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Date of Award


Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)


Pharmaceutical and Chemical Sciences

First Advisor

James Blankenship

First Committee Member

Denis Meerdink

Second Committee Member

Timothy Smith

Third Committee Member

David Fries

Fourth Committee Member

Michael Minon

Fifth Committee Member

George Miljanich


The present investigation focused on three different aspects of polyamine involvement in induction of cell differentiation and neurite outgrowths: effects of polyamines on isolated bovine brain tubulin assembly, effects of polyamines on dopamine levels in PC12 cells, and influence of differentiating agents on polyamine and acetylpolyamine levels in PC12 cells. Among the polyamines, only spermine significantly induced tubulin assembly starting at 60 $\mu$M concentration (p $<$ 0.05). Colchicine at 100 $\mu$M concentration, and calcium chloride at 5 mM concentration inhibited spermine-induced polymerization (p $<$ 0.05). Spermine-induced polymerization was not stable in the presence of calcium or at 4$\sp\circ$C. NGF and dexamethasone increased the dopamine levels compared to that of control. Dopamine levels were increased up to 170% and 160% of control (p $<$ 0.05) with 10 $\mu$M N$\sp8$-acetylspermidine and 10 $\mu$M 7-(N-(3-aminopropyl)amino) heptan-2-one (APAH), respectively, after 48 hours. APAH is an inhibitor of N$\sp8$-acetylspermidine deacetylase. These effects of N$\sp8$-acetylspermidine and APAH appeared to be concentration dependent. Other polyamines did not have any significant effects on dopamine levels in PC12 cells. NGF and dexamethasone did not appear to have a significant effects on polyamine and acetylated polyamine levels in PC12 cells at the time periods studied. The amount of N$\sp8$-acetylspermidine detected after 24 hour treatment with 100 $\mu$M N$\sp8$-acetylspermidine was 18 $\pm$ 3 pmols/mg protein. The levels were increased up to 38 $\pm$ 6 and 52 $\pm$ 11 pmols/mg protein after days 3 and 7, respectively, with 100 $\mu$M N$\sp8$-acetylspermidine treatment. N$\sp8$-Acetylspermidine levels were detectable as early as day 1 with 100 $\mu$M APAH treatment and the levels detected after 1, 3, and 7 day treatments were 7.4 $\pm$ 0.9, 14 $\pm$ 1.2 and 21 $\pm$ 3 pmols/mg protein, respectively. The changes in the dopamine and N$\sp8$-acetylspermidine levels in PC12 cells starting at 10 $\mu$M APAH and N$\sp8$-acetylspermidine from day 1 onwards are well correlated with the morpholigical changes observed from day 3 onwards in an earlier study from our laboratory. The results from the present study suggest that polyamine-induced cell differentiation in PC12 cells is related to the formation of a metabolite N$\sp8$-acetylspermidine and NGF-induced cell differentiation does not appear to involve accumulation of N$\sp8$-acetylspermidine.




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