UBC Theses and Dissertations
Factors in glutamate excitotoxicity, inflammation and epilepsy Zhu, Shanshan
Studying the mechanisms underlying glutamate excitotoxicity and inflammatory responses provides hints to the pathology of neurological diseases such as epilepsy. In this dissertation I investigated the expression and function of Krüppel-like factor 4 (KLF4) in glutamate excitotoxicity. I also studied the distribution and the role of progranulin (PGRN) in inflammatory stimulation, in epilepsy and in astrocytes subjected to glutamate excitotoxicity. First, I studied the role of KLF4 and found that NMDA induced KLF4 expression in cultured neurons and in brain slices. Overexpression of KLF4 upregulated cyclin D1 and downregulated p21Waf1/Cip1, suggesting the neuron’s progression into cell cycle. KLF4 expression also induced the cleavage of caspase-3 under conditions of a subtoxic dose of NMDA. Thus our work suggests that KLF4 might play a role in NMDA-induced apoptosis. Second, I studied the function of PGRN and observed that PGRN was enhanced in activated microglia after pilocarpine-induced epilepsy. In mixed cultures, lipopolysaccharide (LPS) also induced PGRN expression. Recombinant PGRN protein promoted microglial activation in the dentate gyrus after epilepsy and in purified microglial cell culture. PGRN was also required for LPS-induced microglial migration. Our work suggests that PGRN may contribute to microglial activation after epileptic and inflammatory insults. Third, I performed a preliminary study on the role of PGRN in purified culture of astrocytes. I found that our cultured astrocytes express PGRN, and PGRN was required for glutamate-induced lactate release. PGRN was also involved in glutamate-induced glucose uptake and participated in the regulation of monocarboxylate transporter 1 (MCT1) expression in excitotoxic conditions. Our findings suggest that PGRN may be involved in glutamate-evoked increase of glycolysis in cultured astrocytes. In conclusion, our findings provide insights into factors involved in glutamate excitotoxicity, inflammation, and epilepsy.
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