Progress and Prospects in Parkinson's Research/Therapy/Neuroprotection/GDNF
GDNF or Glial_cell_line-Derived_Neurotrophic_Factor is a protein that promotes the survival of many types of neurons. In rodents, GDNF has been shown to stimulate an increase in midbrain dopamine levels, protect dopamine neurons from some neurotoxins, and restore injured dopamine neurons. Trials have been conducted in human patients with mixed results but a Phase II trial is nearing completion (2016). GDNF will not pass the Blood/Brain barrier and therefore research has concentrated on optimising systems for accurately delivering it into the targeted areas of the brain.
Research
edit1996
Gash et al [1] evaluated the effects of GDNF injected intracerebrally in rhesus monkeys with Parkinson's disease symptoms induced by the neurotoxin MPTP.
The recipients of GDNF displayed significant improvements in three of the cardinal symptoms of parkinsonism: bradykinesia, rigidity and postural instability. GDNF administered every four weeks maintained functional recovery. Dopamine levels in the midbrain and globus pallidus were twice as high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density.
2000
Kordower et al [2] injected GDNF into the striatum and substantia nigra of monkeys with Parkinsonism induced by the application of MPTP. The result was a reversal of the motor deficits in a hand reach task.
2003
Gill et al [3] delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial, and noted a a significant improvement in PD symptoms after 18 months.
2009
Johnston et al [4] tested the safety and efficacy of an adeno-associated virus (AAV2) encoding human glial cell-derived neurotrophic factor (GDNF) in aged nonhuman primates. They noted:-
AAV2-GDNF did not significantly affect dopamine in the ipsilateral putamen or caudate, but increased dopamine turnover in HD groups.
2010
Kells et al [5] applied GDNF to rhesus monkeys previously rendered Parkinsonian with MPTP. They observed:-
Progressive amelioration of functional deficits, recovery of dopamine and regrowth of fibers to the striatal neuropil.
Extensive distribution of GDNF within the putamen and transport to the severely lesioned substantia nigra, after convection-enhanced delivery (CED) of AAV2-GDNF into the putamen.
Biju et al [6] took advantage of the fact that bone marrow stem cell–derived macrophages are able to pass the BBB and successfully delivered GDNF to the brains of mice. They were then able to demonstrate the rescue of these mice from MPTP-induced PD.
Further Reading
edit2010
Nevalainen, Nina.;Chermenina, Maria.; Rehnmark, Anna; Berglöf, Elisabet.; Marschinke, Franziska and Strömberg, Ingrid. FULL TEXT Neuroscience 171 (4) 1357 – 1366.
GDNF is crucial for long-term maintenance of the nigrostriatal system.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991620/?tool=pmcentrez
Today
Literature search:
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Related pages
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- Substances with possible neuroprotective properties:
- Caffeine,--Celastrol,--Co-Enzyme Q10,--Creatine,--DHA,--Exendin-4 (EX-4),--GDNF,--Glutathione (GSH),--GM1,--Isradipine,--Melatonin,--Minocycline,--Nicotine,--NSAIDs,--Phenylbutyrate,--Phytic Acid,--Probucol,--Quinoxaline,--Rasagiline,--Riboflavin,--Statins,--Tolcapone,--Urate & Uric Acid,--Vitamin D,--Vitamin E,--
References
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- ↑ Gash, D. M.; Zhang, Z; Ovadia, A.; Cass, W. A.; Yi, A.; Simmerman, L.; Russell, D.; Martin, D.; Lapchak, P. A.; Collins, F.; Hoffer, B. J. and Gerhardt, G. A. ((1996) ) Abstract Nature. 380 (6571):252 - 255. Functional recovery in parkinsonian monkeys treated with GDNF.http://www.ncbi.nlm.nih.gov/pubmed/8637574
- ↑ Kordower, J. H.; Emborg, M. E.; Bloch, J.; Ma, S. Y,; Chu Y.; Leventhal, L.; McBride, J.; Chen, E. Y.; Palfi, S.; Roitberg, B. Z.; Brown W.D.; Holden J. E.; Pyzalski R.; Taylor, M. D.; Carvey, P.; Ling Z.; Trono, D.; Hantraye P.; Déglon, N. and Aebischer, P. ((2000) ) Abstract Science. 290 (5492):767 - 773. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.http://www.ncbi.nlm.nih.gov/pubmed/11052933
- ↑ Gill, S. S.; Patel N. K.; Hotton G. R.; O'Sullivan, K.; McCarter, R.; Bunnage, M.; Brooks, D. J.; Svendsen, C. N. and Heywood, P. ((2003) )Abstract Nat. Med. 9(5):589 - 595. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. http://www.ncbi.nlm.nih.gov/pubmed/12669033
- ↑ Louisa C. Johnston, Louisa C,; Jamie Eberling, Jaimie Pivirotto, Philip; Piotr Hadaczek, Piott; Federoff, Howard J.; Forsayeth, John and Bankiewicz, Krystof S.((2003)) Hum. Gene Ther. 20 (5): 497–510. Clinically Relevant Effects of Convection-Enhanced Delivery Full Textof AAV2-GDNF on the Dopaminergic Nigrostriatal Pathway in Aged Rhesus Monkeys http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767387/?tool=pmcentrez
- ↑ Kells, A. P.; Eberling, J.; X Su. X.; P Pivirotto, P.; Bringas, J.; Hadaczek. P.; Narrow, W. C.; Bowers, W. J.; Federoff, H. J.; Forsayeth, J. and Bankiewicz, K. S. ((2010)) Full Text J. Neurosci. 30 (28): 9567–9577. Regeneration of the MPTP-lesioned Dopaminergic System after Convection-enhanced Delivery of AAV2-GDNF http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914692/?tool=pmcentrez
- ↑ KC Biju, K. C.; Zhou. Qing; Li. Guiming; Imam, Syed Z,; Roberts, James L.; Morgan. William W.; Clark, Robert A. and Li, Senlin: ((2010)) Full Text Mol. Ther. 18 (8) 1536 – 1544: Macrophage-mediated GDNF Delivery Protects Against Dopaminergic Neurodegeneration: A Therapeutic Strategy for Parkinson's Disease. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927058/?tool=pmcentrez