81065-76-1

Biological Activity

euk 134, a synthetic superoxide dismutase (sod)/catalase mimetic, has exhibited potent antioxidant activities and inhibited the formation of β-amyloid and related amyloid fibril.

Biochem/physiol Actions

EUK-134 is a manganese-salen derivative that exhibit potent antioxidant activities. EUK-134 is a superoxide dismutase (SOD) that inhibits amyloid fibril formation, including islet amyloid polypeptide (IAPP), β-amyloid and lysozyme amyloid aggregation. It appears that EUK-134 disrupts the pre-formed amyloid fibrils. EUK-134 increases the viability of the SK-N-MC cells exposed to preformed IAPP fibrils.

in vitro

euk-134, a salen-manganese complex, showed potent catalase and cytoprotective activities and sod activity. after middle cerebral artery occlusion, euk-134 administration at 3 hr significantly reduced brain infarct size, with the highest dose apparently preventing further infarct growth[1]. administration of euk 134 (20 μm) prevented aβ-induced microglial proliferation in vitro[2]. in human neuroblastoma cell line sk-n-mc, pre-treatments with euk134 protected cells against h2o2-induced oxidative stress through inhibition of mapk pathway in a dose-dependent manner.euk134 also decreased the expression of pro-apoptotic genes p53 and bax and enhanced expression of anti-apoptotic bcl-2 gene [3]. incubation of human amylin with euk-134 significantly inhibited amyloid formation at two molar ratios of 1:1 and 5:1 (drugs to protein)[4].

in vivo

compared to the vehicle-injected rats, the euk-134-treated group at doses of 0.5 and 5.0 μmol/kg (0.25 and 2.5 mg/kg, respectively) exhibited infarct volumes that were significantly lower than those of vehicle-injected rats. at 5.0 μmol/kg, euk-134 reduced the infarct volume by 90% when compared with that of the vehicle controls [1].euk-134 protected most of the vulnerable neurons from excitotoxic cell death.euk-134 significantly reduced (p< 0.05) ka-induced neuronal damage in ca1 (22% of total neurons), an almost complete protection in ca3 (7%) and piriform cortex (14%), indicating that euk-134 prevented most but not all neuronal damage resulting from ka-induced seizure activity [5].

references

[1]. baker k, marcus c b, huffman k, et al. synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury[j]. journal of pharmacology and experimental therapeutics, 1998, 284(1): 215-221.[2]. jekabsone a, mander p k, tickler a, et al. fibrillar beta-amyloid peptide aβ 1–40 activates microglial proliferation via stimulating tnf-α release and h 2 o 2 derived from nadph oxidase: a cell culture study[j]. journal of neuroinflammation, 2006, 3(1): 1.[3]. mohammadi m, yazdanparast r. modulation of h2o2‐induced mitogen‐activated protein kinases activation and cell death in sk‐n‐mc cells by euk134, a salenderivative[j]. basic & clinical pharmacology & toxicology, 2011, 108(6): 378-384.[4]. bahramikia s, yazdanparast r. inhibition of human islet amyloid polypeptide or amylin aggregation by two manganese-salenderivatives[j]. european journal of pharmacology, 2013, 707(1): 17-25.[5]. rong y, doctrow s r, tocco g, et al. euk-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology[j]. proceedings of the national academy of sciences, 1999, 96(17): 9897-9902.