Phénix Jasmine, Côté Jonathan, Dieme Denis, Recinto Sherilyn J, Oestereich Felix, Efrem Sasen, Haddad Sami, Bouchard Michèle, Munter Lisa Marie
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Cell Information Systems Group, Montreal, QC, Canada.
Front Pharmacol. 2023 Jul 18;14:1171937. doi: 10.3389/fphar.2023.1171937. eCollection 2023.
High levels of plasma cholesterol, especially high levels of low-density lipoprotein cholesterol (LDL-C), have been associated with an increased risk of Alzheimer's disease. The cholesteryl ester transfer protein (CETP) in plasma distributes cholesteryl esters between lipoproteins and increases LDL-C in plasma. Epidemiologically, decreased CETP activity has been associated with sustained cognitive performance during aging, longevity, and a lower risk of Alzheimer's disease. Thus, pharmacological CETP inhibitors could be repurposed for the treatment of Alzheimer's disease as they are safe and effective at lowering CETP activity and LDL-C. Although CETP is mostly expressed by the liver and secreted into the bloodstream, it is also expressed by astrocytes in the brain. Therefore, it is important to determine whether CETP inhibitors can enter the brain. Here, we describe the pharmacokinetic parameters of the CETP inhibitor evacetrapib in the plasma, liver, and brain tissues of CETP transgenic mice. We show that evacetrapib crosses the blood-brain barrier and is detectable in brain tissue 0.5 h after a 40 mg/kg i.v. injection in a non-linear function. We conclude that evacetrapib may prove to be a good candidate to treat CETP-mediated cholesterol dysregulation in Alzheimer's disease.
高水平的血浆胆固醇，尤其是高水平的低密度脂蛋白胆固醇（LDL-C），与阿尔茨海默病风险增加有关。血浆中的胆固醇酯转运蛋白（CETP）在脂蛋白之间分配胆固醇酯，并增加血浆中的LDL-C。从流行病学角度看，CETP活性降低与衰老过程中的持续认知表现、长寿以及较低的阿尔茨海默病风险相关。因此，药理学上的CETP抑制剂可重新用于治疗阿尔茨海默病，因为它们在降低CETP活性和LDL-C方面安全有效。尽管CETP主要由肝脏表达并分泌到血液中，但它也在大脑中的星形胶质细胞中表达。因此，确定CETP抑制剂是否能够进入大脑很重要。在此，我们描述了CETP抑制剂依折麦布在CETP转基因小鼠的血浆、肝脏和脑组织中的药代动力学参数。我们表明，依折麦布可穿过血脑屏障，在以40mg/kg静脉注射后0.5小时，脑组织中可检测到依折麦布呈非线性分布。我们得出结论，依折麦布可能是治疗阿尔茨海默病中CETP介导的胆固醇失调的良好候选药物。
