Glutamate excitotoxicity activates the MAPK/ERK signaling pathway and induces the survival of rat hippocampal neurons in vivo.

Current knowledge concerning the molecular mechanisms of the cellular response to excitotoxic insults in neurodegenerative diseases is insufficient. Although glutamate (Glu) has been widely studied as the main excitatory neurotransmitter and principal excitotoxic agent, the neuroprotective response enacted by neurons is not yet completely understood. Some of the molecular participants have been revealed, but the signaling pathways involved in this protective response are just beginning to be identified. Here, we demonstrate in vivo that, in response to the cell damage and death induced by Glu excitotoxicity, neurons orchestrate a survival response through the extracellular signal-regulated kinase (ERK) signaling pathway by increasing ERK expression in the rat hippocampal (CA1) region, allowing increased neuronal survival. In addition, this protective response is specifically reversed by U0126, an ERK inhibitor, which promotes cell death only when it is administered together with Glu. Our findings demonstrate that the ERK signaling pathway has a neuroprotective role in the response to Glu-induced excitotoxicity in hippocampal neurons. Therefore, the ERK signaling pathway may be activated as a cellular response to excitotoxic injury to prevent damage and neural loss, representing a novel therapeutic target in the treatment of neurodegenerative diseases.

Antioxidant activity of tryptophan in rats under experimental endotoxic shock.

Tryptophan (TRP), the precursor of the scavenger or immunomodulator molecules melatonin (MLT) and picolinic acid, can be found in the diet; and could be an alternative nutritional supplement used to regulate the immune response in the generation of free radicals. In an experimental model, the systemic administration of lipopolysaccharide (LPS), to promote the synthesis of pro-inflammatory cytokines, reactive oxygen species, and antioxidant enzymes, was performed on adult female, pregnant and lactating rats fed with a diet of TRP content (0.5mg/100g protein). Lung tissue was evaluated for levels of the products of lipoperoxidation (LPO's), malonaldehyde (MDA) and 4-hydroxy alkenals (4-HDA); nitrites (NO2), glutathione peroxidase (Gpx) enzyme activity, and the serum concentration of interferon-gamma (IFN-gamma), which were measured in the following groups: control (CTRL), LPS, MLT, TRP, LPS plus MLT (LPS+MLT), and LPS plus TRP (LPS+TRP). Results showed that the lung tissue levels of MDA and 4-HDA in the LPS+TRP group were significantly lower than in the TRP group. Statistically significant differences were not observed in nitric oxide levels among the groups LPS+MLT and LPS+TRP compared to the group under endotoxic shock (LPS). The Gpx enzyme activity was modified in the LPS+MLT vs the LPS group, but the difference was not statistically significant. The LPS+MLT group showed a smaller serum concentration (98%) of IFN-gamma than the LPS group. Statistically significant differences were not observed among the animals of the LPS+TRP and the LPS groups.