Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo.
Transforming growth factor-betas (TGF-betas) constitute an expanding family of multifunctional cytokines with prominent roles in development, cell proliferation, differentiation, and repair. We have cloned, expressed, and raised antibodies against a distant member of the TGF-betas, growth/differentiation factor-15 (GDF-15). GDF-15 is identical to macrophage inhibitory cytokine-1 (MIC-1). GDF-15/MIC-1 mRNA and protein are widely distributed in the developing and adult CNS and peripheral nervous systems, including choroid plexus and CSF. GDF-15/MIC-1 is a potent survival promoting and protective factor for cultured and iron-intoxicated dopaminergic (DAergic) neurons cultured from the embryonic rat midbrain floor. The trophic effect of GDF-15/MIC-1 was not accompanied by an increase in cell proliferation and astroglial maturation, suggesting that GDF-15/MIC-1 probably acts directly on neurons. GDF-15/MIC-1 also protects 6-hydroxydopamine (6-OHDA)-lesioned nigrostriatal DAergic neurons in vivo. Unilateral injections of GDF-15/MIC-1 into the medial forebrain bundle just above the substantia nigra (SN) and into the left ventricle (20 microgram each) immediately before a 6-OHDA injection (8 microgram) prevented 6-OHDA-induced rotational behavior and significantly reduced losses of DAergic neurons in the SN. This protection was evident for at least 1 month. Administration of 5 microgram of GDF-15/MIC-1 in the same paradigm also provided significant neuroprotection. GDF-15/MIC-1 also promoted the serotonergic phenotype of cultured raphe neurons but did not support survival of rat motoneurons. Thus, GDF-15/MIC-1 is a novel neurotrophic factor with prominent effects on DAergic and serotonergic neurons. GDF-15/MIC-1 may therefore have a potential for the treatment of Parkinson's disease and disorders of the serotonergic system.
Strelau
J
J
Neuroanatomy and Interdisciplinary Center for Neurosciences, University of Heidelberg, D-69120 Heidelberg, Germany.
Sullivan
A
A
Böttner
M
M
Lingor
P
P
Falkenstein
E
E
Suter-Crazzolara
C
C
Galter
D
D
Jaszai
J
J
Krieglstein
K
K
Unsicker
K
K
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003342:Corpus Striatum / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D055436:Growth Differentiation Factor 15; D006801:Humans; D007501:Iron / Q000494:pharmacology; D007698:Kinesis / Q000187:drug effects; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity; D016627:Oxidopamine / Q000037:antagonists & inhibitors; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord; D013378:Substantia Nigra / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D016207:Cytokines; C526140:GDF15 protein, human; C526142:Gdf15 protein, rat; D055436:Growth Differentiation Factor 15; D016212:Transforming Growth Factor beta; D012701:Serotonin; D016627:Oxidopamine; D007501:Iron; D004298:Dopamine