EUK-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology

Abstract

The present study tested the effects of EUK-134, a synthetic superoxide dismutase͞catalase mimetic, on several indices of oxidative stress and neuropathology produced in the rat limbic system as a result of seizure activity elicited by systemic kainic acid (KA) administration. Pretreatment of rats with EUK-134 did not modify the latency for or duration of KA-induced seizure activity. It did produce a highly significant reduction in increased protein nitration, activator protein-1-and NF-B-binding activity, and spectrin proteolysis as well as in neuronal damage resulting from seizure activity in limbic structures. These results support the hypothesis that kainate-induced excitotoxicity is caused, at least in part, by the action of reactive oxygen species. Furthermore, they suggest that synthetic superoxide dismutase͞catalase mimetics such as EUK-134 might be used to prevent excitotoxic neuronal injury.Various mechanisms have been proposed to account for the pathological manifestations observed after systemic administration of the excitotoxin kainic acid (KA). Because drugs blocking seizure activity prevent most of the neuronal damage resulting from KA injection (1, 2), it is clear that the pathology is not a direct consequence of the activation of KA or ␣-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) receptors, but rather is the result of events triggered by seizure activity. Excessive production of oxygen-free radicals and other radical species often has been proposed to play an important role in neuronal pathology resulting from excitotoxic insults (3-8). It generally is admitted that KA administration results in the activation of N-methyl-D-aspartate (NMDA) receptors in vulnerable neuronal populations (9, 10), an event that has been shown to cause the formation of superoxide radicals (11,12). Moreover, we reported previously that levels of lipid peroxidation and protein oxidation, two parameters of oxidative stress, were increased significantly in hippocampus and piriform cortex at 8 and 16 h after KAinduced seizure activity in adult rats (13). We also showed that the DNA-binding activity of two transcription factors, namely activator protein-1 (AP-1) and NF-B, generally considered to be markers of cellular insults (14, 15), was increased in these structures under these conditions (16). However, a causal relationship between oxidative stress and neuronal damage after systemic kainate injection has not been established unambiguously, because many agents used as antioxidants also interfere with seizure activity. In addition, because excitotoxicity also has been shown to be reduced by caspase inhibitors (17), oxidative stress could be a late consequence of the events triggered by seizure activity and leading to neuronal death.Salen-manganese complexes are low-molecular-weight synthetic compounds that exhibit both superoxide dismutase (SOD) and catalase activities, catalytically eliminating both superoxide and hydrogen peroxide, respectively (18 -20). Compared with proteinaceous antioxidant en...

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is a metabolic regulator of intestinal epithelial cell fate

“…We then studied the effect of PGC1α overexpression in colorectal cancer cells and xenografted tumors in the presence of a synthetic combined catalase and SOD2 mimetic referred to as EUK134 (28). Treatment of colorectal cancer cells, and of xenografted tumors with EUK134, completely prevented the PGC1α-induced proapoptotic and tumor-suppressor activity.…”

Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics

“…Brains were cryoprotected with sucrose and sectioned at 25 m on a microtome. Immunocytochemistry was performed by using the avidinbiotin-horseradish peroxidase complex (ABC) method with reagents and instructions of the VECTASTAIN Elite ABC kit from Vector Laboratories as described (17). Free-f loating tissue sections were incubated in 10% normal horse serum diluted in PBS for 1 h at room temperature, and then in the presence of a mAb to oxo8dG͞oxo8G (1:1,000) in 5% horse serum diluted in PBS overnight at 4°C.…”

Treatment Strategies for the NMDA Component of Organophosphorus Convulsions

“…This is a critical difference from other GABAA agonists such as diazepam or midazolam given the predominate role of glutamate and NMDA receptors in both Li-pilo and organophosphorus nerve agent mediated SE (Ormandy et al, 1989;Walton and Treiman, 1991;McDonough and Shih, 1997). The SE-induced NMDA receptor activation leads to an mcreased production of reactive oxygen species (Lafon-Cazal et al, 1993;Michaelis, 1998) that are hypothesized to mediate the neuropathology induced by SE Rong and Baudry, 1996;Rong et al, 1999;Peterson et al, 2002 in Appendix). We propose that propofol's NMDA antagonism would attenuate the NMDA receptor activation while the antioxidant activity suppresses the activity of the reactive oxygen species.…”

“…There is increasing evidence that ROS are responsible for the neuropathology induced by SE Rong and Baudry, 1996;Rong et al, 1999). In that regard, kainic acid (KA)-induced SE activates transcription factors such as nuclear factor KB (NFKB) and activator protein-1 (AP-1) which are known to be activated by oxidative stress (Rong and Baudry, 1996;Rong et al, 1999).…”

“…SE also activates the ROS scavenging enzymes superoxide dismutase (SOD) and catalase indicating a cellular response to increased ROS Ferrer et al, 2000). SE induces ROS mediated protein oxidation as measured by tyrosine nitration Rong et al, 1999) as well as lipid peroxidation as indicated by malondialdehyde . Antioxidants and free radical spin trap agents that react with ROS before they induce damage have been shown to reduce the neuropathology associated with SE (Armstead et al, 1989;Schulz et al, 1995;MacGregor et al, 1996;Rong et al, 1999).…”