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

In Parkinson's disease (PD) dopaminergic neurons in the substantia nigra (SN) become dysfunctional and many ultimately die. We report that the tellurium immunomodulating compound ammonium trichloro(dioxoethylene-O,O'-)tellurate (AS101) protects dopaminergic neurons and improves motor function in animal models of PD. It is effective when administered systemically or by direct infusion into the brain. Multifunctional activities of AS101 were identified in this study. These were mainly due to the peculiar Tellur(IV)-thiol chemistry of the compound, which enabled the compound to interact with cysteine residues on both inflammatory and apoptotic caspases, resulting in their inactivation. Conversely, its interaction with a key cysteine residue on p21(ras), led to its activation, an obligatory activity for AS101-induced neuronal differentiation. Furthermore, AS101 inhibited IL-10, resulting in up-regulation of GDNF in the SN. This was associated with activation of the neuroprotective kinases Akt and mitogen-activated protein kinases, and up-regulation of the antiapoptotic protein Bcl-2. Inhibition of caspase-1 and caspase-3 activities were associated with decreased neuronal death and inhibition of IL-1beta. We suggest that, because multiple mechanisms are involved in the dysfunction and death of neurons in PD, use of a multifunctional compound, exerting antiapoptotic, anti-inflammatory, and neurotrophic-inducing capabilities may be potentially efficacious for the treatment of PD.
 ...
PMID:Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson's disease models. 1731 38

Aquaporin 4 (AQP4) is a predominant water channel protein in mammalian brains, which is localized in the astrocyte plasma membrane. AQP4 has gained much attraction due to its involvement in the physiopathology of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury. But there is almost no evidence whether abnormal AQP4 levels are associated with degenerative diseases, such as Parkinson's disease (PD). In our studies, we established PD animal models by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to test the hypothesis that abnormal AQP4 expression is involved in the pathophysiology of this disease. We show that mutant mice lacking AQP4 were significantly more prone to MPTP-induced neurotoxicity than their wild-type littermates. Furthermore, after administration of MPTP, astroglial proliferation and GDNF protein synthesis were inhibited by AQP4 deficiency. This study demonstrates that AQP4 is important in the MPTP neurotoxic process and indicates that the therapeutic strategy targeted to astrocytic modulation with AQP4 may offer a great potential for the development of new treatment for PD.
 ...
PMID:Hypersensitivity of aquaporin 4-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine and astrocytic modulation. 1735 68

The practice of performing post-hoc power calculations for studies that do not demonstrate statistically significant results has been widely recognized in the scientific literature as being unhelpful and potentially misleading. However, this practice continues to cause confusion in the interpretation of results from clinical trials and other studies. Here, we examine the re-interpretation of a recent randomized, double-blind, placebo-controlled study of intraputamenally administered GDNF in late-stage Parkinson's disease patients [Hutchinson M, Gurney S, Newson R. GDNF in Parkinson disease: an object lesson in the tyranny of type II. J Neurosci Methods 2007;163:190-2]. Their main criticism is that the study was not large enough to detect clinically worthwhile effects and that the observed non-significant result does not contradict the promising results observed in two previous, small, open-label studies. We have carefully assessed the re-analysis of the data performed by Hutchinson et al. and found their conclusions to be flawed, in part because they are based on post-hoc power calculations. We have reaffirmed that the confidence interval for the treatment effect in the placebo-controlled study of GDNF shows that the trial is capable of excluding effects of GDNF of the magnitudes that were observed in the open-label studies and that the conclusions drawn in the original paper remain scientifically sound.
 ...
PMID:GDNF in Parkinson's disease: the perils of post-hoc power. 1754 Apr 54

The development of a maturing T-cell-mediated immune response was characterized in Parkinson's disease subjects receiving recombinant human glial-derived neurotrophic factor (r-metHuGDNF) via continuous bilateral intraputaminal infusion. Eighteen of 34 subjects tested positive for anti-r-metHuGDNF-binding antibodies. Four subjects developed neutralizing activity, three of which demonstrated classic immunoglobulin class switching from IgM to IgG. An increase of anti-r-metHuGDNF IgG-binding antibodies correlated with the development of neutralizing activity. All serum samples from two subjects with neutralizing activity were characterized for IgG subclasses. These data revealed an initial anti-r-metHuGDNF IgG population where IgG1 >> IgG2 >> IgG4, and IgG3 concentrations were negligible. However, continued antigenic stimulation resulted in concentration changes where IgG4 > IgG1> IgG2, indicating a mature immune response. In addition, using in silico techniques, two immunodominant MHC class II T-cell epitopes were predicted for the native GDNF sequence. These data demonstrate development of a mature T-cell-mediated immune response in these subjects.
 ...
PMID:Development of a maturing T-cell-mediated immune response in patients with idiopathic Parkinson's disease receiving r-metHuGDNF via continuous intraputaminal infusion. 1762 19

Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vivo gene therapy. In this pilot study, three 5-year-old female cynomolgus monkeys received a single intracarotid infusion of MPTP, followed 1 week later by MRI-guided stereotaxic intrastriatal and intranigral injections of male hNPCs transgenic for GDNF. Immunosupression with oral cyclosporine (30-40 mg/kg) began 48 h before hNPC transplants and continued throughout the study. We monitored the animals using a clinical rating scale (CRS). Three months postsurgery, we euthanized the animals by transcardiac perfusion, then retrieved and processed their brains for morphological analysis. Our findings include the following. 1) hNPCs survived and produced GDNF in all animals 3 months postsurgery. 2) hNPCs remained in the areas of injection as observed by GDNF immunostaining and in situ hybridization for the human Y chromosome. 3) A "halo" of GDNF expression was observed diffusing from the center of the graft out into the surrounding area. 4) We observed increased TH- and VMAT2-positive fibers in areas of GDNF delivery in two of the three animals. The two animals with TH- and VMAT2-positive fibers also showed reductions in their CRS scores. 5) Some GFAP-positive perivascular cuffing was found in transplanted areas. 6) General blood chemistry and necropsies did not reveal any abnormalities. Therefore, we conclude that hNPCs releasing GDNF may be a possible alternative for intracerebral trophic factor delivery in Parkinson's disease.
 ...
PMID:GDNF-secreting human neural progenitor cells increase tyrosine hydroxylase and VMAT2 expression in MPTP-treated cynomolgus monkeys. 1852 41

There is a great need for the development of noninvasive, highly sensitive, and widely available imaging methods that can potentially be used to longitudinally monitor treatment of Parkinson's disease (PD). Here we report the monitoring of GDNF-induced functional changes of the basal ganglia in hemiparkinsonian monkeys via pharmacological MRI measuring the blood oxygenation level-dependent (BOLD) response to a direct dopamine agonist (apomorphine, APO). After testing BOLD responsiveness to APO in their normal state, two additional scans were taken with the same dose of APO stimulation after induced parkinsonism. Then all animals were chronically treated with GDNF for 18 weeks by a programmable pump and catheter system. The catheter was surgically implanted into the right putamen and connected to the pump via flexible polyurethane tubing, phMRI scans were taken at both 6 and 18 weeks while they received 22.5 microg of GDNF per day. In addition, behavioral changes were monitored throughout the entire study. The primary finding of this study was that APO-evoked activations in the DA denervated putamen were attenuated by the chronic intraputamenal infusion of GDNF accompanied by improvements of parkinsonian features, movement speed, and APO-induced rotation compared to data collected before the chronic GDNF treatment. The results suggest that phMRI methods in combination with administration of a selective DA agonist may be useful for monitoring neurorestorative therapies in PD patients in the future.
 ...
PMID:Pharmacological MRI (phMRI) monitoring of treatment in hemiparkinsonian rhesus monkeys. 1852 44

With an increase in the aging population, the incidence of Parkinson's disease (PD), a disabling neurodegenerative disorder mainly affecting motor function, will inevitably present a challenge to an already overburdened healthcare system. Current medical and surgical therapies offer symptomatic relief but do not provide a cure. Experimental studies suggest that GDNF has the ability to protect degenerating dopamine neurons in PD as well as promote regeneration of the nigrostriatal dopamine system. However, clinical trials of GDNF infusion to date remain inconclusive. This review will examine the experimental and clinical evidence of GDNF use in PD with particular focus on its potential as an effective therapy in the treatment of PD.
 ...
PMID:GDNF therapy for Parkinson's disease. 1859 Apr 82

