Cytisine and cytisine derivatives. More than smoking cessation aids.

Cytisine, a natural bioactive compound that is mainly isolated from plants of the Leguminosae family (especially the seeds of Laburnum anagyroides), has been marketed in central and eastern Europe as an aid in the clinical management of smoking cessation for more than 50 years. Its main targets are neuronal nicotinic acetylcholine receptors (nAChRs), and pre-clinical studies have shown that its interactions with various nAChR subtypes located in different areas of the central and peripheral nervous systems are neuroprotective, have a wide range of biological effects on nicotine and alcohol addiction, regulate mood, food intake and motor activity, and influence the autonomic and cardiovascular systems. Its relatively rigid conformation makes it an attractive template for research of new derivatives. Recent studies of structurally modified cytisine have led to the development of new compounds and for some of them the biological activities are mediated by still unidentified targets other than nAChRs, whose mechanisms of action are still being investigated. The aim of this review is to describe and discuss: 1) the most recent pre-clinical results obtained with cytisine in the fields of neurological and non-neurological diseases; 2) the effects and possible mechanisms of action of the most recent cytisine derivatives; and 3) the main areas warranting further research.

Varenicline aggravates atherosclerotic plaque formation in nicotine-pretreated ApoE knockout mice due to enhanced oxLDL uptake by macrophages through downregulation of ABCA1 and ABCG1 expression.

Varenicline is a widely used and effective drug for smoking cessation. We previously reported that varenicline aggravates atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. However, it remains unknown whether varenicline affects cardiovascular events in patients with nicotine addiction. Here, we examined the effect of varenicline on atherosclerotic plaque formation in nicotine-pretreated ApoE KO mice and oxidized low-density lipoprotein (oxLDL) uptake in nicotine-treated peritoneal macrophages. Varenicline caused significant progression of plaque formation in the whole aorta and aortic root and further accelerated the increased formation of a macrophage-rich plaque area in the aortic root in nicotine-pretreated ApoE KO mice. Varenicline (10 µM) enhanced oxLDL uptake in peritoneal macrophages. Furthermore, this treatment significantly further lowered the decreased protein levels of ATP-binding cassette (ABC) transporter without affecting the expression of scavenger receptors LOX-1 and CD36 in RAW264.7 cells treated with 100 nM nicotine. Varenicline enhanced nicotine-induced oxLDL uptake in macrophages through decreased expression of cholesterol efflux transporters ABCA1 and ABCG1 and thereby progressed atherosclerotic plaque formation. Taken together, we tentatively conclude that nicotine exposure before and/or during varenicline treatment can aggravate varenicline-increased atherosclerotic plaque formation and progression. Therefore, this enhanced risk requires special consideration when prescribing varenicline to smoker patients.