Intraputamenal infusion of exogenous neurturin protein restores motor and dopaminergic function in the globus pallidus of MPTP-lesioned rhesus monkeys.
The neurorestorative effects of exogenous neurturin (NTN) delivered directly into the putamen via multiport catheters were studied in 10 MPTP-lesioned rhesus monkeys expressing stable parkinsonism. The parkinsonian animals were blindly assigned to receive coded solutions containing either vehicle (n = 5) or NTN (n = 5, 30 microg/day). Both solutions were coinfused with heparin using convection-enhanced delivery for 3 months. The NTN recipients showed a significant and sustained behavioral improvement in their parkinsonian features during the treatment period, an effect not seen in the vehicle-treated animals. At study termination, locomotor activity levels were increased by 50% in the NTN versus vehicle recipients. Also, DOPAC levels were significantly increased by 150% ipsilateral (right) to NTN infusion in the globus pallidus, while HVA levels were elevated bilaterally in the NTN-treated animals by 10% on the left and 67% on the right hemisphere. No significant changes in DA function were seen in the putamen. Volumetric analysis of putamenal NTN labeling showed between-subject variation, with tissue distribution ranging from 214 to 744 mm3, approximately equivalent to 27-93% of area coverage. Our results support the concept that intraparenchymal delivery of NTN protein may be effective for the treatment of PD. More studies are needed to determine strategies that would enhance tissue distribution of exogenous NTN protein, which could contribute to optimize its trophic effects in the parkinsonian brain.
Department of Anatomy & Neurobiology, University of Kentucky Medical Center, Lexington, KY 40536-0098, USA. rcgron0@uky.edu
R
R
Grondin
Z
Z
Zhang
Y
Y
Ai
F
F
Ding
A A
AA
Walton
S P
SP
Surgener
G A
GA
Gerhardt
D M
DM
Gash
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D009043:Motor Activity / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D051101:Neurturin / Q000008:administration & dosage / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D011699:Putamen / Q000187:drug effects*
D015259:Dopamine Agents; D009498:Neurotoxins; D051101:Neurturin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine