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)

Altered glial cell function occurring in substantia nigra in Parkinson' disease may lead to the release of cytokines and impairment of neurotrophic factor production, which in turn, may cause dopaminergic apoptosis. To evaluate this concept, primary cultures of rat brain astrocytes were activated with lipopolysaccharide (LPS), depleted of glutathione with L-buthionine-[S,R]-sulfoximine or subjected to complex I inhibition with 1-methyl-4-phenylpyridinium. The effects on tumour necrosis factor-alpha (TNF-alpha) release, dopamine-stimulated glial cell line derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) release were determined. LPS activation or inhibition complex I activity, but not glutathione depletion, stimulated TNF-alpha release. Glutathione depletion or complex I inhibition, but not LPS-induced activation, impaired dopamine-stimulated GDNF release. None of these treatments altered BDNF release. Thus, altered glial function leading to TNF-alpha-mediated or GDNF withdrawal-induced dopaminergic apoptosis may contribute to nigral degeneration in Parkinson's disease.
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PMID:Dysfunction of rat forebrain astrocytes in culture alters cytokine and neurotrophic factor release. 1078 8

Parkinson disease (PD) is a progressive neurological disorder with a prevalence of 1-2% in people over the age of 50. It has a world-wide distribution and has no gender preference. The neurological hallmark of PD is the presence of Lewy bodies and is characterized by the degeneration of nigrostriatal dopaminergic neurons. The causes of PD are unknown but considerable evidence suggests a multifactorial etiology involving genetic and environmental factors. A molecular genetic approach identified three genes and at least two additional loci in rare familial forms of PD. Two of these genes are involved in the ubiquitin mediated pathway of protein degradation and the third one is a highly expressed protein in the synaptic terminal and is called alpha-synuclein. In animal models, it has been shown that use of the household pesticide which is known to contain rotenone, causes PD. Thus, a combined action of genetic and environmental factors is responsible for the pathogenesis of PD. Although use of levodopa or dopamine agonists can substantially reduce clinical symptoms, and transplantation of fetal nerve tissue still remains as an alternative therapy (although it has been recently shown to be having no overall benefit), directed delivery of glial cell derived neurotrophic factor (known to have trophic effects on dopaminergic neurons) may also be a beneficial therapeutic option for PD patients.
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PMID:Parkinson disease: etiology, pathogenesis and future of gene therapy. 1153 88

This study focuses on the potential protective effects of intracerebral adeno-viral mediated glial cell line derived neurotrophic factor (GDNF) gene transfer in a rat model of Parkinson's disease (PD). Thirty-five SD rats were divided into three groups to receive perinigral injections of recombinant adenovirus encoding GDNF (Ad-GDNF), LacZ (Ad-LacZ) or PBS, respectively. One week later, an intrastriatal injection of 6-hydroxydopamine (6-OHDA) was administered to induce the progressive degeneration of dopaminergic neurons. Immunohistochemistry showed that GDNF treatment prior to neuronal damage could promote survival and morphological recovery of tyrosine hydroxylase (TH)-positive neurons in the midbrain. Approximately 70% of nigral TH-positive cells survived in the Ad-GDNF group, compared to approximately 30% for the Ad-LacZ or PBS control group. Histochemical analysis of monoamine levels in the striatum demonstrated that the dopamine content was higher for the Ad-GDNF group than the control groups. Similarly, Ad-GDNF treated animals showed improved apomorphine-induced rotational behavior. The exogenous GDNF gene was efficiently expressed in the brain as detected by ELISA. This work demonstrates that intracerebral adeno-viral mediated GDNF gene transfer can protect dopaminergic neurons in vivo from 6-OHDA-induced injuries. The approach used in this study could potentially be used therapeutically in patients with PD and further work is required to explore this idea in depth.
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PMID:Protective effects of intracerebral adenoviral-mediated GDNF gene transfer in a rat model of Parkinson's disease. 1449 99

We have examined the possibility of using herpes simplex virus (HSV)-based vectors to prevent neuronal cell death and enhance functional recovery after injury. In the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD) and after proximal spinal root injury, direct stereotactic injection of HSV-based vectors constructed to express the glial cell derived neurotrophic factor (GDNF) or the anti-apoptotic peptide Bcl-2 prevented neuronal death and enhanced recovery. Gene transfer may be useful in the treatment of neurologic disorders in which neuronal cell death occurs in a restricted anatomic distribution.
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PMID:Therapeutic gene transfer with herpes-based vectors: studies in Parkinson's disease and motor nerve regeneration. 1459 21

The recent identification of neurotrophic factors, such as the glial cell line derived neurotrophic factor (GDNF), acting on mesencephalic dopaminergic neurons, offers the possibility to stimulate the axonal regeneration of these cells which are affected in Parkinson's disease. Nevertheless, a safe and efficient GDNF delivery system that may be used in clinical trials is still lacking. We have developed GDNF-releasing microspheres capable of releasing the neurotrophic factor for at least 2 months in vivo. In this study we demonstrate that these microspheres, when implanted in the brains of 'Parkinsonian' rats, were well tolerated, and were able to induce sprouting of the preserved dopaminergic fibers with synaptogenesis. Moreover, this neural regeneration was accompanied by functional improvement. The implantation of GDNF-releasing microspheres could be a promising strategy in the treatment of Parkinson's disease.
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PMID:Striatal implantation of GDNF releasing biodegradable microspheres promotes recovery of motor function in a partial model of Parkinson's disease. 1460 82

