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Alghamdi, Hajar (2024) On-Demand Dopamine Receptor Activation via Photoresponsive Nanoparticle-Dopamine Conjugates with an Emphasis on Parkinson’s Disease. PhD thesis, University of Nottingham.

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Abstract

INTRODUCTION

Parkinsons’ Disease is a complex neurodegenerative disease with unknown pathological mechanism associated with the reduction of dopamine content in the brain. Dopamine, in the form of L-DOPA, is used as a replacement therapy which provides temporary symptomatic relief. Long-term treatment with L-DOPA induces side effects such as involuntary movements (e.g., dyskinesia) due to the continuous and un-discriminatory exposure to dopamine.

Here, we aim to address this by developing an on-demand dopamine receptor stimulation system that reduces dopamine over-exposure. To achieve that we designed a nanoparticle system displaying a photoresponsive spiropyran molecule conjugated to dopamine to stimulate activation of the D1R receptor as needed, we are able to non-invasively control dopamine receptor activation on-demand in two different cell model.

MATERIALS AND METHODS

Molecular docking was used to explore the interaction of spiropyran-dopamine (SP-DA) platform with a dopaminergic receptor. The SP-DA design was then realized by preparing silica nanoparticles via the Stöber method, followed by particle surface modification with SP and DA. To prepare an in vitro model system for PD, SH-SY5Y cells were treated with 1 mM of neurotoxin (MPP+) which results in decrease cAMP levels in the cells. cAMP-Glo assays were performed on the cells to test the SP-DA modified particles effect after treatment. Furthermore, DRD1/CRE transfected HEK293 cells were used to assess the activity of the system using a luminescence assay to measure the receptor activity.

RESULTS AND DISCUSSION

Molecular docking of SP-DA to dopaminergic receptors shows high affinity of the active merocyanine compared to the inactive spiropyran. In addition, light responsive materials that display dopamine on demand upon activation by UV light were fabricated and characterised. Applying the open, active merocyanine (MC) form of this material to cells of the PD model with low level of cAMP results in a significant increase of the amount of cAMP compared to control samples. Furthermore, transient, DRD1/CRE transfected HEK293 cells responded significantly to the developed dopamine-spiropyran-silica nanoparticles.

CONCLUSION

Light activation of our synthesized Dopamine-spiropyran-SiNP shows significant differences in cellular cAMP levels in both cell models, which can be associated with different levels of receptor stimulation.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Zelzer, Mischa Mantovani, Giuseppe Gershkovich, Pavel
Keywords:	Parkinson's Disease, spiropyran, merocyanine, photoresponsive, dopamine, receptors
Subjects:	Q Science > QD Chemistry > QD450 Physical and theoretical chemistry Q Science > QP Physiology > QP501 Animal biochemistry
Faculties/Schools:	UK Campuses > Faculty of Science > School of Pharmacy
Item ID:	78032
Depositing User:	alghamdi, hajar
Date Deposited:	24 Jul 2024 04:43
Last Modified:	24 Jul 2024 04:43
URI:	https://eprints.nottingham.ac.uk/id/eprint/78032

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