Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's disease.
Neurotrophic factors are promising candidates for the treatment of Parkinson's disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) belongs to a novel evolutionarily conserved family of neurotrophic factors. We examined whether MANF has neuroprotective and neurorestorative effect in an experimental model of PD in rats. We also studied the distribution and transportation of intrastriatally injected MANF in the brain and compared it with glial cell line-derived neurotrophic factor (GDNF). Unilateral lesion of nigrostriatal dopaminergic system was induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). Amphetamine-induced turning behavior was monitored up to 12 weeks after the unilateral lesion. The local diffusion at the injection site and transportation profiles of intrastriatally injected MANF and GDNF were studied by immunohistochemical detection of the unlabeled growth factors as well as by autoradiographic and gamma counting detection of (125)I-labeled trophic factors. Intrastriatally injected MANF protected nigrostriatal dopaminergic nerves from 6-OHDA-induced degeneration as evaluated by counting tyrosine hydroxylase (TH)-positive cell bodies in the substantia nigra (SN) and TH-positive fibers in the striatum. More importantly, MANF also restored the function of the nigrostriatal dopaminergic system when administered either 6 h before or 4 weeks after 6-OHDA administration in the striatum. MANF was distributed throughout the striatum more readily than GDNF. The mechanism of MANF action differs from that of GDNF because intrastriatally injected (125)I-MANF was transported to the frontal cortex, whereas (125)I-GDNF was transported to the SN. Our results suggest that MANF is readily distributed throughout the striatum and has significant therapeutic potential for the treatment of PD.
Voutilainen
Merja H
MH
Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Bäck
Susanne
S
Pörsti
Eeva
E
Toppinen
Liisa
L
Lindgren
Lauri
L
Lindholm
Päivi
P
Peränen
Johan
J
Saarma
Mart
M
Tuominen
Raimo K
RK
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000188:drug therapy; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D013997:Time Factors
D051100:Glial Cell Line-Derived Neurotrophic Factor; C099695:MANF protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D016627:Oxidopamine; D004298:Dopamine