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)

Immunohistochemistry using both a newly developed polyclonal, and a commercially available monoclonal, anti-insulin receptor antibody was done on the midbrain from cases of idiopathic Parkinson's disease (PD), Alzheimer's disease, amyotrophic lateral sclerosis, vascular parkinsonism and non-neurological controls. Both antibodies gave identical patterns of neuronal staining. The neurons of the oculomotor nucleus were immunopositive in all the brains. However, the neurons in the pars compacta of the substantia nigra, paranigral nucleus, parabrachial pigmental nucleus, tegmental pedunculopontine nucleus, supratrocheal nucleus, cuneiform nucleus, subcuneiform nucleus and lemniscus medialis, which were positive in other diseases and in non-neurological controls, were not stained by these antibodies in PD brains. These results suggest that, in PD, a dysfunction of the insulin/insulin receptor system may precede death of the dopaminergic neurons.
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PMID:Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson's disease. 801 69

At present, search for the causes of neurodegenerative diseases represents a major topic in brain research. Acquired disturbances of cell metabolism are supposed to be a cause of the two most important neurodegenerative disorders in ageing, like senile dementia of the Alzheimer type and Parkinson's disease, resulting in measurable decreases of in vivo and post mortem cerebral glucose metabolism. Accumulating evidence indicates that insulin plays an important role in the regulation of brain glucose homeostasis in the central nervous system and has trophic effects on neurons. It has been suggested that the reduction of brain glucose metabolism in neuro-degenerative disorders may be related to a defect of the neuronal insulin-insulin receptor-interaction. It will be the aim of our study to demonstrate whether there exist any changes in the content of insulin, its receptor and/or in the functionality of the insulin receptor and its signal transduction in neurodegenerative disorders as Alzheimer's and Parkinson's disease.
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PMID:Altered regulation of brain glucose metabolism as a cause of neurodegenerative disorders? 882 Oct 49

Neurotrophic effects resulting from the insulin/insulin receptor system have been recognized as important in determining the etiological basis of neurodegenerative disorders. In Parkinson's disease, selective neuronal loss in the substantia nigra is accompanied by decreased immunoreactivity of the insulin receptor as determined using immunohistochemical studies. We performed semiquantitative mRNA analysis by reverse transcription-polymerase chain reaction (RT-PCR) using specific primers for human insulin receptor exon 22, which encodes a region of the beta subunit of the receptor serving as a tyrosine kinase domain. The relative levels of mRNA in the substantia nigra from Parkinson's brain tissues showed a marked depression compared with those of normal controls. Further investigations are needed to decide whether this is a primary, disease-specific alteration of gene expression or merely a secondary process.
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PMID:Insulin receptor mRNA in the substantia nigra in Parkinson's disease. 893 65

Insulin resistance is known to play a pivotal role in type 2 diabetes. Senile individuals, besides being prone to insulin resistance and, consequently, to type 2 diabetes, manifest diseases of the central nervous system (CNS) that may be influenced by disturbances of insulin signaling in the brain, such as memory impairment, Parkinson disease, and Alzheimer disease. We investigated the expression and response to insulin of elements involved in the insulin-signaling pathway in the forebrain cortex and cerebellum of rats ages 1 d to 60 wk. The protein content of insulin receptors and SRC homology adaptor protein (SHC) did not change significantly along the time frame analyzed. However, insulin-induced tyrosine phosphorylation of the insulin receptor and SHC, and the association of SHC/growth factor receptor binding protein-2 (GRB2) decreased significantly from d 1 to wk 60 of life in both types of tissues. Moreover, the expression of SH protein tyrosine phosphatase-2 (SHP2), a tyrosine phosphatase involved in insulin signal transduction and regulation of the insulin signal, decreased significantly with age progression, in both the forebrain cortex and the cerebellum of rats. Thus, elements involved in the insulin-signaling pathway are regulated at the expression and/or functional level in the CNS, and this regulation may play a role in insulin resistance in the brain.
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PMID:Effects of age on elements of insulin-signaling pathway in central nervous system of rats. 1195 67

