Citicoline in cardiovascular protection: mechanistic roles of choline and acetylcholine.

Citicoline (CDP-choline) is a rate-limiting precursor for phosphatidylcholine synthesis and acetylcholine production, and thus a unique metabolic hub linking membrane phospholipid homeostasis with cholinergic signaling. The biochemical rationale for the therapeutic potential of citicoline in heart disease is rooted in fundamental metabolic principles and conserved cytoprotective pathways. However, the cardiovascular evidence base for citicoline is not as extensive as its established neuroprotective profile. The cardioprotection is mainly mediated by the cholinergic system, including vagal efferent activity and the non-neuronal cardiac cholinergic system (NNCCS). This initiates a wide signaling network including PI3K/AKT, JAK/STAT, SIRT3/AMPK, IP3/calcium and MAPK cascades that inhibit inflammation, oxidative stress and apoptosis. Moreover, cholinergic signaling modulates proteasomal activity and microRNA expression, as well as post-transcriptional gene regulation to provide cardioprotection. This review summarizes experimental and clinical evidence in support of this hypothesis with particular emphasis on citicoline-activated mechanisms that are directly relevant for myocardial protection. These include phospholipid replacement of damaged sarcolemmal membranes and pleiotropic actions such as activation of survival kinase activation, suppression of inflammatory mediators, attenuation of oxidative injury and preservation of mitochondrial bioenergetics. Based on these safety data, we recommend that citicoline should be tested in further translational studies as an adjunctive treatment during reperfusion following myocardial infarction. Its antiarrhythmic effects, cholinergic engagement, downstream signaling modulation and miRNA regulation should be specifically highlighted as these may help limit infarct size, prevent adverse remodeling and improve clinical outcome in ischemic heart disease.