Ability of GDNF to diminish free radical production leads to protection against kainate‐induced excitotoxicity in hippocampus

Abstract

The primary aim of this study is to explore the protective mechanisms of glial-derived neurotrophic factor (GDNF) during excitotoxicity by kainate in the hippocampus. After a 15-min microinjection with kainate, excitotoxicity was induced in the rat hippocampus. The protective effect of GDNF in the hippocampus was evaluated by administering GDNF 14 min after injection of kainate. The resulting hydroxyl free radicals were quantified by microdialysis of the hippocampus. The results show that GDNF can effectively suppress the production of kainate-induced hydroxyl free radical production. In addition, histological observation indicated the ability of GDNF to decrease the damage level of pyramidal neurons in the CA3 and CA4 areas of the hippocampus. Superoxide dismutase (SOD) activity in the hippocampus was elevated significantly at 30 min and 7 days after kainate induction, while glutathione peroxidase (cGPx) activity did not increase significantly until the seventh day. With GDNF treatment, SOD and cGPx activity in the hippocampus was elevated significantly 7 days after kainate induction. We suggest that mechanisms including a decrease in free radical generation and scavenging of free radicals might be involved in GDNF protection against kainate-induced excitotoxicity.

Driving GDNF expression: The green and the red traffic lights

“…These observations are consistent with the finding that GDNF significantly elevates the activity of superoxide dismutase, catalase, glutathione peroxidase (Chao and Lee, 1999;Cheng et al, 2004), and the levels of reduced glutathione (Onyango et al, 2005). Accordingly, GDNF suppresses the accumulation of oxygen radicals in vitro (Irie and Hirabayashi, 1999;Sawada et al, 2000) and in vivo (Cheng et al, 2004). In addition, GDNF decreases NOS expression (Hermann et al, 2001) and activity (Wang et al, 2002).…”

“…Furthermore, in neuron-glia substantia nigra cell cultures, GDNF up-regulation in response to H 2 O 2 down-regulates the expression of heme oxygenase-1, a marker of oxidative stress (Saavedra et al, 2005). These observations are consistent with the finding that GDNF significantly elevates the activity of superoxide dismutase, catalase, glutathione peroxidase (Chao and Lee, 1999;Cheng et al, 2004), and the levels of reduced glutathione (Onyango et al, 2005). Accordingly, GDNF suppresses the accumulation of oxygen radicals in vitro (Irie and Hirabayashi, 1999;Sawada et al, 2000) and in vivo (Cheng et al, 2004).…”

Histaminergic Neurons Protect the Developing Hippocampus from Kainic Acid-Induced Neuronal Damage in an Organotypic Coculture System

“…In fact, excitotoxic neuronal damage has been ameliorated by different neurotrophic factors (Mattson et al, 1993;Culmsee et al, 1999;Cheng et al, 2004). In our culture system, however, the possible protective effect of serum-derived factors would have had similar effect on HI, HI plus HY (POST), and HI plus HY (ANT).…”

GDNF modulates HO-1 expression in substantia nigra postnatal cell cultures

“…The down-regulation of HO-1 by GDNF can be mediated by a decrease in oxidative stress levels, because GDNF was shown to suppress the accumulation of oxygen radicals induced by bleomycin sulfate in mesencephalic cultures [20] or by kainate in hippocampus [61] and to significantly elevate the activities of superoxide dismutase, catalase, and glutathione peroxidase [21,61]. Another hypothesis is that GDNF may be modulating HO-1 expression at the transcriptional level, as was suggested for other growth factors [22,23,62,63].…”