GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed common marmosets.
Parkinson's disease (PD) is associated with a progressive loss of dopamine neurons in the substantia nigra and degeneration of dopaminergic terminals in the striatum. Although L-DOPA treatment provides the most effective symptomatic relief for PD it does not prevent the progression of the disease, and its long-term use is associated with the onset of dyskinesia. In rodent and primate studies, glial cell line-derived neurotrophic factor (GDNF) may prevent 6-OHDA- or MPTP-induced nigral degeneration and so may be beneficial in the treatment of PD. In this study, we investigate the effects of GDNF on the expression of dyskinesia in L-DOPA-primed MPTP-treated common marmosets, exhibiting dyskinesia. GDNF or saline was administered by two intraventricular injections, 4 weeks apart, to MPTP-treated, L-DOPA-treated common marmosets primed to exhibit dyskinesia. Prior to GDNF or saline administration, all animals displayed marked dyskinesia when treated with L-DOPA. GDNF administration produced a significant improvement in motor disability and, following the second injection of GDNF, a significant improvement in the locomotor activity was observed. Following the administration of L-DOPA there was a greater reversal of disability and a reduction in the intensity of L-DOPA-induced dyskinesia in GDNF-treated animals compared to saline-treated controls. However, there was no significant difference in L-DOPA's ability to increase locomotor activity between GDNF-treated and saline-treated animals. GDNF treatment caused a significant increase in the number of tyrosine hydroxylase-positive neurons in the substantia nigra, but no change in [(3)H]mazindol binding to dopamine terminals was found in the striatum of GDNF-treated animals compared to saline-treated controls. In GDNF-treated animals a small but significant reduction in enkephalin mRNA was observed in the caudate nucleus but not in the putamen or the nucleus accumbens. Substance P mRNA expression was equally reduced in the caudate nucleus and the putamen of the GDNF-treated animals but not in the nucleus accumbens. Intraventricular administration of GDNF improved MPTP-induced disability and reversed dopamine cell loss in the substantia nigra. GDNF also diminished L-DOPA-induced dyskinesia, which may relate to its ability to partly restore nigral dopaminergic transmission or to modify the activity of striatal output pathways.
Iravani
M M
MM
Neurodegenerative Disease Research Centre, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London SE1 1UL, UK.
Costa
S
S
Jackson
M J
MJ
Tel
B C
BC
Cannizzaro
C
C
Pearce
R K
RK
Jenner
P
P
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001835:Body Weight; D002144:Callithrix; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology; D004745:Enkephalins / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007980:Levodopa / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008454:Mazindol / Q000378:metabolism / Q000494:pharmacology; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020127:Recovery of Function / Q000187:drug effects; D013378:Substantia Nigra / Q000201:enzymology; D015320:Tachykinins / Q000235:genetics; D014316:Tritium; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D000978:Antiparkinson Agents; D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; C044206:preprotachykinin; D014316:Tritium; D007980:Levodopa; C033660:preproenkephalin; D008454:Mazindol; D014446:Tyrosine 3-Monooxygenase