The aim of the present study is to provide a review of the expression and action of trophic factors in the carotid body. In glomic type I cells, the following factors have been identified: brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, artemin, ciliary neurotrophic factor, insulin-like growth factors-I and -II, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-alpha and -beta1, interleukin-1beta and -6, tumour necrosis factor-alpha, vascular endothelial growth factor, and endothelin-1 (ET-1). Growth factor receptors in the above cells include p75LNGFR, TrkA, TrkB, RET, GDNF family receptors alpha1-3, gp130, IL-6Ralpha, EGFR, FGFR1, IL1-RI, TNF-RI, VEGFR-1 and -2, ETA and ETB receptors, and PDGFR-alpha. Differential local expression of growth factors and corresponding receptors plays a role in pre- and postnatal development of the carotid body. Their local actions contribute toward producing the morphologic and molecular changes associated with chronic hypoxia and/or hypertension, such as cellular hyperplasia, extracellular matrix expansion, changes in channel densities, and neurotransmitter patterns. Neurotrophic factor production is also considered to play a key role in the therapeutic effects of intracerebral carotid body grafts in Parkinson's disease. Future research should also focus on trophic actions on carotid body type I cells by peptide neuromodulators, which are known to be present in the carotid body and to show trophic effects on other cell populations, that is, angiotensin II, adrenomedullin, bombesin, calcitonin, calcitonin gene-related peptide, cholecystokinin, erythropoietin, galanin, opioids, pituitary adenylate cyclase-activating polypeptide, atrial natriuretic peptide, somatostatin, tachykinins, neuropeptide Y, neurotensin, and vasoactive intestinal peptide.
 ...
PMID:Trophic factors in the carotid body. 1877 56

Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (Abeta(1-42)) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and Abeta(1-42)-induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer's and Parkinson's disease and can be viewed as possible candidates for studies on cell-based therapy.
 ...
PMID:The neuroprotective effect of dental pulp cells in models of Alzheimer's and Parkinson's disease. 1897 63

A new generation of multifunctional fusion proteins presents a potential solution to overcome the challenges associated with brain drug delivery and development of treatments for neurological disorders, including stroke, Alzheimer's disease, Parkinson's disease and inherited mucopolysaccharidosis. These biotherapeutics are engineered i) to cross the blood-brain barrier (BBB) following i.v. administration and ii) to produce a brain therapeutic effect. These fusion proteins are comprised of both a transport and a therapeutic domain. The transport domain is a monoclonal antibody (MAb) directed to an exofacial epitope of the BBB human insulin receptor (HIR), which uses the BBB endogenous insulin transport system to gain access to the brain via receptor-mediated transcytosis without interfering with the normal transport of insulin. Both human-chimeric and fully humanized versions of the anti-human HIRMAb have already been produced. The therapeutic domain of these fusion proteins consists of the peptide or protein of interest fused to the carboxyl terminus of the C(H)3 region of the heavy chain of the anti-human HIRMAb. A variety of HIRMAb fusion proteins were engineered aiming at the development of therapeutics for the central nervous system (CNS), i.e., stroke and Parkinson's disease, as in the case of HIRMAb-BDNF and HIRMAb-GDNF, respectively, HIRMAb-IDUA for the treatment of Hurler's disease, HIRMAb-A beta single chain antibody for passive immunotherapy of Alzheimer's disease, and HIRMAb-avidin as delivery system for biotinylated drugs, like siRNAs. The multifunctionality of these fusion proteins has been validated in preclinical work, including brain update in primates. Pending further development into pharmacological and toxicological studies, and clinical trials, members of the biotherapeutic family discussed in the present review, designed to overcome the brain drug delivery hurdle, are positioned to become a new generation of neuropharmaceutical drugs for the treatment of human CNS disorders.
 ...
PMID:A new generation of neurobiological drugs engineered to overcome the challenges of brain drug delivery. 1918 Feb 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>