Abstract
Liver growth factor (LGF) is a hepatic mitogen purified some years ago that promotes proliferation of different cell types and the regeneration of damaged tissues, including brain tissue. Considering the possibility that LGF could be used as a therapeutic agent in Parkinson's disease, we analyzed its potential neuroregenerative and/or neuroprotective activity when peripherally administered to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. For these studies, rats subjected to nigrostriatal lesions were treated intraperitoneally twice a week with LGF (5 microg/rat) for 3 weeks. Animals were sacrificed 4 weeks after the last LGF treatment. The results show that LGF stimulates sprouting of tyrosine hydroxylase-positive terminals and increases tyrosine hydroxylase and dopamine transporter expression, as well as dopamine levels in the denervated striatum of 6-OHDA-lesioned rats. In this structure, LGF activates microglia and raises tumor necrosis factor-alpha protein levels, which have been reported to have a role in neuroregeneration and neuroprotection. Besides, LGF stimulates the phosphorylation of MAPK/ERK1/2 and CREB, and regulates the expression of proteins which are critical for cell survival such as Bcl2 and Akt. Because LGF partially protects dopamine neurons from 6-OHDA neurotoxicity in the substantia nigra, and reduces motor deficits in these animals, we propose LGF as a novel factor that may be useful in the treatment of Parkinson's disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Animal / drug effects
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Bilirubin / isolation & purification
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Bilirubin / pharmacology*
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Corpus Striatum / drug effects*
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Disease Models, Animal
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Dopamine / metabolism
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Dopamine Plasma Membrane Transport Proteins / genetics
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Dopamine Plasma Membrane Transport Proteins / metabolism
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Female
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Gene Expression Regulation
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Neuroprotective Agents / isolation & purification
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Neuroprotective Agents / pharmacology*
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Oxidopamine
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Parkinson Disease, Secondary / chemically induced
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Parkinson Disease, Secondary / drug therapy*
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Parkinson Disease, Secondary / genetics
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Parkinson Disease, Secondary / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Serum Albumin / isolation & purification
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Serum Albumin / pharmacology*
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Serum Albumin, Human
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Signal Transduction
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Substantia Nigra / drug effects*
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / metabolism
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Tyrosine 3-Monooxygenase / genetics
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Tyrosine 3-Monooxygenase / metabolism
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bcl-Associated Death Protein / genetics
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bcl-Associated Death Protein / metabolism
Substances
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Cyclic AMP Response Element-Binding Protein
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Dopamine Plasma Membrane Transport Proteins
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Neuroprotective Agents
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Serum Albumin
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Tumor Necrosis Factor-alpha
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albumin-bilirubin complex
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bcl-Associated Death Protein
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Oxidopamine
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Tyrosine 3-Monooxygenase
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Bilirubin
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Dopamine
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Serum Albumin, Human
Grants and funding
This work was supported by the Spanish Fondo de Investigaciones Sanitarias (FISS PI060315) and Agencia Laín Entralgo (NDG7/09). LC and RG-G were the recipients of Agencia Laín Entralgo and FiBio Hospital Ramón y Cajal fellowships, respectively, and MRS was the recipient of a Contrato de Personal de Apoyo a la Investigación (FISS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.