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Dissertation
trans-Banglene as a neurotrophic agent
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007815
Abstract
To gain deeper insight into the cellular systems influenced by the neurotrophic small molecule, trans-banglene (t-BG), a global proteomic profiling approach was employed to identify protein expression changes upon treatment. The primary objective was to compare these changes with those induced by nerve growth factor (NGF), a well-characterized neurotrophic molecule that promotes neuronal survival, differentiation, and synaptic plasticity through TrkA receptor-mediated signaling. This study sought to determine whether t-BG exerts its effects through the NGF/TrkA axis or follows an alternative mechanism.
Proteomic analysis revealed that, rather than directly interacting with the NGF/TrkA pathway, t-BG treatment significantly altered the expression of proteins associated with iron binding and regulation. These findings suggest that t-BG’s biological activity may be linked to iron homeostasis rather than classical neurotrophic signaling. Notably, t-BG upregulated ferritin light chain (Ftl), suggesting increased iron sequestration and reduced free cytosolic iron levels, which could influence oxidative stress. Additionally, both NGF and t-BG treatment conditions led to the downregulation of mitochondrial iron-binding proteins, potentially indicating disruptions in mitochondrial function. The unexpected link between t-BG and iron regulation suggests a novel neuroprotective mechanism that could be therapeutically relevant for iron-related neuropathologies.
Further investigation into t-BG’s mechanism of action involved photoaffinity labeling (PAL) to identify its direct protein binding partners. A photoaffinity probe was synthesized by incorporating an aliphatic diazirine and a terminal alkyne into t-BG. The synthesis process required optimization of cyclopropanation reactions, catalyst selection, and purification steps. Neurotrophic activity assays in PC-12 cells confirmed t-BG bioactivity but required technical refinements, including improved imaging protocols to mitigate background noise and cell clumping. However, the bioactivity of the PAL probe has yet to be tested.
Despite challenges in probe isolation and assay reproducibility, this study successfully optimized the synthesis of a t-BG-based PAL probe and established a foundation for identifying its molecular target. Future research will focus on improving neurotrophic quantification techniques and completing the PAL workflow to elucidate t-BG’s precise molecular interactions. These findings contribute to a broader understanding of alternative neuroprotective strategies beyond traditional NGF-mimetic approaches.
Details
- Title: Subtitle
- trans-Banglene as a neurotrophic agent
- Creators
- Piyumi Wijesiri Gunawardana
- Contributors
- Florence J Williams (Advisor)James Gloer (Committee Member)F. Christopher Pigge (Committee Member)Tori M Forbes (Committee Member)Mark A Arnold (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Chemistry
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007815
- Publisher
- University of Iowa
- Number of pages
- xxxii, 298 pages
- Copyright
- Copyright 2025 Piyumi Wijesiri Gunawardana
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Date submitted
- 04/28/2025
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 271-298).
- Public Abstract (ETD)
- Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, occur when brain cells become damaged and die, leading to memory loss, movement difficulties, and other serious health problems. Finding ways to protect and support brain cells is crucial for developing effective treatments. My research focuses on understanding how banglene, a natural compound from the plant Zingiber purpureum, helps promote brain cell survival and growth. Studies have shown that when banglene is taken orally, it increases the formation of new brain cells in mice, suggesting it may have protective effects. However, scientists still do not fully understand how banglene works at a molecular level. My project aims to uncover the specific biological processes triggered by banglene in brain cells. To do this, I use photoaffinity labeling, a technique that helps identify the exact proteins banglene interacts with. By mapping out these interactions, we can clarify how banglene activates brain-protective pathways. One surprising discovery in my research is that banglene may influence or regulate iron levels. Iron is essential for brain function, but imbalances can contribute to neurodegenerative diseases like Alzheimer’s or Parkinson’s. My findings suggest that banglene may support brain health by helping cells manage iron more effectively, which is distinct from other well-known brain-protective molecules like nerve growth factor (NGF). By understanding how banglene protects brain cells, my research could contribute to the development of new treatments for neurodegenerative diseases. If banglene’s effects are confirmed, it could lead to therapies that help prevent or slow down brain cell damage, offering hope for millions of people affected by these conditions.
- Academic Unit
- Chemistry
- Record Identifier
- 9984830921402771
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