Parkinson's disease and novel neuroprotective strategies

Dr David Dexter

Dr Dexter have been principally involved in research relating to Parkinson’s Disease and neurodegeneration for over 27 years. This research theme has stemmed and developed from my PhD studies. Since that time I have developed a consistent theme of research investigating the mechanisms underlying neurodegeneration in Parkinson’s disease and subsequently developing novel therapeutic approaches to prevent neurodegeneration or modify the disease symptoms. The research has yielded some seminal papers particularly in the field of oxidative stress and mitochondrial dysfunction. Current research has mainly developed from these ideas and is underpinned by an extensive grant portfolio and is carried out by a research team of 15 staff.

Current research topics include:

• The development of antioxidants and metal chelators as neuroprotectory agents for treating Parkinson’s.
• Role of glutamate metabotropic receptor drugs in symptom amelioration and neuroprotection in Parkinson’s.
• Role of inflammation in the disease process and the beneficial effects of anti-inflammatory agents.
• Sex differences in the incidence of Parkinson’s disease and the neuroprotectory effects of estrogen.
• The involvement of stress in the development of Parkinson’s.
• Role of genetics, risk genes and Gene expression studies in Parkinson’s.
• Role of histone deacetylases (HDAC) in the neurodegenerative process in Parkinson’s and the potential use of HDAC-inhibitors.
• Development of nano-particles as drug delivery vehicles across the blood brain barrier
• Involvement of Calcium homeostasis in the neurodegenerative process in Parkinson’s
• Developing animal and cellular model of Parkinson’s.
• Running and developing the Parkinson’s UK Tissue Bank

Dr Dexter was the principle person responsible for establishing the Parkinson’s UK Tissue Bank in 2002 via a program grant from the Parkinson’s UK with the tremendous assistance of Professor R Reynolds, scientific director MS Tissue Bank. The Tissue Bank is now jointly funded together with its sister Multiple Sclerosis Tissue Bank, by a programme grant from the MS Society and Parkinson’s UK. The joint Tissue Bank now has a growing list of almost 10,000 potential donors, has collected over a 1,000 brains and supplies researchers with high quality tissue both in the UK and around the world. The joint Tissue Bank is recognised as one of the leading international resource centres for providing high quality, highly characterised samples of Parkinson’s and MS brain, spinal cord and CSF. Dr Dexter has collaborated in the international Parkinson’s disease consortium to supply Parkinson’s brain samples for multinational GWAS studies which has recently discovered 15 risk genes for the development of Parkinson’s disease which has been published in the Lancet.

Both Tissue Banks were involved in a Frame Work 6 EU Network of Excellence grant – Brain Net II –where 18 Tissue Bank across Europe to standardise procedures and quality, improve tissue supply for research and advance research into common neurodegenerative conditions. In addition, Dr Dexter has participated in and helped develop EU COST actions in chemistry for biological applications for the past 20 years. These have allowed extensive collaborations across Europe with synthetic chemists, physical chemists and biochemists for the development of novel compounds and models.

The principal focus of the research group has been to understand the neurodegenerative mechanisms causing Parkinson’s disease utilising human tissue along with cellular and in vivo animal models and to identify drug target sites for the development of novel therapies. Such novel therapies are then tested on a variety of animal models of Parkinson’s with the long-term goal of translating successful pre-clinical therapeutics into clinical trials. A major recent achievement in this translational approach has been the initiation of a pilot clinical trial in Parkinson’s disease with the iron chelator Deferiprone. We were the first group in the world to conclusively prove that increased brain iron levels are associated with the neurodegenerative process in Parkinson’s and subsequently went on to demonstrate that iron chelators can remove excess brain iron and are neuroprotective in animal models of Parkinson’s which has given support for the clinical trial. With the support of the Parkinson’s disease clinical trials unit at Imperial, hopefully this pipeline approach will yield further clinical trials to hopefully halt this devastating disease.

Dr Dexter also has a cross faculty collaboration with Dr Alex Porter, in engineering, working on the development of nano-particles as drug delivery platforms for not only delivering drugs across the blood brain barrier but also then to target specific cell types in the brain.  

Dr Dexter Group Members                          

Dr Djordje Gveric – Research Fellow, Tissue Bank manager

Miss Louisa McGuiness – Research technician Joint Tissue Bank

Miss Julia Steele – Research technician Joint Tissue Bank

Miss Amanda Rojers – Research technician Joint Tissue Bank

Miss Laura Williams – Administrator Parkinson’s Tissue Bank

Mrs Sue Fordham – Administrator MS Tissue Bank

Mr Daniel Gaonzales-Carter – Research assistant/PhD student

Dr Michael Hurley – Post-doc

Dr Michael Motskin – Post-doc

Miss Claire Williams – PhD student

Mr Ian Harrison – PhD student

Miss Komal Nayak – Technician

Mrs Christina Kaaba – Research nurse

Dr Antonio Bastida – Clinical Research Fellow

Dr Ilaria Bravi - Neuropathologist

Direct Funding of Research to Fight Parkinson's: Imperial College is a registered charity and we welcome direct donations to fully fund or part fund research into this highly delbilitating disease. No donation is too small since together we can cure Parkinson's.

