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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder involving a progressive loss of dopaminergic (DA) neurons projecting from the substantia nigra (SN) to the striatum
We show that IP-Liver growth factor (LGF) regulates the expression of proteins that are critical for cell survival, and modulates the activity of both, the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK1/2) and the phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathways
To verify the neuroregenerative activity exerted by LGF treatment in vivo, unilaterally 6-OHDA-lesioned rats were treated IP twice a week with vehicle or LGF (5 mg/rat) for 3 weeks
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder involving a progressive loss of dopaminergic (DA) neurons projecting from the substantia nigra (SN) to the striatum. Neurotrophic factors are compounds that enhance the survival and differentiation of selected types of neurons, including DA neurons [1]. Recent studies show that LGF promotes proliferation of different cell types [5,6,7,8,9] and the regeneration of damaged cells and tissues, including brain tissue. The intracerebral infusion of LGF stimulates the sprouting of DA terminals in the striatum of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats [10], and promotes the expansion of neural precursors and the generation of new neurons in this experimental model of PD [11]. Its delivery into the brain enhances cell viability of grafted neural stem cells, and favors their differentiation to an endothelial-like phenotype [12]
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