Redox modulation of the liver with chronic antioxidant enzyme mimetic treatment prevents age‐related oxidative damage associated with environmental stress

Abstract

A reduction in stress tolerance is a hallmark of the aging process, and the lowered functional capacity observed in aged organisms is associated with an increased rate of oxidative stress and a greater susceptibility of aged tissues to oxidative injury. In this report, we show that chronic systemic administration of a superoxide dismutase (SOD)/catalase mimetic (EUK-189), delivered over a 1 month period via osmotic pump, prevents heat stress-induced liver injury by dramatically decreasing oxidative damage in aged animals. Widespread liver injury was present in old but not young vehicle-treated rats in response to a 2 day heating protocol. However, SOD/catalase mimetic treatment markedly decreased the hyperthermia-induced liver injury associated in old animals. The reversal of damage with EUK-189 was associated with an improvement in intracellular redox status and a striking reduction in hepatocellular lipid peroxidation. EUK-189 treatment also blocked the activation of activator protein-1 (AP-1), which is a redox-sensitive early response transcription factor involved in the regulation of cellular stress responses. These results demonstrate that oxidative stress plays a unique role in age-related hyperthermic injury and suggest that therapeutic strategies aimed at improving redox potential, such as chronic SOD/catalase mimetic treatment, can prevent the oxidative-mediated damage associated with environmental stress.

Ameliorative Action of Mn-Salen Derivatives on CCl<sub>4</sub>-Induced Destructive Effects and Lipofuscin-Like Pigment Formation in Rats’ Liver and Brain: Post-Treatment of Young Rats with EUKs

“…In current study, post-treatment of rats with the Mn-salen derivatives (compounds 1-6) strengthened the defense system and prevented depletion of GSH probably via either ROS scavenging and/or the stimulation of gene expression of antioxidant enzymes [30] [38]. Present results are complementary to the observations reported earlier about the ameliorative effects of some natural and synthetic antioxidants on the activity of CAT, SOD and GPX as well as the level of GSH in animal and cell culture models [11] [12] [14] [30] [39].…”

“…The Mn-macrocyclic complexes have SOD activity, but not other ROS scavenging properties. The Mn-porphyrins and Mn-salen complexes are synthetic compounds with both SOD and catalase activities [14] [15]. Furthermore, these complexes have the ability of reacting with nitrite ion and lipid peroxides and thus, they have shown efficacy in a wide variety of biological models for ROS-associated diseases [13].…”

“…EUK-134 attenuates kainite-induced neuropathology, and significantly decreases DNA-binding activity of two transcription factors, activator protein-1 (AP-1) and NF-κB [16] [17]. Furthermore, EUK-189 has been known as a neuroprotective agent to increase survival, to suppress oxidative pathologies in mice lacking Mn-SOD, to prolong lifespan in the nematode C. elegans, to attenuate age-associated learning impairment and to protect heat-induced liver injury in old rats [14]. The present investigation has evaluated the beneficiary of post-treatment with Mn-salen derivatives on the extent of lipofuscin formation in the CCl 4 -exposed rats.…”

Iron and Paraquat as Synergistic Environmental Risk Factors in Sporadic Parkinson's Disease Accelerate Age-Related Neurodegeneration

“…Animals were killed at day 4 or 7 after final administration. Administration of the salen manganese complex, EUK-189, was performed as described previously (Zhang et al, 2004;Peng et al, 2005 TH staining and stereology. Mice were fixed by perfusion as described previously (Peng et al, 2004).…”

“…To investigate whether EUK-189 inhibited the increased dopaminergic neuronal death after paraquat administration in the 12-month-old iron-fed mice previously fed iron versus those treated with paraquat alone, we implanted mice with osmotic minipumps containing either 5% mannitol (as vehicle control) or 15 mM EUK-189 3 d before paraquat treatment (Zhang et al, 2004;Peng et al, 2005). At this age, neonatal iron exposure alone does not result in dopaminergic SN cell loss (Kaur et al, 2007).…”