Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson's disease after administration into the striatum or the lateral ventricle.
Both glial cell line-derived neurotrophic factor (GDNF) and its recently discovered congener, neurturin (NTN), have been shown to exert neuroprotective effects on lesioned nigral dopamine (DA) neurons when administered at the level of the substantia nigra. In the present study, we have explored the relative in vivo potency of these two neurotrophic factors using two alternative routes of administration, into the striatum or the lateral ventricle, which may be more relevant in a clinical setting. In rats subjected to an intrastriatal (IS) 6-hydroxydopamine (6-OHDA) lesion, GDNF and NTN were injected every third day for 3 weeks starting on the day after the 6-OHDA injection. GDNF provided almost complete (90-92%) protection of the lesioned nigral DA neurons after both IS and intracerebroventricular (ICV) administration. NTN, by contrast, was only partially effective after IS injection (72% sparing) and totally ineffective after ICV injection. Although the trophic factor injections protected the nigral neurons from lesion-induced cell death, the level of expression of the phenotypic marker, tyrosine hydroxylase (TH), was markedly reduced in the rescued cell bodies. The extent of 6-OHDA-induced DA denervation in the striatum was unaffected by both types of treatment; consistent with this observation, the high rate of amphetamine-induced turning seen in the lesioned control animals was unaltered by either GDNF or NTN treatment. In the GDNF-treated animals, and to a lesser extent also after IS NTN treatment, prominent axonal sprouting was observed within the globus pallidus, at the level where the lesioned nigrostriatal axons are known to end at the time of onset of the neurotrophic factor treatment. The results show that GDNF is highly effective as a neuroprotective and axon growth-stimulating agent in the IS 6-OHDA lesion model after both IS and ICV administration. The lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
Rosenblad
C
C
Department of Physiology and Neuroscience, Wallenberg Neuroscience Center, Lund University, Sweden. carl.rosenblad@mphy.lu.se
Kirik
D
D
Devaux
B
B
Moffat
B
B
Phillips
H S
HS
Björklund
A
A
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000906:Antibodies; D001058:Apomorphine / Q000494:pharmacology; D001284:Atrophy; D001835:Body Weight; D002552:Cerebral Ventricles / Q000166:cytology; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D051959:ELAV Proteins; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006863:Hydrogen-Ion Concentration; D007276:Injections, Intraventricular; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051101:Neurturin; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000473:pathology*; D013565:Sympatholytics; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000276:immunology
D000906:Antibodies; D015259:Dopamine Agents; D018491:Dopamine Agonists; D051959:ELAV Proteins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D051101:Neurturin; C495057:Nrtn protein, rat; D016601:RNA-Binding Proteins; D013565:Sympatholytics; D016627:Oxidopamine; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine