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Summary by Mari Luz González Casas
Translation by Marion Clark
To hear the entire presentation in Spanish on mp3, go to the following link: http://download.yousendit.com/E8936AB97340FD6D
Encuentro Ataxias (Ataxia Encounter) 2008
Organized by the
Colectivo Ataxias en Movimiento
(Ataxias on the Move Coalition)
Madrid, April 29, 2008
Second scientific presentation:
Dr. Eulalia Bazán, Research Team, Ramon y Cajal University Hospital
“Presentation on the advances in the research project into growth factor LGF, which acts as a possible treatment agent for different types of ataxia”
Dr. Eulalia Bazán
This work initially was not developed in an experimental model of ataxia, but rather, in an experimental model of Parkinson’s disease. But it is thought that based on the results obtained thus far, this work will be transferable to other models of neurodegeneration. The research team of Ramon y Cajal Hospital has been working for years with hepatic growth factor (LGF). The objective has been to promote the stimulation of endogenous neuronal stem cells, that is, those which are already found in the central nervous system of adult mammals. This would be done through the application of growth factors.
The many stem cells found in the central nervous system are located in the subventricular zone of the lateral ventricles of the anterior cerebrum. In this zone we have a population of proliferating cells which express nestin, a cellular marker of undifferentiated neural progenitors. The known function of these cells is to generate a population of neuroblasts, that is, neural progenitors which follow a specific path to reach the olfactive bulb, where they generate new neurons. Researchers think that in case of neuronal damage it would be possible, through the application of growth factors, to increase the proliferation of these cells, to facilitate the migration of the neuronal progenitors to regions where neurons are lacking, and to promote their differentiation into adult neurons which could replace those which are lacking. LGF (hepatic growth factor) is a complex of albumin-bilirubin purified by Dr. Diaz Gil of the Puerta de Hierro Hospital. It is a potent hepatic mitogen which also increases the proliferation of other cell types and which regenerates damaged tissues.
Shown here are the results obtained in experimental models of hypertension. LGF improves vascular structure and function in hypertensive rats. It’s interesting to note that the target cell of this factor is an endothelial cell of the portal vein, and it is known that endothelial cells liberate certain factors which promote neurogenesis, the generation of new neurons from stem cells. This is why it is thought that LGF could be an excellent candidate for the promotion of neurogenesis in models of neurodegeneration.
With this objective, we began applying LGF in the lateral ventricle of a parkinsonian rat model. Cellular proliferation was observed to increase significantly, both in the subventricular zone of these animals and in the striatal parenchyma in the cerebral structure next to this structure.
In addition, the expression of nestin increased, and all this was in comparison with a healthy animal as well as in comparison with an animal treated with vehicle.
Inside this striatal parenchyma cells were seen which were doubly marked both with nestin and with the marker of proliferation, suggesting that these cells were neural progenitors which had proliferated as a result of the application of LGF. These neural progenitors of the subventricular zone function to generate new neurons which normally would go to the olfactory bulb. An immunohistochemical determination was done with doublecortin, a neuronal marker; it was observed that when saline was infused, the arrangement of the neuroblasts was very similar to that seen in normal animals, that is, in the subventricular zone, which is that called the lateral horn/wing.
When LGF was applied, this distribution changed noticeably. In the parkinsonian rat model treated with LGF, there is a distribution of neuroblasts in the striatal parenchyma, especially in the most dorsal regions, those closest to the vertebral column.
Other animals were even more spectacular since they presented a distribution of neuroblasts in the regions dorsal, medial, and ventral to the striatum. It was concluded that with [LGF] neurogenesis had been stimulated. This was corroborated by doing double marking with a marker of proliferation and with a neuronal marker, doublecortin. It was observed that these new cells which were generated doubly marked the two immunostainings.
In addition, these neurons, which in principle are very young neurons, are capable of initiating the expression of more specific markers of adult neurons. This leads to the conclusion that LGF is a potent neurogenic factor when applied in the cerebrum of a parkinsonian rat model.
As an alternative to applying LGF in the lateral ventricle of these animals, it was also decided to apply it directly in the striated body, in the striatal parenchyma close to the subventricular region. With this strategy we were not able to attain neurogenesis. Nevertheless, LGF proved to be a potent neuroregenerative factor.
In this way an immunohistochemical determination was done for the enzyme tyrosine hydroxylase, which is the limiting enzyme in the synthesis of catecholamines. We saw that in animals infused with LGF, in the striatum in the zone near the infusion, and in the medial striatum, there was practically no immunodetection of tyrosine hydroxylase. Nevertheless, upon applying LGF to these animals, we see a great expression of tyrosine hydroxylase at all the levels of the striatum that were studied. The bar graph shows the percentage of the total area of the striatum which presents positive tyrosine hydroxylase immunostaining in parkinsonian animals, animals treated with saline, animals treated with LGF, and animals treated with another factor, that of basic fibroblasts. It can be seen how the percentage of area innervated by tyrosine hydroxylase is significantly increased, and the most interesting aspect of this effect is that when the asymmetrical rotational behavior test was done in the animals, a significant decrease was seen upon comparing them with the animals treated with saline, indicating that LGF promotes an improvement in function in these animals.
When LGF was applied intraperitoneally, similar results were obtained. In other words, this means that in order to work with a factor useful in the treatment of neurodegenerative diseases, we can’t think about the possibility of applying it directly in the cerebrum; we have to look for simpler routes. It was decided to apply the factor LGF in the peritoneum of the parkinsonian rats, and from the point of view of neuroregeneration, the results obtained were very similar to those obtained when LGF was applied in the striatum. There was an increase in the percentage of dopaminergic innervation in the striatum of those animals when compared with animals treated with saline. An improvement was also observed in these animals’ behavior.
Conclusion: LGF is a potent neurogenic and neuroregenerative factor. Due to these positive results, and at the invitation of the Ataxias on the Move Coalition, we have decided to design a research project directed at studying the effectiveness of LGF in experimental models of ataxia.
The objective is to determine if LGF is useful for the ataxias. Two experimental models will be involved—one in rats with a lesion of the inferior oliva, induced by the neurotoxin 3-acetylpyridine (3AP), and the second an experimental model in mice of Friedreich’s ataxia caused by deletion of frataxin in the adult mouse.
The routes of administration of the factor will be the intracerebral-intraventricular route in the rat, and the intraperitoneal route in the rat and in the mouse.
The parameters to be evaluated are:
--Evaluation of motor coordination (rotarod test)
--Evaluation of neuroprotective capacity using immunohistochemical techniques, analyzing immunoreactivity for the protein GAP-43, associated with axonic growth
--Evaluation of neurogenic capacity of LGF using immunohistochemical techniques, studying immunoreactivity for markers of proliferation and for neuronal markers such as, for example, doublecortin
--Biochemical study to determine the levels of amino acids glutamate and GABA, using HPLC (high performance liquid chromatography) techniques
--Biochemical study to determine the levels of frataxin using Western blot technique.
It has been proven in addition that LGF is a factor with antioxidant potential. For this reason, we will study the activity of the respiratory chain complexes COX (cytochrome oxidase) and SDH (succinate dehydrogenase), in the central nervous system as well as in the heart.
For further information on the work of Dr. Bazán on LGF and Parkinson’s disease, go to the following link (in Spanish):
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Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:
1) Gene Therapy for Friedreich's Ataxia research project:
The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.
2) Frataxin delivery research project:
The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.
The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.