MDL 28170, a cell permeable, reversible, peptidic aldehyde inhibitor of calpain (Ki= 0.01µM; Ki for cathepsin B = 0.025µM)[1]. MDL 28170 caused the death of Leishmania amazonensis with an IC50 value of 15µM and triggered depolarization of mitochondrial membranes[2]. MDL 28170 has been used as a neuroprotective agent in many rodent models of neurotrauma, including spinal cord injury, neonatal hypoxic-ischemia, and focal cerebral ischemia, and has reduced neuronal loss and improved motor function in mouse models of Parkinson's disease [3].
In vitro, MDL 28170 treatment at 50μM for 30min prevented Aβ25-35-induced cell death and increased cell survival in SH-SY5Y cells[4]. MDL 28170 treatment (2.5μM; 72h) reduced high glucose-induced cell death, reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, and normalized reactive oxygen species[5].
In vivo, MDL 281709 treatment via intraperitoneal injection at 10mg/kg/day for 14 days can improve nociception and behavioral deficits in diabetic neuropathy, reduce calpain activity, oxidative stress, and neuroinflammation in diabetic neuropathy, and improve neurological function parameters in diabetic rats[6]. A single rapid injection of MDL 28170 at 30mg/kg in the tail vein of Wistar rats 30min before traumatic brain injury (TBI) significantly reduced the mean number of damaged axons in the analyzed brainstem fiber bundles[7]. A single dose of MDL 28170 (1.0μL; 50000µM; i.c.) in the acute phase of TBI within rats during 7 days can improve the brain microenvironment by inhibiting inflammation, promoting the survival of transplanted GFP-bone marrow-derived mesenchymal stem cells (BMSCs), reducing the apoptosis of transplanted cells, and decreasing the lesion cavity[8].
References:
[1] Saatman K E, Creed J, Raghupathi R. Calpain as a therapeutic target in traumatic brain injury[J]. Neurotherapeutics, 2010, 7(1): 31-42.
[2] Marinho F A, Gonçalves K C S, Oliveira S S C, et al. The calpain inhibitor MDL28170 induces the expression of apoptotic markers in Leishmania amazonensis promastigotes[J]. PLoS One, 2014, 9(1): e87659.
[3] Thompson S N, Carrico K M, Mustafa A G, et al. A pharmacological analysis of the neuroprotective efficacy of the brain-and cell-permeable calpain inhibitor MDL-28170 in the mouse controlled cortical impact traumatic brain injury model[J]. Journal of neurotrauma, 2010, 27(12): 2233-2243.
[4] Seyb K I, Schuman E R, Ni J, et al. Identification of small molecule inhibitors of β-amyloid cytotoxicity through a cell-based high-throughput screening platform[J]. Journal of biomolecular screening, 2008, 13(9): 870-878.
[5] Ong S B, Lee W H, Shao N Y, et al. Calpain inhibition restores autophagy and prevents mitochondrial fragmentation in a human iPSC model of diabetic endotheliopathy[J]. Stem cell reports, 2019, 12(3): 597-610.
[6] Kharatmal S B, Singh J N, Sharma S S. Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy[J]. Neuropharmacology, 2015, 97: 113-121.
[7]Buki A, Farkas O, Doczi T, et al. Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury[J]. Journal of neurotrauma, 2003, 20(3): 261-268.
[8] Hu J, Chen L, Huang X, et al. Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury[J]. Stem cell research & therapy, 2019, 10(1): 96.
MDL 28170是一种细胞渗透性、可逆的肽醛类抑制剂，可抑制钙蛋白酶（Ki=0.01µM；对组织蛋白酶B的Ki=0.025µM）。MDL 28170能诱导亚马逊利什曼原虫死亡（IC50=15µM），并引发线粒体膜去极化[2]。MDL 28170在多种神经创伤啮齿类模型（包括脊髓损伤、新生儿缺氧缺血和局灶性脑缺血）中作为神经保护剂应用，并在帕金森病小鼠模型中减少神经元丢失、改善运动功能[3]。
在体外，50μM的MDL 28170处理30分钟可抑制Aβ25-35诱导的SH-SY5Y细胞死亡并提高细胞存活率[4]。MDL 28170 （2.5μM； 72小时）处理原代人主动脉内皮细胞减少了高糖诱导的细胞死亡，减少了线粒体碎片，同时维持了ATP的生成，并使活性氧水平正常化[5]。
在体内，糖尿病神经病变大鼠经腹腔注射MDL 28170（10mg/kg/day）14天可改善痛觉和行为缺陷，降低钙蛋白酶活性、氧化应激和神经炎症，并改善神经功能参数[6]。Wistar大鼠在创伤性脑损伤（TBI）前30分钟经尾静脉单次快速注射30mg/kg剂量的MDL 28170，显著减少脑干纤维束的轴突损伤数量[7]。TBI急性期大鼠单次给予MDL 28170（1.0μL, 50000µM; i.c.）治疗7天，可抑制炎症、提高移植GFP骨髓间充质干细胞（BMSC）存活率、减少移植细胞凋亡和缩小病变腔并改善脑微环境[8]。