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Title: Evaluation of brain permeability and neuroprotection of novel 3-hydroxy-4-pyridinone bidentate iron chelators for the treatment of Parkinson's disease
Author: Azizi, Juzaili Bin
ISNI:       0000 0004 7963 9172
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2018
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Iron has been linked with the neurodegenerative process in Parkinson's disease (PD) as autopsied Parkinsonian showed increases in iron level in the brain, especially in the basal ganglia. Treatment with the blood-brain barrier (BBB) permeable iron chelator, deferiprone (CP20) shows improvement in motor symptoms among PD patients possibly by neuroprotective mechanism. However, serious side effects such as agranulocytosis and neutrocytopenia limit its use especially for the elderly PD patients that are more prone such toxicity. A series of CP20 derivatives with chiral functional group have been developed by chemical modification and showed better toxicity profiles than CP20 when tested in rodents. However, the structural modifications of CP20 might change their brain permeability profile and reduce their effectiveness as neuroprotective agents. For this reason, the aim of the studies reported in this thesis was to investigate the brain permeability of CP20 derivatives by in situ brain perfusion. In addition, a CP20 derivative that is conjugated with glucose was also investigated as a strategy to improve BBB permeation. This was followed by investigation of the neuroprotective capability on dopaminergic cell death in in vitro and in vivo models of cell death in PD. The effect of functional group chirality on the biological experiments were also evaluated. Seven out of eight of the CP20 derivatives tested showed successful brain penetration as assessed by in situ brain perfusion. From these seven brain penetrant CP20 derivatives, one (CP84) show superior brain uptake, three CN128, CN226 and CN228) showed comparable brain uptake, and three (CN116, CN118 and CN126) showed lower brain uptake than CP20. Glucose conjugated CP20 derivative failed to cross the BBB. The in vitro neuroprotection study in SH-SY5Y neuroblastoma cells revealed neuroprotective effect of the brain penetrant CP20 derivatives against H2O2-, 6-OHDA-, and FeNTA- but not MG-132-induced cell death. Some of the CP20 derivatives showed better neuroprotection at equimolar concentration of CP20. In both studies, molecules chirality did not have effect on in situ brain permeability or in vitro neuroprotection. One CP20 derivative (CN128) was selected for in vivo neuroprotection study with 6-OHDA rat model of PD. CN128 showed comparable neuroprotection of dopaminergic neurons in the nigro-striatal dopamine pathway. In conclusion, these studies showed that all but the glucose-conjugated derivative of CP20 can permeate the BBB and are neuroprotective in 10 experimental models of PD suggesting these novel iron chelators may be used as potential neuroprotective agent in the treatment of PD.
Supervisor: Salvage, Sarah ; Begley, David John ; Preston-Kennedy, Jane Elizabeth Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available