epidermal-growth-factor and Parkinson-Disease--Secondary

One of the drawbacks with fetal ventral mesencephalic (VM) grafts in Parkinson's disease is the limited outgrowth into the host striatum. In order to enhance graft outgrowth, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were administered by implantation of bioactive rods to the lateral part of the striatum to support grafted fetal VM implanted to the medial portion of the striatum. The polymer-based bioactive rods allow for a local secretion of neurotrophic factors over a time period of approximately 2 weeks. Moreover, glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta1 (TGFbeta1) were administered using the same technique. Concomitant administration of GDNF and TGFbeta1 was achieved by insertion of one GDNF and one TGFbeta1 rod. This was performed to investigate possible additive effects between GDNF and TGFbeta1. Rotational behavior, outgrowth from and nerve fiber density within the VM graft, and the number of TH-positive cells were studied. Functional compensation by reduction of rotational behavior was significantly enhanced in animals carrying bFGF and GDNF rods in comparison with animals carrying only VM graft. EGF and bFGF significantly increased the innervation density. Moreover, the nerve fiber density within the grafts was significantly enhanced by bFGF. Cell counts showed that a significantly higher number of TH-positive neurons was found in grafts treated with bFGF than that found in GDNF-treated grafts. An additive effect of TGFbeta1 and GDNF was not detectable. These results suggest that bioactive rods is a useful tool to deliver neurotrophic factors into the brain, and since bFGF was a potent factor concerning both functional, immunohistochemical and cell survival results, it might be of interest to use bFGF-secreting rods for enhancing the overall outcome of VM grafts into patients suffering from Parkinson's disease.

Topics: Animals; Cell Count; Corpus Striatum; Delayed-Action Preparations; Disease Models, Animal; Drug Implants; Drug Therapy, Combination; Epidermal Growth Factor; Female; Fibroblast Growth Factor 2; Glial Cell Line-Derived Neurotrophic Factor; Glial Fibrillary Acidic Protein; Graft Survival; Growth Substances; Mesencephalon; Nerve Growth Factors; Nerve Tissue Proteins; Oxidopamine; Parkinson Disease, Secondary; Polyvinyls; Rats; Rats, Sprague-Dawley; Recovery of Function; Transforming Growth Factor beta; Tyrosine 3-Monooxygenase

Progenitor cells were isolated from the developing human central nervous system (CNS), induced to divide using a combination of epidermal growth factor and fibroblast growth factor-2, and then transplanted into the striatum of adult rats with unilateral dopaminergic lesions. Large grafts were found at 2 weeks survival which contained many undifferentiated cells, some of which were migrating into the host striatum. However, by 20 weeks survival, only a thin strip of cells remained at the graft core while a large number of migrating astrocytes labeled with a human-specific antibody could be seen throughout the striatum. Fully differentiated graft-derived neurons, also labeled with a human-specific antibody, were seen close to the transplant site in some animals. A number of these neurons expressed tyrosine hydroxylase and were sufficient to partially ameliorate lesion-induced behavioral deficits in two animals. These results show that expanded populations of human CNS progenitor cells maintained in a proliferative state in culture can migrate and differentiate into both neurons and astrocytes following intracerebral grafting. As such these cells may have potential for development as an alternative source of tissue for neural transplantation in degenerative diseases.

Topics: Amphetamine; Animals; Astrocytes; Brain Tissue Transplantation; Cell Count; Cell Differentiation; Cell Movement; Cell Survival; Cells, Cultured; Corpus Striatum; Dopamine; Epidermal Growth Factor; Fetal Tissue Transplantation; Fibroblast Growth Factor 2; Glial Fibrillary Acidic Protein; Graft Survival; Humans; Motor Activity; Nerve Tissue Proteins; Neurons; Oligodendroglia; Oxidopamine; Parkinson Disease, Secondary; Rats; Recombinant Fusion Proteins; Stem Cell Transplantation; Stem Cells; Tyrosine 3-Monooxygenase

The most recent attempt at surgical treatment of Parkinson's disease is represented by implant of dopaminergic tissue in the striate nuclei. Growth factors have been associated to the neural implants in order to favor successful grafting and functional survival. Among diverse growth factors Epidermal Growth Factor (EGF) is active in vitro on axonal regeneration of dopaminergic cells of the substantia nigra. Our research group has recently assessed the effect of a 35-day delayed intracerebroventricular infusion of EGF on the survival and function of the dopaminergic neurons in rats made hemiparkinsonian by unilateral mechanical transection of rat nigrostriatal pathway. EGF infusion resulted in a two-fold increase in the number of surviving tyrosine hydroxylase (TH)-positive substantia nigra neurons and a significant increase in ipsilateral striatal TH-positive fiber staining compared to controls. In addition there was a persistent enhancement of behavioral recovery, as indicated by a reduction in amphetamine-induced rotations. In the present study EGF is tested at a lower dosage starting administration at the time of lesion. Effects have been assessed by the available functional and biochemical methods. Results confirm that neurotrophic effect of EGF on dopaminergic neurons in the nigro-striatal pathways follow early administration also at low dosage.

Topics: Amphetamine; Animals; Biomarkers; Cell Count; Corpus Striatum; Dopamine; Epidermal Growth Factor; Injections, Intraventricular; Male; Motor Activity; Nerve Tissue Proteins; Neurons; Parkinson Disease, Secondary; Postoperative Period; Rats; Rats, Sprague-Dawley; Substantia Nigra; Tyrosine 3-Monooxygenase

We assessed the effect of a 35-day delayed intracerebroventricular (ICV) infusion of epidermal growth factor (EGF) on the survival and function of the substantia nigra (SN) dopaminergic neurons after a unilateral mechanical transection of rat nigrostriatal pathway. EGF infusion for 28 days resulted in a twofold increase in the number of surviving tyrosine-hydroxylase (TH)-positive SN neurons and a significant increase in ipsilateral striatal TH-positive fiber staining compared to controls at 200 days following the injury. In addition, there was a persistent enhancement of behavioral recovery, as indicated by a reduction in amphetamine-induced rotations. We conclude that EGF exerts a neurotrophic effect on the dopaminergic neurons in this experimental model of parkinsonism.

Topics: Animals; Corpus Striatum; Epidermal Growth Factor; ErbB Receptors; Hemiplegia; Male; Medial Forebrain Bundle; Motor Activity; Nerve Regeneration; Parkinson Disease, Secondary; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior; Substantia Nigra; Tyrosine 3-Monooxygenase