Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's Disease

Merja Voutilainen, Susanne Bäck, Eeva Pörsti, Liisa Toppinen, Lauri Lindgren, Päivi Lindholm, Johan Peränen, Mart Saarma, Raimo K Tuominen

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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 I-125-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 I-125-MANF was transported to the frontal cortex, whereas I-125-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.
Originalspråkengelska
TidskriftJournal of Neuroscience
Volym29
Utgåva30
Sidor (från-till)9651-9659
Antal sidor9
ISSN0270-6474
DOI
StatusPublicerad - 2009
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 317 Farmaci

Citera det här

Voutilainen, Merja ; Bäck, Susanne ; Pörsti, Eeva ; Toppinen, Liisa ; Lindgren, Lauri ; Lindholm, Päivi ; Peränen, Johan ; Saarma, Mart ; Tuominen, Raimo K. / Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's Disease. I: Journal of Neuroscience. 2009 ; Vol. 29, Nr. 30. s. 9651-9659.
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title = "Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's Disease",
abstract = "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 I-125-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 I-125-MANF was transported to the frontal cortex, whereas I-125-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.",
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author = "Merja Voutilainen and Susanne B{\"a}ck and Eeva P{\"o}rsti and Liisa Toppinen and Lauri Lindgren and P{\"a}ivi Lindholm and Johan Per{\"a}nen and Mart Saarma and Tuominen, {Raimo K}",
year = "2009",
doi = "10.1523/JNEUROSCI.0833-09.2009",
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volume = "29",
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Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's Disease. / Voutilainen, Merja; Bäck, Susanne; Pörsti, Eeva; Toppinen, Liisa; Lindgren, Lauri; Lindholm, Päivi; Peränen, Johan; Saarma, Mart; Tuominen, Raimo K.

I: Journal of Neuroscience, Vol. 29, Nr. 30, 2009, s. 9651-9659.

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

TY - JOUR

T1 - Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's Disease

AU - Voutilainen, Merja

AU - Bäck, Susanne

AU - Pörsti, Eeva

AU - Toppinen, Liisa

AU - Lindgren, Lauri

AU - Lindholm, Päivi

AU - Peränen, Johan

AU - Saarma, Mart

AU - Tuominen, Raimo K

PY - 2009

Y1 - 2009

N2 - 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 I-125-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 I-125-MANF was transported to the frontal cortex, whereas I-125-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.

AB - 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 I-125-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 I-125-MANF was transported to the frontal cortex, whereas I-125-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.

KW - 317 Pharmacy

U2 - 10.1523/JNEUROSCI.0833-09.2009

DO - 10.1523/JNEUROSCI.0833-09.2009

M3 - Article

VL - 29

SP - 9651

EP - 9659

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 30

ER -