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 pro liferation, differentiation, and repair. We have cloned, expressed, and rai sed antibodies against a distant member of the TGF-betas, growth/differenti ation factor-15 (GDF-15). GDF-15 is identical to macrophage inhibitory cyto kine-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 cu ltured from the embryonic rat midbrain floor. The trophic effect of GDF-15/ MIC-1 was not accompanied by an increase in cell proliferation and astrogli al maturation, suggesting that GDF-15/MIC-1 probably acts directly on neuro ns. GDF-15/MIC-1 also protects 6-hydroxydopamine (6-OHDA)-lesioned nigrostr iatal DAergic neurons in vivo. Unilateral injections of GDF-15/MIC-1 into t he medial forebrain bundle just above the substantia nigra (SN) and into th e left ventricle (20 mug each) immediately before a 6-OHDA injection (8 mug ) prevented 6-OHDA-induced rotational behavior and significantly reduced lo sses of DAergic neurons in the SN. This protection was evident for at least 1 month. Administration of 5 mug of GDF-15/MIC-1 in the same paradigm also provided significant neuroprotection. GDF-15/MIC-1 also promoted the serot onergic phenotype of cultured raphe neurons but did not support survival of rat motoneurons. Thus, GDF-15/MIC-1 is a novel neurotrophic factor with pr ominent effects on DAergic and serotonergic neurons. GDF-15/MIC-1 may there fore have a potential for the treatment of Parkinson's disease and disorder s of the serotonergic system.