. However, therapeutic approaches to increase myelin repair in humans are not yet available. The substance cytidine-5'-diphosphocholine, CDP-choline, is ubiquitously present in eukaryotic cells and plays a crucial role in the synthesis of cellular phospholipids. Regenerative properties have been shown in various animal models of diseases of the central nervous system. We have already shown that the compound CDP-choline improves myelin regeneration in two animal models of multiple sclerosis. However, the results from the animal models have not yet been studied in patients with multiple sclerosis. In this review, we summarise the beneficial effects of CDP-choline on biolipid metabolism and turnover with regard to inflammatory and regenerative processes. We also explain changes in phospholipid and sphingolipid homeostasis in multiple sclerosis and suggest a possible therapeutic link to CDP-choline.

Keywords: CDP-choline; astrocytes; cuprizone; microglia; multiple sclerosis; oligodendrocytes.

Figure 1

Simplified scheme of the different membrane lipids. Adapted from Casares et al. (2019), Poitelon et al. (2020), Javaid et al. (2021), and Nelson and Cox (2021).

Figure 2

Simplified depiction of phosphatidylcholine turnover and possible positive effects of exogenously administered CDP-choline. Simplified scheme of the de novo synthesis of phosphatidylcholine (PtdCho) (Kennedy pathway, area is highlighted in green) and its degradation (the area is colored in yellow), highlighting its importance in the production of lipid-derived signaling mediators under physiological and pathophysiological conditions (inflammation is shown in red colors, red arrows indicate an increase in expression during inflammatory processes due to endogenous or exogenous insults, blue arrows represent chemical subtraction or degradation reactions, orange arrows indicate addition reactions, and grey arrows point to some other type of chemical reaction). CDP-choline exerts protective effects by attenuating inflammation-related processes and restoring the levels of membrane lipids and thus cellular and mitochondrial membrane structures. In addition, CDP-choline serves as a source of choline, thus improving cognitive and antioxidant functions (glutathione production) and other epigenetic changes (DNA methylation). AGPAT: Acylglycerophosphate acyltransferase; BADH: betaine aldehyde dehydrogenase; CAT: choline acetyltransferase; CCT: phosphocholine cytidylyltransferase; CHDH: choline dehydrogenase; CK: choline kinase; CPT: cholinephosphotransferase; DAG: diacylglycerol; FFA: free fatty acids; GPD: glycerophosphodiesterase; LPA: lysophosphatidic acid; Lyso-PLA2: lysophospholipase A2; PAF: platelet-activating factor; PIP2: phosphatidylinositol-4,5-bisphosphat; PLA2: phospholipase A2; PLC: phospholipase C; PLD: phospholipase D; ROS: reactive oxygen species; SMase: sphingomyelinase; SMS: sphingomyeline synthase. Adapted from Adibhatla and Hatcher (2008), Fagone and Jackowski (2013), and Saito et al. (2022).