Protein injection studies of the glial cell line derived neurotrophic factor (GDNF) family member Neurturin (NTN) have demonstrated neuroprotective effects on dopaminergic (DA) neurons, which are selectively lost during Parkinson's disease (PD). However, unlike GDNF, NTN has not previously been applied in PD models using an in vivo gene therapy approach. Difficulties with lentiviral gene delivery of wild type (wt) NTN led us to examine the role of the pre-pro-sequence, and to evaluate different NTN constructs in order to optimize gene therapy with NTN. Results from transfected cultured cells showed that wt NTN was poorly processed, and secreted as a pro-form. A similarly poor processing was found with a chimeric protein consisting of the pre-pro-part from GDNF and mature NTN. Moreover, we found that the biological activity of pro-NTN differs from mature NTN, as pro-NTN did not form a signaling complex with the tyrosine kinase receptor Ret and GFRalpha2 or GFRalpha1. Deletion of the pro-region resulted in significantly higher secretion of active NTN, which was further increased when substituting the wt NTN signal peptide with the immunoglobulin heavy-chain signal peptide (IgSP). The enhanced secretion of active mature NTN using the IgSP-NTN construct was reproduced in vivo in lentiviral-transduced rat striatal cells and, unlike wt NTN, enabled efficient neuroprotection of lesioned nigral DA neurons, similar to GDNF. An in vivo gene therapy approach with a modified NTN construct is therefore a possible treatment option for Parkinson's disease that should be further explored.
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PMID:Efficient in vivo protection of nigral dopaminergic neurons by lentiviral gene transfer of a modified Neurturin construct. 1591 76

Parkinson's disease is characterized by bradykinesia, rigidity and a resting tremor and the underlying basis for those symptoms is the loss of dopaminergic cells in the nigrostriatal system. Similar to PD, an age-related decrease locomotor activity and the expression of tyrosine hydroxylase immunoreactivity has been observed in rhesus monkeys, but the reason for this decrease in dopaminergic function remains to be elucidated. Trophic factors such as glial cell line derived neurotrophic factor (GDNF) and neurturin sustain the dopaminergic phenotype in midbrain neurons and act through a common receptor tyrosine kinase (RET). Examination of RET expression by immunohistochemistry was performed on sections of tissue containing the substantia nigra pars compacta of young, middle, and old aged rhesus monkeys. Stereological estimates of the number and cellular area of RET-immunoreactive cells found no change with age. Estimation of changes in RET protein using fluorescence intensity measurement was also similar across age groups. The results indicate that the mechanisms of GDNF and neurturin signaling remain intact with age, and therefore these trophic factors may be able to enhance the dopaminergic function of neurons in the nigrostriatal system, when administered to individuals of any age.
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PMID:RET expression does not change with age in the substantia nigra pars compacta of rhesus monkeys. 1595 Mar 22

Adoptive transfer of lymphoid cells from Copolymer 1 (Cop-1) immunized mice leads to T cell accumulation within the substantia nigra, modulation of microglial responses, upregulation of glial cell derived neurotrophic factor, and protection of the nigrostriatum following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. We now demonstrate that T cells isolated from lymph nodes and spleens of Cop-1 immunized animals protect the nigrostriatal system from MPTP-induced neurodegeneration in a dose-dependent manner. CD4+ T cells elicited the most significant neuroprotective response while high titers of anti-Cop-1 antibodies showed no effect. These data further support the use of immunomodulatory strategies for Parkinson's disease.
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PMID:CD4+ T cells from Copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. 1719 66

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Current therapies are symptomatic and, although these therapies are efficacious during the early stages of the disease, they present important side effects when they are used for a long time. The ideal therapy would be the one that would slow down or stop the progression of the disease. This can be achieved, for instance, with neuroprotective and neurorestorative therapies. Among them, cell therapy and therapy with trophic factors such as glial cell line derived neurotrophic factor (GDNF) are the most challenging and promising ones for the scientific community. Although the use of GDNF as a treatment for Parkinson s disease was proposed several years ago, it is necessary to develop alternative strategies to deliver GDNF appropriately to concrete areas of the brain. Here, the use of microspheres as the most suitable tool for the administration of this neurotrophic factor is discussed.
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PMID:[Neuroprotective and neurorestorative therapies for the treatment of Parkinson's disease]. 1722 35

Although a good deal is known about the pathophysiology of Parkinson's disease and information is emerging about its cause, there are no pharmacological treatments shown to have a significant, sustained capacity to prevent or attenuate the condition. However, accumulating clinical evidence suggests that physical exercise can provide this much needed treatment, and studies of animal models of the dopamine deficiency associated with the motor symptoms of Parkinson's disease further support this hypothesis. Thus, in our collaborative research efforts, we seek to understand the biological basis for exercise-induced protection in order to assist in the development of a safe and clinically effective intervention based on increased physical activity. In addition, we recognize that some individuals cannot or will not engage in physical exercise, and believe that mechanistic studies of exercise-induced protection will provide insights into the development of drugs that could emulate its effects. Using toxins that induce a deficiency of dopamine, we have affirmed that physical exercise can reduce behavioral and neurobiological deficits induced by such toxins, and suggest that these neuroprotective effects are likely to involve the activation of signaling cascades by neurotrophic factors such as glial cell line derived neurotrophic factor.
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PMID:Neurorestoration by physical exercise: moving forward. 2216 17


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