Title

Neuronal responses to stroke-type injury: Evidence for distinct and opposing pathways

Date of Completion

January 2003

Keywords

Biology, Molecular|Biology, Neuroscience

Degree

Ph.D.

Abstract

Cellular responses to a variety of stimuli are integral in fate determination in all organs of the body. There are two major avenues a cell can follow in the face of injury; one is survival the other is pathogenesis. The brain, being one of the most vital and complex organs of the body, responds to injury in one of the above ways. One injury that particularly targets the brain is stroke-type pathology, resulting from the over-activation of the glutamate receptors. Glutamergic receptors, including NMDA and AMPA-type receptors, play a role in stroke-type excitotoxic damage that particularly targets the hippocampus. Neurons deprived of blood and oxygen are compromised and begin to die almost immediately. To survive such insults, the cell initiates a variety of signaling cascades that either lead to recovery of cellular health or conversely contribute to the injury process. Some signal transduction molecules such as transcription factors appear to have a dual role in responding to a single stimulus. The inducible transcription factor nuclear factor-κB (NF-κB), appears to have a controversial dual role in excitotoxicity. Organotypic hippocampal slice cultures from rat were used as the model system to evaluate cellular responses to stroke-type insult. NF-κB translocation, used as a marker for cellular response to excitotoxicity, exhibited a biphasic response profile, consisting of an early (0.5–2 h post-insult) and delayed phase (5–24 h). The work presented here demonstrates that the two phases of the cellular response are distinct and possibly opposing by several parameters. These are (1) different subunit composition of NF-κB in the two phases; (2) biphasic degradation profile of the inhibitory protein; (3) phase selective activation of MAPK; (4) distinct influence of a pathogenic and a protective condition; (5) different gene expression profiles in the two phases. ^ Accordingly, data obtained from this study identifies that the early phase of the cellular response is associated with survival mechanisms, whereas the delayed phase contributes to injury. Unraveling the nature of cellular responses, possibly mediated by NF-κB activation, that result in opposing responses will shed light into the orchestration of anti- and pro-apoptotic signaling pathways. Finally, these data will identify key targets to help develop treatments for stroke-type excitotoxicity. ^