Potential signalling pathways underlying corticotrophin‐releasing hormone‐mediated neuroprotection from excitotoxicity in rat hippocampus

Abstract

In several neurological disorders including cerebral ischaemia, glutamate has been implicated as a neurotoxic agent in the mechanisms leading to neuronal cell death. The role of corticotrophin-releasing hormone (CRH), the 41-amino acid peptide, which activates the HPA axis in response to stressful stimuli, remains controversial. In this study, we report that CRH in low physiological concentrations (2 pM), prevented glutamate-induced neurotoxicity via receptor-mediated mechanisms when administered to organotypic hippocampal cultures both during and after the glutamate-induced insult. Detailed investigations on the mechanisms mediating this neuroprotective effect showed that activation of the adenylate cyclase pathway and induction of MAP kinase phosphorylation mediate the CRH action. In addition we showed that CRH can inhibit the phosphorylation of JNK/SAPK by glutamate. Most importantly, we showed that CRH can afford neuroprotection against neurotoxicity up to 12 h following the insult, suggesting that CRH is acting at a late stage in the neuronal death cycle, and this might be important in the development of novel neuroprotective agents in order to improve neuronal survival following the insult.

Galanin acts as a neuroprotective factor to the hippocampus

“…Organotypic cultures were prepared as described (24,25). In brief, the hippocampi from 5-to 6-day-old pups were rapidly removed under a dissection microscope and sectioned transversely at 400 m by using a McIlwain tissue chopper (Mickle Laboratory Engineering, Guildford, Surrey, U.K.).…”

“…These two techniques are complimentary because the dispersed hippocampal cultures ensure that observed effects are neuronspecific, whereas the organotypic cultures preserve the synaptic and anatomical organization of the neuronal circuitry (24) as well as retaining many of the functional characteristics found in vivo (31). In organotypic hippocampal culture, afferent fibers are cut and thereafter degenerate; however, all neuronal and gill cell types survive, and there is no evidence that the lack of afferent inputs results in the selective loss of a particular cell type (32).…”

“…To further dissect the neuroprotective role played by galanin in a more tractable in vitro system, we used both primary dispersed and organotypic hippocampal cultures (24). These two techniques are complimentary because the dispersed hippocampal cultures ensure that observed effects are neuronspecific, whereas the organotypic cultures preserve the synaptic and anatomical organization of the neuronal circuitry (24) as well as retaining many of the functional characteristics found in vivo (31).…”

Corticotropin-releasing hormone activates ERK1/2 MAPK in specific brain areas

“…The involvement of ERK1͞2 in several CRH actions has been described in neuronal cell cultures, such as neuroprotection against excitotoxicity in hippocampal cells (52) and the antiapoptotic activity of CRH in retinoblastoma cells (53). In cell cultures, ERK1͞2 phosphorylation takes place within a range of minutes after the receptor activation (33,54).…”

Mitogen-Activated Protein Kinase Signaling in the Hippocampus and Its Modulation by Corticotropin-Releasing Factor Receptor 2: A Possible Link between Stress and Fear Memory

“…Studies with cell lines indicate that CRF activates both the PKA and Mek-1/2 signaling pathways (Elliott-Hunt et al, 2002) by acting through CRF 1 (Pedersen et al, 2002;Radulovic et al, 2003) or CRF 2 (Rossant et al, 1999). Thus, CRF receptors might also modulate Erk-1/2 signaling in vivo.…”