Growth/Differentiation Factor-15/Macrophage Inhibitory Cytokine-1 Is a Novel Trophic Factor for Midbrain Dopaminergic Neurons In Vivo

• Published in: The Journal of neuroscience Vol. 20; no. 23; pp. 8597 - 8603
• Main Authors: Strelau, Jens, Sullivan, Aideen, Bottner, Martina, Lingor, Paul, Falkenstein, Elisabeth, Suter-Crazzolara, Clemens, Galter, Dagmar, Jaszai, Jozsef, Krieglstein, Kerstin, Unsicker, Klaus
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01-12-2000; Society for Neuroscience
• Subjects: Animals; Cell Survival - drug effects; Cells, Cultured; Cloning, Molecular; Corpus Striatum - drug effects; Cytokines - genetics; Cytokines - metabolism; Cytokines - pharmacology; Dopamine - metabolism; Female; Growth Differentiation Factor 15; Humans; Iron - pharmacology; Kinesis - drug effects; Mesencephalon - cytology; Mesencephalon - drug effects; Mesencephalon - embryology; Mesencephalon - metabolism; Motor Neurons - cytology; Motor Neurons - drug effects; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Organ Specificity; Oxidopamine - antagonists & inhibitors; Raphe Nuclei - cytology; Raphe Nuclei - drug effects; Raphe Nuclei - embryology; Raphe Nuclei - metabolism; Rats; Rats, Sprague-Dawley; Rats, Wistar; Serotonin - metabolism; Spinal Cord; Substantia Nigra - drug effects; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - pharmacology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.20-23-08597.2000

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.