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dc.contributor.authorZhang, Chong
dc.date.accessioned2018-05-23T20:18:39Z
dc.date.available2018-05-23T20:18:39Z
dc.date.issued2017
dc.identifier.isbn9780355310368
dc.identifier.other1981340022
dc.identifier.urihttp://hdl.handle.net/10477/77337
dc.description.abstractThis dissertation investigated subtypes of PDE4 as an example to shed light on possible applications of subtype selective modulators of PDEs. Rolipram is a prototypical PDE4 inhibitor that was developed in the early 1990s and was found to have potential value as an antidepressant and memory enhancing agent. However, it was discontinued after clinical trial due to its narrow therapeutic window and ability to cause significant gastrointestinal side effects. One possible solution was to separate the modulation of different PDE4 subtypes, as rolipram is a non-selective pan-PDE4 inhibitor. The hypothesis of the current dissertation project is that by using modulators that target specific subtypes of PDE4, the adverse effects that are commonly seen with pan-PDE4 inhibitors such as rolipram, may be greatly reduced, and these allosteric modulators may regulate different categories of behavior. To test this hypothesis, this dissertation work was divided into three parts: 1. Comparison of the pharmacological profiles of PDE4B (A-33) and PDE4D (D159687) inhibitors (Chapter 2) Inhibition of cyclic AMP (cAMP)-specific PDE4 has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4D in the brain) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions. 2. The memory enhancing effects of a PDE4D negative allosteric modulator BPN14770 and its improved therapeutic window compared to rolipram (Chapter 3) This part of the dissertation uses a novel PDE4D allosteric modulator BPN14770 that exhibits high selectivity based on its close interaction with a single amino acid phenylalanine present at primate UCR2 of PDE4D. In mice, a tyrosine is conserved at this amino acid site throughout all PDE4 subtypes. Therefore, a humanized mouse model carrying a point mutation at PDE4D UCR2 region was used in this study. We show a direct involvement of PDE4D in mediating memory that was demonstrated by a shift in dose-response sensitivity in the humanized mouse model. Moreover, compared to rolipram, the minimum effective dose that improved memory performance was much lower than the minimum toxic dose found in a surrogate test for emesis. Improvement of memory was likely achieved by an elevation of brain cAMP. The behavioral changes induced by BPN14770 were supported by altered synaptic plasticity as evidenced by enhanced hippocampal long-term potentiation (LTP), as well as both pre- and postsynaptic related proteins. These results prove that PDE4D plays a critical role in mediation of learning and memory, and our findings may benefit the advancement of current treatment regimen for memory and cognitive disorders associated with multiple neuropathological conditions. (Abstract shortened by ProQuest.)
dc.languageEnglish
dc.sourceDissertations & Theses @ SUNY Buffalo,ProQuest Dissertations & Theses Global
dc.subjectBiological sciences
dc.subjectHealth and environmental sciences
dc.subjectCamp
dc.subjectDepression
dc.subjectMemory
dc.subjectPhosphodiesterases
dc.subjectSubtype selective
dc.titleNeuropsychopharmacological Effects of Selective Inhibitors of Subtypes of Phosphodiesterase-4 in Mice
dc.typeDissertation/Thesis


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