Liver Growth Factor Induces Glia-Associated Neuroprotection in an In Vitro Model of Parkinson´s Disease.

Rafael Gonzalo-Gobernado,Diana Reimers,Juan José Diaz-Gil,Adriano Jiménez-Escrig,Gonzalo M Ulzurrun De Asanza,María José Casarejos,Manuela Vallejo-Muñoz,Eulalia Bazán,Lucía Calatrava Ferreras

doi:10.3390/brainsci10050315

Abstract

Parkinson’s disease is a neurodegenerative disorder characterized by the progressive death of dopaminergic (DA) neurons in the substantia nigra (SN), which leads to a loss of the neurotransmitter dopamine in the basal ganglia. Current treatments relieve the symptoms of the disease, but none stop or delay neuronal degeneration. Liver growth factor (LGF) is an albumin–bilirubin complex that stimulates axonal growth in the striatum and protects DA neurons in the SN of 6-hydroxydopamine-lesioned rats. Our previous results suggested that these effects observed in vivo are mediated by microglia and/or astrocytes. To determine if these cells are LGF targets, E14 (embryos from Sprague Dawley rats of 14 days) rat mesencephalic glial cultures were used. Treatment with 100 pg/mL of LGF up-regulated the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinases 1/2 (ERK1/2) and the cyclic AMP response element binding protein (CREB) phosphorylation in glial cultures, and it increased the microglia marker Iba1 and tumor necrosis factor alpha (TNF-alpha) protein levels. The treatment of E14 midbrain neurons with a glial-conditioned medium from LGF-treated glial cultures (GCM-LGF) prevented the loss of DA neurons caused by 6-hydroxy-dopamine. This neuroprotective effect was not observed when GCM-LGF was applied in the presence of a blocking antibody of TNF-alpha activity. Altogether, our findings strongly suggest the involvement of microglia and TNF-alpha in the neuroprotective action of LGF on DA neurons observed in vitro.

Highlights

Parkinson disease (PD) is a neurodegenerative disorder characterized by a series of motor symptoms like tremors, slowness of movement, rigidity, and bradykinesia [1]
We used mixedofglial neuroprotective activity of Liver growth factor (LGF) observed in vivo [16,17,19]
Our previous results suggested that microglia and/or astrocytes could mediate the neuroprotective effect of LGF on dopaminergic neurons observed in vivo [16,17,19]

Summary

Introduction

Parkinson disease (PD) is a neurodegenerative disorder characterized by a series of motor symptoms like tremors, slowness of movement, rigidity, and bradykinesia [1]. Though the cause of the disease remains difficult to elucidate, different mechanisms such as dopamine-dependent oxidative stress, mitochondrial dysfunction, excitotoxicity, Brain Sci. 2020, 10, 315; doi:10.3390/brainsci10050315 www.mdpi.com/journal/brainsci. Brain Sci. 2020, 10, 315 and proteasomal dysfunction have been associated with the loss of these neurons. Current treatments relieve the symptoms of the disease, but none stop or delay neuronal degeneration [1]. Neurotrophic factors are molecules that promote the survival, differentiation, and maintenance of neurons during development and in the adult nervous system [7]. These factors are potential tools for the treatment of neurodegenerative diseases, including PD. In experimental models of PD glial-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF)

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