Liver Growth Factor as a Tissue Regenerating Factor in Neurodegenerative Diseases

Abstract

Liver growth factor (LGF) is a hepatic mitogen purified by our group in 1986. In the following years we demonstrated its activity both in “in vivo” and “in vitro” systems, stimulating hepatocytes mitogenesis as well as liver regeneration in several models of liver injury. Furthermore, we established its chemical composition (albumin-bilirubin complex) and its mitogenic actions in liver. From 2000 onwards we used LGF as a tissue regenerating factor in several models of extrahepatic diseases.The use of Liver growth factor as a neural tissue regenerator has been recently protected (Patent No US 2014/8,642,551 B2).LGF administration stimulates neurogenesis and neuron survival, promotes migration of newly generated neurons, and induces the outgrowth of striatal dopaminergic terminals in 6-hidroxydopamine-lesioned rats. Furthermore, LGF treatment raises striatal dopamine levels and protects dopaminergic neurons in hemiparkinsonian animals. LGF also stimulates survival of grafted foetal neural stem cells in the damaged striatum, reduces rotational behaviour and improves motor coordination. Interestingly, LGF also exerts a neuroprotective role both in an experimental model of cerebellar ataxia and in a model of Friedrich´s ataxia. Microglia seem to be the cellular target of LGF in the CNS. Moreover, the activity of the factor could be mediated by the stimulation of MAPK´s signalling pathway and by regulating critical proteins for cell survival, such as Bcl-2 and phospho-CREB. Since the factor shows neuroprotective and neurorestorative effects we propose LGF as a patented novel therapeutic tool that may be useful for the treatment of Parkinson´s disease and cerebellar ataxias. Currently, our studies have been extended to other neurological disorders such as Alzheimer’s disease (Patent No: US 2014/0113859 A1).

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

“…According to present results, LGF up-regulated Iba1 protein expression and increased TNF-alpha protein levels. These are two features associated with the transient activation of microglia that were also observed in our in vivo studies [15,19].…”

“…The activation of astroglia [51] and microglia by several stimuli promotes the synthesis and secretion of various factors with neuroprotective activity [52][53][54]. Among them, the cytokine TNF-alpha seems to play an important role in the mitogenic cascade of LGF in the liver, as well as in LGF-induced neuroregeneration (reviewed by Gonzalo-Gobernado et al, 2014) [15]. Moreover, several studies have shown the involvement of TNF-alpha in neuronal survival [21,55,56] and neurites outgrowth [57].…”

“…Diaz-Gil and colleagues demonstrated that LGF is an albumin-bilirubin complex whose concentration is virtually undetectable in rat and human serum from healthy individuals, but it increases significantly in the process of liver damage [11,12]. Several studies have shown that LGF increases the proliferation of different cell types and promotes regeneration of damaged tissues, including the brain [13][14][15]. Thus, the intracerebral administration of LGF to hemiparkinsonian rats was found to be able to stimulate axonal growth in the striatum, as well as to improve rotational behavior stimulated by apomorphine [16].…”

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice

“…The receptors for the advanced glycation end products (RAGE) located in the endothelium could be good candidates, since AGE products have similar biochemical properties to LGF, i.e., they are mostly albumins bound to glucose, which changes albumin conformation [50]. Moreover, RAGE stimulation elicits the release of TNF-α, which is a cytokine that participates in LGF-mediated proliferation and neuroregeneration [15]. …”

“…Recent studies show that LGF is a pleiotropic factor capable of stimulating cell proliferation, and tissue regeneration in hepatic and extrahepatic pathologies [10,11,12,13,14]. The use of LGF as a neural tissue regenerator has been recently protected (Patent No US 2014/8,642,551 B2) [15]. The administration of LGF stimulates the sprouting of DA terminals in the striatum of hemiparkinsonian rats [16,17,18], stimulates the generation of new neurons, and promotes their migration in this experimental model of Parkinson’s disease [17], and its delivery into the brain stimulates the survival of grafted fetal neural stem cells and their differentiation to an endothelial-like phenotype [19].…”