Protective action of recombinant neurturin on dopaminergic neurons in substantia nigra in a rhesus monkey model of Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disease characterized by muscular trembling palsy due to lack of dopamine (DA) in the substantia nigra-striatum (nigrostriatal) system resulting from the degeneration and necrosis of dopaminergic neurons. No effective cure has been found. Neurturin (NTN) has been demonstrated to act specifically on midbrain (mesencephalic) dopaminergic neurons with protective actions specifically. In the present study, we induced rhesus monkey model of Parkinson's disease by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Rhesus monkeys were randomly divided into a PD model group, NTN treatment group and normal control groups. In the NTN treatment group, 1 mg of E. coli-derived recombinant human NTN was injected into the cerebral ventricles 48 h before the injection of MPTP. Results indicated that Rhesus monkeys in the PD model group acquired PD symptoms that increasingly aggravated over time, while monkeys treated with NTN had less apparent or no symptoms. Using fluorospectrophotometry, the dopamine (DA), 5, 5-hydroxytrytamine (5-HT) and the 5-hydroxyindoleacetic acid (5-HIAA) contents of DA, 5-HT and 5-HIAA in substantia nigra, putamen and caudate nucleus in monkeys from the model group was found to be significantly lower than in the normal control group. While no significant differences were found between monkeys treated with NTN and normal control groups, the contents of DA, 5-HT and 5-HIAA in the NTN treatment group were higher than those observed in the PD model group. A dramatic loss of neurons in the substantia nigra in monkeys in the PD model group was observed by light microscopy, while no obvious loss was observed in the NTN treatment group in which the numbers of neurons were similar to those in normal controls. These results indicate that recombinant human NTN can prevent PD symptoms as well as protect dopaminergic neurons and preserve DA content in midbrain substantia nigra in rhesus monkeys exposed to MPTP.
Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Kunming, Yunnan, People's Republic of China.
Hongjun
H
Li
Zhanlong
Z
He
Ting
T
Su
Yanbing
Y
Ma
Shuaiyao
S
Lu
Changbai
C
Dai
Maosheng
M
Sun
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000032:analysis / Q000378:metabolism; D007276:Injections, Intraventricular; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D008253:Macaca mulatta; D023421:Models, Animal; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051101:Neurturin; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D051101:Neurturin; D011994:Recombinant Proteins; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine