Abstract
Cardiovascular diseases, like atherosclerosis, and neurodegenerative diseases affecting the central nervous system (CNS) are closely linked to alterations of cholesterol metabolism. Therefore, innovative pharmacological approaches aiming at counteracting cholesterol imbalance display promising therapeutic potential. However, these approaches need to take into account the existence of biological barriers such as intestinal and blood-brain barriers which participate in the organ homeostasis and are major defense systems against xenobiotics. Interest in cyclodextrins (CDs) as medicinal agents has increased continuously based on their ability to actively extract lipids from cell membranes and to provide suitable carrier system for drug delivery. Many novel CD derivatives are constantly generated with the objective to improve CD bioavailability, biocompatibility and therapeutic outcomes. Newly designed drug formulation complexes incorporating CDs as drug carriers have demonstrated better efficiency in treating cardiovascular and neurodegenerative diseases. CD-based therapies as cholesterol-sequestrating agent have recently demonstrated promising advances with KLEPTOSE® CRYSMEB in atherosclerosis as well as with the 2-hydroxypropyl-β-cyclodextrin (HPβCD) in clinical trials for Niemann-Pick type C disease. Based on this success, many investigations evaluating the therapeutical beneficial of CDs in Alzheimer’s, Parkinson’s and Huntington’s diseases are currently on-going.
Highlights
Alteration in lipid metabolism is a feature of atherosclerosis and several neurological disorders (NDs) suggesting that innovative pharmacological approaches aiming at counteracting cholesterol imbalance display promising therapeutic potentials in these diseases
In addition to physical barrier properties, the blood-brain barrier (BBB) establishes a metabolic barrier allowing permanent exchanges between blood and central nervous system (CNS). These are achieved by means of transmembrane transporters, receptors and cytoplasmic enzymes involved in nutrient transportation across the BBB as well as constant elimination of toxic metabolites from the CNS and exclusion of circulating xenobiotics to enter the CNS processed by ATP-dependent efflux pumps such as ABCB1 (P-glycoprotein (P-gp)) [4] or ABCG2 (breast cancer resistance protein (BCRP))
It is likely that this cholesterol-depletion deeply affects the cellular process that controls the transfer of membrane cholesterol to extracellular high density lipoproteins (HDL) via the reverse cholesterol transport (RCT, Figure 1)
Summary
Alteration in lipid metabolism is a feature of atherosclerosis and several neurological disorders (NDs) suggesting that innovative pharmacological approaches aiming at counteracting cholesterol imbalance display promising therapeutic potentials in these diseases. CNS disorders still remain very difficult to treat In such a context, the usage of cyclodextrins and their derivatives appears as a highly relevant therapeutical challenge. Getting access to the brain still remains a major challenging task for pharmaceutical industries in their attempts to improve drug delivery to the brain and to evaluate xenobiotic toxicity In this context, the therapeutical benefits of CD at the BBB level are highly promising in regards to the ability of CDs to extract lipids from cell membranes in addition to its drug delivery potential
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