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.
Gash et al  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.
Kordower et al  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.
Gill et al  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.
Johnston et al  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.
Kells et al  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  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.
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.
- Use the following links to query the PubMed, PubMed Central and Google Scholar databases using the Search terms:- Parkinson's_Disease GDNF.
- This will list the latest papers on this topic. You are invited to update this page to reflect such recent results, pointing out their significance.
- 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,--
- 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