Recent Publications

1. Vernon AC, Croucher MJ, Dexter DT. Additive neuroprotection by metabotropic glutamate receptor subtype-selective ligands in a rat Parkinson’s model. Neuroreport. 2008 ;19(4):475-8.
2. Bell JE, Alafuzoff I, Al-Sarra, S, Arzberger T, Bogdanovic N, Budka H, Dexter DT, Falkai P, Ferrer I, Gelpi E, Gentleman SM, Giaccone G, Huitinga I, Ironside JW, Klioueva N, Kovacs GG, Meyronet D, Palkovits M, Parchi P, Patsouris E, Reynolds R, Riederer P, Roggendorf W, Seilhean D, Schmitt A, Schmitz P, Streichenberger N, Schwalber A, Kretzschmar H. Management of a twenty-first century brain bank: experience in the BrainNet Europe consortium. Acta Neuropathol. 2008 ;115(5):497-507.
3. Ward RJ, Lallemand F, de Witte P, Dexter DT. Neurochemical pathways involved in the protective effects of nicotine and ethanol in preventing the development of Parkinson’s disease: Potential targets for the development of new therapeutic agents. Prog Neurobiol. 2008 ;85(2):135-47.
4. Crichton RR, Dexter DT, Ward RJ. Metal based neurodegenerative diseases: ­From molecular mechanisms to therapeutic strategies. Coord. Chem. Rev. (2008) 252, Issues 10-11, 1051-1286
5. Marinova-Mutafchieva L, Sadeghian M, Broom L, Davis JB, Medhurst AD, Dexter DT. Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson’s disease. J Neurochem. 2009 ;110(3):966-75.
6. Aitchison K, Datla K, Rooprai H, Fernando J, Dexter DT. Regional distribution of clomipramine and desmethylclomipramine in rat brain and peripheral organs on chronic clomipramine administration.J Psychopharmacol. 2010 ;24(8):1261-8.
7. Durrenberger PF, Fernando S, Kashefi SN, Ferrer I, Hauw J, Seilhean D, Ironside JW, Walker R, Al-Sarraj S, Troakes C, Palkovits M, Kasztner M, Huitinga I, Arzberger T, Dexter DT, and Reynolds R. Effects of ante- and post-mortem variables on human brain mRNA quality: a BrainNet Europe Study. J Neuropathol Exp Neurol. 2010;69(1):70-81.
8. Pienaar IS, Dexter DT and Burkhard PR. Mitochondrial proteomics as a selective tool for unravelling Parkinson’s disease pathogenesis. Expert Rev. Proteomics 2010;7(2):205-26.
9. International Parkinson Disease Genomics Consortium including Dexter DT. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet.2011;377(9766):641-9.
10. Ward RJ, Lallemand F, de Witte P, Crichton RR, Piette J, Tipton K, Hemmings K, Pitard A, Page M, Della Corte L, Taylor D, Dexter DT. Anti-inflammatory actions of a taurine analogue, ethane β-sultam, in phagocytic cells, in vivo and in vitro. Biochem Pharmacol. 2011;81(6):743-51.
11. Broom L, Marinova-Mutafchieva L, Sadeghian M, Davis JB, Medhurst AD, Dexter DT. Neuroprotection by the selective iNOS inhibitor GW274150 in a model of Parkinson disease. Free Radic Biol Med. 2011;50(5):633-40.
12. Dexter DT, Statton SA, Whitmore C, Freinbichler W, Weinberger P, Tipton KF, Della Corte L, Ward RJ, Crichton RR. Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson's disease after peripheral administration. J Neural Transm. 2011 ;118(2):223-31.
13. Chan H, Paur H, Vernon AC, Zabarsky V, Datla KP, Croucher MJ, Dexter DT. Neuroprotection and Functional Recovery Associated with Decreased Microglial Activation Following Selective Activation of mGluR2/3 Receptors in a Rodent Model of Parkinson's Disease. Parkinsons Dis. 2010 ;2010. pii: 190450.
14. Ward RJ, Crichton RR, Taylor DL, Della Corte L, Srai SK, Dexter DT. Iron and the immune system. J Neural Transm. 2011;118(3):315-28.
15. Crichton RR, Dexter DT, Ward RJ. Brain iron metabolism and its perturbation in neurological diseases. J Neural Transm. 2011;118(3):301-14.
16. International Parkinson Disease Genomics Consortium including Dexter DT. A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease. PLOS GENET 7(6): Article number e1002142 Jun 2011.
17. Ward RJ, Lallemand F, de Witte P, Crichton RR, Piette J, Tipton K, Hemmings K, Pitard A, Page M, Della Corte L, Taylor D, Dexter DT. Anti-inflammatory actions of a taurine analogue, ethane β-sultam, in phagocytic cells, in vivo and in vitro.Biochem Pharmacol. 2011 Mar 15;81(6):743-51. Epub 2011 Jan 11.
18. Hurley MJ and Dexter DT. Voltage-gated calcium channels and Parkinson’s disease. Pharmacol. and Therapeutics 2012; 133 (3):324-333.
19. Pienaar I, Burn D and Dexter DT. Synaptic protein alterations in Parkinson's disease – Review. Molecular Neurobiology (in press).