Alagebrium chloride (ALT711) is a thiazolium derivative which breaks advanced glycation end products (AGE) crosslinks. Alagebrium chloride has been used to study the treatment of diastolic heart failure, arterial stiffness, diabetic nephropathy, and hypertension[1][2].
In vitro, human breast cancer MDA-MB-231 cells were embedded in collagen gels glycated with glucose or ribose at different concentrations. Samples were treated with 1mM Alagebrium chloride overnight for about 16h in media. Increases in cell spreading, contractility, migration velocity, distance travelled, and motile fraction due to glycation could be inhibited by Alagebrium chloride to disrupt AGEs[3]. Rat cardiomyocytes were treated with AGE-bovine serum albumin or Alagebrium chloride (10mg/L) for 48 hours in complete growth medium. Alagebrium chloride exerts protective effect on AGEs-treated cardiomyocytes by inhibiting the increased oxidative stress[4].
In vivo, the streptozotocin-induced diabetic rats were treated with 10mg/kg Alagebrium chloride for 4 weeks. Alagebrium chloride was mixed with pulverized standard chow to a final Alagebrium chloride concentration of 0.015% (wt/wt). Alagebrium chloride treatment in diabetic rats significantly inhibits neointimal hyperplasia and inhibited the increase in formation of connective tissue and extracellular matrix[5]. Wide-typed and RAGE-/- C57BL/6J diabetic mice were randomized to receive Alagebrium chloride by oral gavage at 1mg/kg/day for 24 weeks. Alagebrium chloride significantly attenuated diabetes-driven albuminuria, glomerulosclerosis, and tubulointerstitial expansion, restored renal mitochondrial ATP production, and reduced both cytosolic and mitochondrial superoxide generation[6]. Female non-obese diabetic (NOD) mice were either given no treatment or daily, subcutaneous injections of Alagebrium chloride (1mg/kg/day) for 50 days from day 50 to 100 of life. Alagebrium chloride therapy from modestly delayed the age of diabetes onset, but there were no differences in disease incidence. Female NODShiLt mice were received subcutaneous injections of Alagebrium chloride (1mg/kg/day) for 28–32 days from day 50 of life. Short-Term Therapy with Alagebrium chloride slightly Increases Insulin Secretion[7].
References:
[1] William C Little W C, Zile M R, Kitzman D W, et al. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail. 2005 Apr;11(3):191-5.
[2] Wang H F, Weihrauch D, Kersten J R, et al. Alagebrium inhibits neointimal hyperplasia and restores distributions of wall shear stress by reducing downstream vascular resistance in obese and diabetic rats. Am J Physiol Heart Circ Physiol. 2015 Oct;309(7):H1130-40.
[3] Rowe M M, Wang W J, Taufalele P V, Reinhart-King C A. AGE-breaker ALT711 reverses glycation-mediated cancer cell migration.Soft Matter. 2022 Nov 16;18(44):8504-8513.
[4] Guo Y, Lu M, Qian J, Cheng Y L. Alagebrium chloride protects the heart against oxidative stress in aging rats. J Gerontol A Biol Sci Med Sci. 2009 Jun;64(6):629-35.
[5] Kim J B, Song B W, Park S H, et al. Alagebrium chloride, a novel advanced glycation end-product cross linkage breaker, inhibits neointimal proliferation in a diabetic rat carotid balloon injury model. Korean Circ J. 2010 Oct;40(10):520-6.
[6] Tan A L Y, Sourris K C, Harcourt B E, et al. Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition, or dietary AGE control in experimental diabetic nephropathy. Am J Physiol Renal Physiol. 2010 Mar;298(3):F763-70.
[7] Borg D J, Faridi P, Giam K L, et al. Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model. Metabolites. 2021 Jun 28;11(7):426.
Alagebrium chloride (ALT711)是一种噻唑鎓衍生物，可断裂晚期糖基化终产物(AGE)交联。Alagebrium chloride已被用于研究舒张性心力衰竭、动脉僵硬、糖尿病肾病和高血压的治疗[1][2]。
体外实验中，将人乳腺癌MDA-MB-231细胞包埋于经不同浓度葡萄糖或核糖糖化的胶原凝胶中。样本在培养基中用1mM Alagebrium chloride处理过夜约16h。糖化引起的细胞铺展、收缩性、迁移速度、迁移距离及运动分数的增加均可被Alagebrium chloride通过破坏AGEs而抑制[3]。大鼠心肌细胞在完全培养基中用AGE-牛血清白蛋白或Alagebrium chloride(10mg/L)处理48h。Alagebrium chloride通过抑制氧化应激的增加，对AGEs处理的心肌细胞发挥保护作用[4]。
体内实验中，链脲佐菌素诱导的糖尿病大鼠以10mg/kg Alagebrium chloride治疗4周。将Alagebrium chloride与粉碎的标准饲料混合至终浓度0.015% (wt/wt)。Alagebrium chloride治疗显著抑制糖尿病大鼠的新生内膜增生，并抑制结缔组织及细胞外基质的增加[5]。野生型和RAGE-/- C57BL/6J糖尿病小鼠被随机分组，通过口服灌胃给予1mg/kg/day Alagebrium chloride，持续24周。Alagebrium chloride显著减轻糖尿病驱动的白蛋白尿、肾小球硬化和肾小管间质扩张，恢复肾脏线粒体ATP生成，并减少胞质和线粒体超氧阴离子的产生[6]。雌性非肥胖糖尿病(NOD)小鼠不接受治疗或从第50天至第100天每日皮下注射Alagebrium chloride (1mg/kg/day)，共50天。Alagebrium chloride治疗略微延迟糖尿病发病年龄，但发病率无差异。雌性NODShiLt小鼠从第28至第32天接受皮下注射Alagebrium chloride(1mg/kg/day)，短期Alagebrium chloride治疗轻度增加胰岛素分泌[7]。