Nature 380, 252 - 255 (21 March 1996); doi:10.1038/380252a0

Functional recovery in parkinsonian monkeys treated with GDNF

Don M. Gash, Zhiming Zhang, Aliza Ovadia, Wayne A. Cass, Ai Yi, Linda Simmerman, Deborah Russell^*, David Martin^*, Paul A. Lapchak^*, Frank Collins^*, Barry J. Hoffer^† & Greg A. Gerhard^†

Department of Anatomy and Neurobiology, University of Kentucky, College of Medicine, Lexington, Kentucky 40536, USA
^*AMGEN Inc., Thousand Oaks, California 91320-1789, USA
^†Departments of Pharmacology and Psychiatry, Neuroscience Training Program and Rocky Mountain Center for Sensor Technology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA

PARKINSON 's disease results from the progressive degeneration of dopamine neurons that innervate the striatum^1,2. In rodents, glial-cell-line-derived neurotrophic factor (GDNF) stimulates an increase in midbrain dopamine levels, protects dopamine neurons from some neurotoxins, and maintains injured dopamine neurons^3–9. Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally into rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)^10–14. 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. On the lesioned side of GDNF-treated animals, dopamine levels in the midbrain and globus pallidus were twice s high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density. The results indicate that GDNF may be of benefit in the treatment of Parkinson's disease.

References

1.	Jellinger, K. Adv. Neurol. 45, 1−18 (1986).
2.	Hornykiewicz, O. & Kish, S. J. Adv. Neurol. 45, 19−34 (1986).
3.	Lin, L.-F. H., Doherty, D. H., Lile, J. D., Bektesh, S. & Collins, F. Science 260, 1130−1132 (1993). | PubMed | ISI | ChemPort |
4.	Beck, K. D. et al. Nature 373, 339−341 (1995). | Article | PubMed | ISI | ChemPort |
5.	Bowenkamp, K. E. et al. J. comp. Neurol. 355, 479−489 (1995). | Article | PubMed | ISI | ChemPort |
6.	Hoffer, B. J. et al. Neurosci. Lett. 182, 107−111 (1994). | Article | PubMed | ISI | ChemPort |
7.	Hudson, J. et al. Brain Res. Bull. 36, 425−432 (1995). | Article | PubMed | ISI | ChemPort |
8.	Tomac, A. et al. Nature 373, 335−339 (1995). | Article | PubMed | ISI | ChemPort |
9.	Kearns, C. M. & Gash, D. M. Brain Res. 672, 104−111 (1995). | Article | PubMed | ChemPort |
10.	Ovadia, A., Zhang, Z. & Gash, D. M. Neurobiol. Aging 16, 931−937 (1995). | Article | PubMed | ISI | ChemPort |
11.	Gash, D. M. et al. J. comp. Neurol. 363, 345−358 (1995). | Article | PubMed | ISI | ChemPort |
12.	Bankiewicz, K. S. et al. Life Sci. 39, 7−16 (1986). | Article | PubMed | ISI | ChemPort |
13.	Bankiewicz, K. S., Mandel, R. J. & Sofroniew, M. V. Expl Neurol. 124, 140−149 (1993). | Article | ChemPort |
14.	Smith, R. D., Zhang, Z., Kurlan, R., McDermott, M. & Gash, D. M. Neuroscience 52, 7−16 (1993). | Article | PubMed | ChemPort |
15.	DeLong, M. R. Trends Neurosci. 13, 281−289 (1990). | Article | PubMed | ISI | ChemPort |
16.	Robertson, G. S. & Robertson, H. A. Neurosci. Lett. 89, 204−208 (1988). | Article | PubMed | ChemPort |
17.	Robertson, G. S. & Robertson, H. A. J. Neurosci. 9, 3326−3331 (1989). | PubMed | ChemPort |
18.	Dougle, K. L. & Crocker, A. D. Proc. natn. Acad. Sci. U.S.A. 92, 1669−1673 (1995).
19.	Greenamyre, J. T. et al. Ann. Neurol. 35, 655−661 (1994). | Article | PubMed | ChemPort |
20.	Coggeshall, R. E. Trends Neurosci. 15, 9−13 (1992). | Article | PubMed | ISI | ChemPort |
21.	West, M. J. Neurobiol. Aging 14, 275−285 (1993). | Article | PubMed | ISI | ChemPort |
22.	Harding, A. J., Halliday, G. M. & Cullen, K. J. Neurosci. Meth. 51, 83−89 (1994). | ChemPort |