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.
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.