The neuroprotective role of anti-apoptotic proteins following acute neurological insults.

摘要

The post mitotic nature of neurons poses a particular problem in the context of acute neurological insults. It is of great interest in the field to both understand the mechanisms of pathological neuronal death as well as be in a position to offer protection to subsets of vulnerable neurons in these acute conditions. A substantial amount of work has been carried out in establishing the regulators of insult-induced neuronal demise. Two morphologically unique forms of death, necrosis and apoptosis, call into action a number of different intracellular mediators and gene products. Studies demonstrate that a variety of beneficial genes can be delivered, following acute neurological disturbances, which diminish the necrotic phase of cell death with preservation of physiological function. In contrast, little is known regarding the prevalence of classical apoptosis following such insults and the efficacy of targeting different stages of the apoptotic pathway. In this thesis, I have theoretically and experimentally addressed many of these issues, ultimately refining the understanding of acute cell death and implications for neuroprotection.; I have utilized a number of viral anti-apoptotic gene products to test their neuroprotective capabilities and further understand the mechanisms of neuronal collapse. I have utilized a strategy whereby the use of pharmacological models of physiological stressors such as seizure and metabolic disruption allow me to mimic selective neuronal vulnerability. In order to selectively deliver genes of interest to neurons, amidst the surrounding population of cells, I have used the neurotropic properties of Herpes Simplex Virus vectors. I document that while the overexpression of anti-apoptotic molecules such as caspase inhibitors or Bcl-2 family members are cytoprotective, especially following neuronal excitotoxicity, they protect under circumstances where there is little or no evidence for a classical manifestation of the apoptotic program. I further demonstrate that these inhibitors, classically characterized to be conventional inhibitors of apoptosis, are protective against a variety of the necrotic features of cell death. Collectively examined, these data add to the growing body of knowledge regarding the mechanisms of acute neuron death and offer insight into aspects of neurotoxicity in the adult brain, and possible avenues for future therapeutic strategies.