Maraviroc, the first CCR5 antagonist, has been approved for the treatment of HIV infection, IC50 on hERG ion channel＞10μM[1]. Maraviroc also has been viewed as a new therapeutic strategy to treat neuroinflammatory diseases such as multiple sclerosis, Rasmussen encephalitis [2].
Maraviro (3µg/ml for 48 hours) could regulate the release of pro-inflammatory factors related to liver fibrosis in LX-2 cells (a human hepatic stellate cell line). These pro-inflammatory factors led to an increase in the expression levels of cyclin D1 and p21, while the expression of p53 decreases, thereby blocking cell growth in the S phase. Therefore, maraviro may play an important role in the treatment of liver fibrosis[3].
Maraviroc (20mg/kg for 3 days) significantly enhanced tissue preservation and improved neurological function in traumatic brain injury (TBI) mice[4]. Maraviroc treatment (120mg/kg, 200μl, twice/day) also significantly reduced blood and brain viral loads and reduced HIV induced increase in amyloid-beta (Aβ)-42, gamma-secretase activating protein (GSAP), and phospho-Tau in NOD/scid–IL-2Rγc null (NSG) mice, thereby reducing viremia, preserving the BBB and neurons, increasing brain Aβ efflux, and reducing AD-like neuropathologies[5].
[1] Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005;49(11):4721-32. doi: 10.1128/aac.49.11.4721-4732.2005. PubMed PMID: 16251317.
[2] Martin-Blondel G, Brassat D, Bauer J, Lassmann H, Liblau RS. CCR5 blockade for neuroinflammatory diseases--beyond control of HIV. Nat Rev Neurol. 2016;12(2):95-105. Epub 20160118. doi: 10.1038/nrneurol.2015.248. PubMed PMID: 26782333.
[3] Coppola N, Perna A, Lucariello A, Martini S, Macera M, Carleo MA, et al. Effects of treatment with Maraviroc a CCR5 inhibitor on a human hepatic stellate cell line. J Cell Physiol. 2018;233(8):6224-31. Epub 20180312. doi: 10.1002/jcp.26485. PubMed PMID: 29336497.
[4] Liu XL, Sun DD, Zheng MT, Li XT, Niu HH, Zhang L, et al. Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes. Neural Regen Res. 2023;18(1):141-9. doi:10.4103/1673-5374.344829. PubMed PMID: 35799534.
[5] Bhargavan B, Woollard SM, McMillan JE, Kanmogne GD. CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice. Mol Neurodegener. 2021;16(1):78. Epub 20211122. doi: 10.1186/s13024-021-00500-0. PubMed PMID: 34809709.
马拉韦罗作为第一款CCR5拮抗剂已被批准用于治疗HIV感染，对hERG离子通道的IC50＞10μM[1]。马拉韦罗也被视为治疗神经炎症性疾病如多发性硬化症、拉斯穆森脑炎的新型治疗策略[2]。
马拉韦罗(3µg/ml持续48小时)可以调控LX-2细胞（人肝星状细胞系）中肝纤维化有关的促炎因子的释放，这些促炎因子会导致细胞周期蛋白D1和p21的表达水平增加，p53的表达减少，从而阻滞细胞在S期的生长。因此，马拉韦罗在肝纤维化的治疗中可能发挥重要作用[3]。
马拉韦罗（20mg/kg，持续3天）显著提高了创伤性脑损伤（TBI）小鼠的组织保存并改善了神经功能[4]。马拉韦罗治疗（120mg/kg，200μl，每天两次）也显著降低了NOD/scid–IL-2Rγc null (NSG)小鼠血液和大脑病毒载量以及减少HIV诱导的β淀粉样-42、γ分泌酶激活蛋白(GSAP)和磷酸化Tau的增加，因此减少了病毒血症，保护了血脑屏障和神经元，增加了脑β淀粉样流出并且减少类阿尔茨海默病[5]。