Miron, Veronica

Lyons, David

Mahmood, Ayisha

National Centre for the 3Rs

2023-09-26T13:04:15Z

2023-09-26T13:04:15Z

2023-09-26

Microglia dysfunction is increasingly implicated as a converging feature across neurodegenerative conditions. In particular, microglia are key regulators of myelin repair (remyelination) in the CNS. Yet, this process fails in aging and neurodegenerative disease in association with impaired microglia functions. Despite this growing body of evidence, there is a paucity of effective treatments for neurodegeneration which therapeutically modulate microglia. Prior work from our lab has shown that, in the context of driving remyelination, microglia must experience an upregulation in cell death which mediates a transition on activation phenotype from pro-inflammatory to pro-regenerative, a key state required to support core processes involved in remyelination. In conditions such as multiple sclerosis where remyelination fails, this phenotypic transition is compromised. While the exact mechanism of inducing the pro-regenerative phenotype remains unknown, there is evidence to suggest pharmacologically-induced microglia turnover could promote regeneration in the brain. Here, I developed a microglia-based screening platform to identify compounds that can enhance cell death phenotypes in in vitro microglia. Through conducting a proof-of-concept screening study, followed by implementation of in silico methods to predict and profile biological activity of hit compounds, I identified four candidates compounds with potential for repurposing to promote remyelination through potentially novel mechanisms of action. Nimodipine, a calcium channel inhibitor, was also identified from literature as a drug of interest for repurposing to therapeutically promote remyelination. Through predictive profiling, I identified a potential novel pro-inflammatory microglia-specific interaction with nimodipine. Application of nimodipine to ex vivo organotypic brain slice cultures revealed preliminary evidence that nimodipine may alter microglia population dynamics through a cell death-proliferation mechanism.

https://hdl.handle.net/1842/40955

http://dx.doi.org/10.7488/era/3707

en

The University of Edinburgh

Mahmood, A. & Miron, V. E. Microglia as therapeutic targets for central nervous system remyelination. en. Current Opinion in Pharmacology 63, 102188. issn: 1471-4892. https: //www.sciencedirect.com/science/article/pii/S1471489222000121 (2023) (Apr. 2022).

Molina-Gonzalez I, Holloway RK, Jiwaji Z, Dando O, Emelianova K, Lloyd AF, Forbes LH, Mahmood A, Skripuletz T, Gudi V, Febery JA, Johnson JA, Fowler JH, Kuhlmann T, Williams A, Chandran S, Stangel M, Howden AJM, Hardingham GE & Miron VE. Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration. bioRxiv. 2022. DOI: 10.1101/2022.10.04.510850.

microglia-based phenotypic screening platform

regenerative therapies

Microglia dysfunction

neurodegenerative conditions

myelin repair (remyelination)

neurodegenerative disease

microglia functions

remyelination

phenotypic transition

pro-regenerative phenotype

cell death phenotypes

in vitro microglia

Nimodipine

pro-inflammatory microglia-specific interaction

pro-inflammatory microglia-specific interaction with nimodipine

Developing a microglia-based phenotypic screening platform to identify novel regenerative therapies

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy