Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factors have been shown to be involved in the regulation of division and differentiation of neuroepithelial cells. In the present study we examined the ability of various factors to influence the development of dopamine precursors. Primary neuronal cultures were prepared from the embryonic day 12 (E12) rat ventral mesencephalon, a time and place which coincides with the beginning of the birth of the dopamine neurons of the substantia nigra pars compacta. At low plating density in serum-free medium, the dopamine precursors divide for approximately 1 d in vitro. We report here that basic fibroblast growth factor (bFGF) can expand the period of dopamine precursor division at least until day 8 in culture, which is well beyond the normal division of these cells. This increase in cell division was accompanied by a delay in differentiation as compared to untreated control cultures. Upon differentiation, the high-affinity dopamine uptake values in bFGF-treated cultures were 20 times maximal control values. Mature dopamine neurons appeared at the same time as astrocytes, which may be playing a role in inducing dopamine neuron differentiation. IGF-I, GDNF, and EGF were unable to mimic the effect of bFGF on division and differentiation of dopamine precursors. Expanding in vitro the number of dopamine precursors provides tissue that may be suitable for transplantation in patients with Parkinson's disease.
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PMID:Basic fibroblast growth factor increases division and delays differentiation of dopamine precursors in vitro. 747 68

Studies in rodents suggest that PC12 cells, encapsulated in semipermeable ultrafiltration membranes and implanted in the striatum, have some potential efficacy for the treatment of age- and 6-OHD-induced sensorimotor impairments (22, 70, 71, 74). The objectives of this study were to: (1) determine if baby hamster kidney cells engineered to secrete glial cell line-derived neurotrophic factor (BHK-GDNF) would survive encapsulation and implantation in a dopamine-depleted rodent striatum, (2) compare polymer-encapsulated PC12 and PC12A cells in terms of their ability to survive and produce catecholamines in vivo in a dopamine-depleted striatum, and (3) determine if BHK-GDNF, PC12, or PC12A cells reduce parkinsonian symptoms in a rodent model of Parkinson's disease. Capsules with BHK-GDNF or PC12 cells contained viable cells after 90 days in vivo, with little evidence of host tissue damage/gliosis. In rats with tyrosine hydroxylase (TH)-positive fibers remaining in the lesioned striatum, there was TH-positive fiber ingrowth into the membranes of the BHK-GDNF capsules. PC12-containing capsules had higher basal release of both dopamine and L-DOPA after 90 days in vivo than before implantation, while basal release of both dopamine and L-DOPA decreased in the PC12A-containing capsules. Both encapsulated PC12 and PC12A cells, but not encapsulated BHK-GDNF cells, decreased apomorphine-induced rotations. Parkinsonian symptoms (akinesia, freezing/bracing, sensorimotor neglect) related to the extent of dopamine depletion were evident even in rats with dopamine depletions of only 25%. Evidence that encapsulated cells may attenuate these parkinsonian symptoms was not detected but most of the rats were more severely depleted of dopamine than Parkinson's patients (less than 2% dopamine remaining in the entire striatum), and these tests were not sensitive to differences between rats with less than 10% dopamine remaining. These results suggest that cell encapsulation technology can safely provide site-specific delivery of dopaminergic agonists or growth factors within the CNS, without requiring suppression of the immune system, and without using fetal tissue. Of the three types of encapsulated cells examined in the present study, PC12 cells seem to offer the most therapeutic potential in rats with severe dopamine depletions.
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PMID:Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and parkinsonian symptoms. 772 Aug 27

The survival of ventral mesencephalic substantia nigra (SN) dopamine neurons, which degenerate in Parkinson's disease, is enhanced by glial cells in vitro. The recent isolation of glial cell line-derived growth factor (GDNF), a molecule with apparently selective effects on dopamine (DA) neurons in vitro, raises the question of whether this factor is found in normal brain cells. In this study, the polymerase chain reaction (PCR) was employed to determine the regional distribution and cellular localization of GDNF in the rat central nervous system. GDNF was expressed by SN and basal forebrain Type 1 (T1) astrocytes, with trace transcript levels present in cortical T1 astrocytes. Neuronal cultures of embryonic SN also expressed GDNF. Regionally, postnatal striatum contained the highest GDNF mRNA levels in vivo under the PCR conditions employed. Our data suggest a role for GDNF in both local and target-derived support of DA neurons, as well as potential involvement in the support of other neuronal populations in vivo.
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PMID:Regional and cell-specific expression of GDNF in rat brain. 828 32

Since the discovery of the novel neurotrophic factor GDNF in 1993 [25], the molecule has received a great deal of attention from neuroscientists studying all aspects of neurotrophic factor physiology and pharmacology. GDNF instantly became a focus of basic research when it was discovered that GDNF was a potent neurotrophic factor for at least two diverse neuronal populations including dopaminergic neurons and motor neurons [25,47] magnitude. A comprehensive review of the pharmacology of GDNF and hypotheses concerning its possible clinical uses is presented. Based upon our current knowledge of GDNF's pharmacology, it appears that the molecule may be useful in the treatment of neurodegenerative diseases, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MND) and cholinergic deficit-related dementia.
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PMID:Therapeutic potentials for glial cell line-derived neurotrophic factor (GDNF) based upon pharmacological activities in the CNS. 891 90

It is estimated that only 5-10% of dopamine (DA) neurons implanted into the striatum of patients undergoing fetal-nigral transplantation as a treatment for Parkinson's Disease survive. Because it is often necessary to store fetal tissue prior to transplantation, we evaluated various storage parameters that could influence DA neuron viability in rostral mesencephalic tegmentum (RMT) cultures using tyrosine hydroxylase immunoreactive (THir) cell counts as an index of DA neuron survival. A high K+ hibernation media (HM) was used in all studies. We found that RMT cell viability and THir cell counts decreased as storage duration increased (up to 120 h). Storage at 37 degrees C in HM killed all cells, while storage at 10 degrees C yielded higher survival rates than 4 degrees C. In comparison to trypsinization, mechanical dissociation of tissue increased cell viability. Neutral pH and a storage density of at least 1 x 10(6) cells/mL were found to be optimal, while striatal coculture of RMT cells with striatal feeder layers increased THir viability up to 16-fold in comparison to monocultures. The nurturing effect of striatal coculture may be explained by the release of autotrophic factors, and we tested this hypothesis by supplementing the HM with human placental cord serum (HPCS, 8%), glial-derived neurotrophic factor (GDNF; 10 microg/mL), and brain-derived neurotrophic factor (BDNF; 10 microg/mL). GDNF and HPCS supplements increased RMT cell viability by 10-15%, while GDNF, BDNF, and HPCS increased viability of THir cells by approximately 40% at all time points studied. As Klenow enzyme labeling technique indicated that 33% of stored RMT cells were undergoing apoptosis, we found that GDNF, BDNF, and HPCS reduced apoptosis by 50%. DNA laddering and DAPI nuclear stain confirmed the presence of apoptosis in hibernated RMT cells, leading us to postulate that the high viability counts seen with trypan blue exclusion are misleading.
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PMID:The effects of storage conditions and trophic supplementation on the survival of fetal mesencephalic cells. 917 Nov 62

As a novel trial of neuroprotective therapy of neurodegenerative diseases, we have constructed a recombinant adenovirus vector (rAdv) bearing a neurotrophic factor gene to deliver the factor to rescue neurons in vivo. In the present study, human glial cell line-derived neurotrophic factor (hGDNF) was chosen to examine the applicability of our strategy to a mouse model of Parkinson's disease. During the construction of the rAdv, we found that the strong constitutive hGDNF expression unit somehow inhibited the appearance of the rAdv. Therefore we adopted a self-contained tetracycline-regulated expression system to acquire an rAdv expressing hGDNF. By analyzing the condition medium of SH-SY5Y cells infected with our constructed virus vector, we confirmed that biologically active GDNF was successfully expressed in vitro. For an animal study, we delivered this virus vector directly to the C57 black mouse brain and then exposed the animal to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to injure the nigrostriatal dopaminergic neurons. One week after the MPTP exposure, the neuroprotective effect of the virus vector was estimated by measurement of the dopamine content in the striatum of the mouse brain. The mice that had received our constructed virus had significantly higher dopamine levels in their striatum, demonstrating that our rAdv expressing hGDNF has therapeutic potential to protect the nigrostriatal dopaminergic neurons in vivo.
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PMID:Adenovirus-mediated transduction with human glial cell line-derived neurotrophic factor gene prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine depletion in striatum of mouse brain. 929 53

A recombinant adeno-associated virus (rAAV) vector capable of infecting cells and expressing rat glial cell line-derived neurotrophic factor (rGDNF), a putative central nervous system dopaminergic survival factor, under the control of a potent cytomegalovirus (CMV) immediate/early promoter (AAV-MD-rGDNF) was constructed. Two experiments were performed to evaluate the time course of expression of rAAV-mediated GDNF protein expression and to test the vector in an animal model of Parkinson's disease. To evaluate the ability of rAAV-rGDNF to protect nigral dopaminergic neurons in the progressive Sauer and Oertel 6-hydroxydopamine (6-OHDA) lesion model, rats received perinigral injections of either rAAV-rGDNF virus or rAAV-lacZ control virus 3 weeks prior to a striatal 6-OHDA lesion and were sacrificed 4 weeks after 6-OHDA. Cell counts of back-labeled fluorogold-positive neurons in the substantia nigra revealed that rAAV-MD-rGDNF protected a significant number of cells when compared with cell counts of rAAV-CMV-lacZ-injected rats (94% vs. 51%, respectively). In close agreement, 85% of tyrosine hydroxylase-positive cells remained in the nigral rAAV-MD-rGDNF group vs. only 49% in the lacZ group. A separate group of rats were given identical perinigral virus injections and were sacrificed at 3 and 10 weeks after surgery. Nigral GDNF protein expression remained relatively stable over the 10 weeks investigated. These data indicate that the use of rAAV, a noncytopathic viral vector, can promote delivery of functional levels of GDNF in a degenerative model of Parkinson's disease.
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PMID:Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson's disease in rats. 939 Nov 56

GDNF is a pleitropic neurotrophic factor which stimulates the dopaminergic phenotype in vitro and in vivo by way of activation of the GDNF/RET receptor complex. The pharmacologic profile of GDNF in two well-characterized animal models of Parkinson's disease suggests that the molecule may be useful in the treatment of neurodegenerative diseases involving dopaminergic dysfunction such as Parkinson's disease. This review summarizes the preclinical development path which was taken to develop GDNF as a novel therapeutic approach to treat Parkinson's disease based on GDNF's ability to regenerate dopamine neurons, including a description of the pharmacologic/biologic activities of GDNF. The overall aim will be to discuss these issues in the context of their potential therapeutic usefulness of GDNF to treat Parkinson's disease.
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PMID:A preclinical development strategy designed to optimize the use of glial cell line-derived neurotrophic factor in the treatment of Parkinson's disease. 961 19

The success of embryonic neural transplants as a treatment for patients with Parkinson's disease has been limited by poor survival of transplanted dopamine neurons. To see if a new partially intact tissue preparation method improves survival, we have developed a technique for extruding embryonic tissue into strands. We expected this method to reduce cell damage and improve transplant survival as well as provide improved tissue delivery. We have compared transplants of tissue strands with mechanically dispersed suspensions of embryonic day 15 rat ventral mesencephalon. Tissue from ventral mesencephalon was transplanted into a single site in dopamine denervated striatum of unilateral 6-hydroxydopamine (6-OHDA) lesioned rats. To evaluate the effects of striatal cografts and growth factors on dopamine cell survival, dispersed mesencephalic cells were cotransplanted with dispersed striatal cells. Another group had dispersed mesencephalic cells cotransplanted with striatal cells incubated in the cold for 2 h with glial cell line-derived neurotrophic factor (GDNF, 100 ng/ml), insulin-like growth factor-I (IGF-I, 1500 ng/ml), and basic fibroblast growth factor (bFGF, 150 ng/ml). Behavioral improvement was assessed monthly by changes in methamphetamine-induced rotational behavior. Animals were sacrificed after 3 months, and dopamine neurons were identified by tyrosine hydroxylase (TH) immunohistochemistry. Transplants of tissue strands produced better dopamine neuron survival and led to more robust behavioral restoration than did cell suspensions even when suspensions were supported with cografts of striatal cells or pretreatment with growth factors.
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PMID:Strands of embryonic mesencephalic tissue show greater dopamine neuron survival and better behavioral improvement than cell suspensions after transplantation in parkinsonian rats. 973 8

Parkinson's disease is an obvious target for the development of gene therapy procedures which could involve both the delivery of the gene encoding tyrosine hydroxylase to boost dopamine production or the delivery of genes encoding neurotrophic factors such as GDNF to promote the survival of dopaminergic neurons. A variety of different viral and nonviral methods for achieving such gene delivery are described together with the particular advantages of herpes simplex virus-based vectors which have the potential to deliver multiple therapeutic genes in a single virus vector.
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PMID:Viral vectors in the treatment of Parkinson's disease. 1063 36


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