Protein-tyrosine kinase (PTKase) and protein-tyrosine phosphatase (PTPase) regulate the intracellular signal transduction in various biological processes. PTPase often negatively regulates the intracellular protein-tyrosine phosphorylation. PTPases are considered to be involved in the etiology of diabetes mellitus and neural diseases, such as Alzheimer's disease and Parkinson's disease. Therefore, PTPase inhibitors should be useful tools to study the role of PTPases in these diseases and other biological phenomena, and they hopefully may be developed into chemotherapeutic agents. We first discovered a naturally occurring PTPase inhibitor, dephostatin, in 1993. Later, we developed stable and safe dephostatin analogues by a molecular design approach employing the concept of CH/pi interaction. We prepared Et-3,4-dephostatin as a stable analogue and found it to inhibit PTP-1B and SHPTP-1 PTPases selectively. Et-3,4-dephostatin increased the tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), with or without insulin, in differentiated 3T3-L1 mouse adipocytes. It also increased the phosphorylation and activation of Akt. The analogue also enhanced translocation of glucose transporter 4 (GLUT4) from the cytoplasm to the membrane and 2-deoxyglucose transport. It also showed an in vivo antidiabetic effect in terms of reducing the high blood glucose level in KK-Ay mice after oral administration. Since Et-3,4-dephostatin contains a nitrosamine moiety, we designed nitrosamine-free dephostatin analogues employing the concept of CH/pi interaction. Then, we synthesized methoxime- and hexyl-methoxime-3,4-dephostatin as nitrosamine-free analogues. These analogues also showed antidiabetic activity in vivo and illustrate the utility of the CH/pi interaction molecular design approach.
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PMID:Molecular design and biological activities of protein-tyrosine phosphatase inhibitors. 1280 96

Transvascular gene therapy of Parkinson's disease (PD) is a new approach to the gene therapy of PD and involves the global distribution of a therapeutic gene to brain after an intravenous administration and transport across the blood-brain barrier (BBB). This is enabled with the development of a nonviral gene transfer technology that encapsulates plasmid DNA inside pegylated immunoliposomes or PILs. An 85- to 100-nm liposome carries the DNA inside the nanocontainer, and the liposome surface is conjugated with several thousand strands of 2000-Da polyethyleneglycol (PEG). This PEGylation of the liposome stabilizes the structure in the blood stream. The liposome is targeted across the BBB via attachment to the tips of 1-2% of the PEG strands of a receptor-specific monoclonal antibody (mAb) directed at a BBB receptor, such as the insulin receptor or transferrin receptor (TfR). Owing to the expression of the insulin receptor or the TfR on both the BBB and the neuronal plasma membrane, the PIL is able to reach the neuronal nuclear compartment from the circulation. Brain-specific expression is possible with the combined use of the PIL gene transfer technology and brain-specific gene promoters. In the 6-hydroxydopamine rat model of experimental PD, striatal tyrosine hydroxylase (TH) activity is completely normalized after an intravenous administration of TfRmAb-targeted PILs carrying a TH expression plasmid. A treatment for PD may be possible with dual gene therapy that seeks both to replace striatal TH gene expression with TH gene therapy, and to halt or reverse neurodegeneration of the nigro-striatal tract with neurotrophin gene therapy.
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PMID:Tyrosine hydroxylase replacement in experimental Parkinson's disease with transvascular gene therapy. 1571 64

Increased oxidative stress and susceptibility of brain endothelium are contributing factors in the development of central nervous system complications in neuro-degenerative disorders in diabetes, Alzheimer's and Parkinson's disease. The molecular mechanisms underpinning the vulnerability of brain endothelial cells to chronic oxidative challenge have not been elucidated. Here, we investigated the oxidative susceptibility of human brain endothelial cells (IHEC) to chronic hyperglycemic stress and insulin signaling and cytoprotection. Chronic hyperglycemia exacerbated IHEC apoptosis in accordance with exaggerated cytosolic and mitochondrial glutathione and protein-thiol redox imbalance, and actin/Keap-1 S-glutathionylation. Insulin attenuated hyperglycemia-induced apoptosis via restored cytosolic and mitochondrial redox. Insulin stimulated glutamate-L-cysteine ligase (GCL) activity by activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling, increased serine phosphorylation and nuclear translocation of nuclear NF-E2-related factor 2 (Nrf2), and upregulation of Nrf2-dependent GCL-catalytic (GCLc) subunit expression. Expression of the GCL-modulatory subunit (GCLm) was unchanged. Inhibitors of insulin receptor tyrosine kinase, PI3K, Akt and mTOR abrogated insulin-induced Nrf2-mediated GCLc expression, redox balance, and IHEC survival. Collectively, these results demonstrate that human brain endothelial cells exhibit vulnerability to hyperglycemic stress which is associated with marked cytosolic and mitochondrial redox shifts. Activation of insulin signaling through PI3K/Akt/mTOR/Nrf2/ GCLc pathway affords significant cell protection by maintaining cellular redox balance.
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PMID:NRF2-dependent glutamate-L-cysteine ligase catalytic subunit expression mediates insulin protection against hyperglycemia- induced brain endothelial cell apoptosis. 1710 20

Glial-derived neurotrophic factor (GDNF) is a neurotrophin that could be developed as a neurotherapeutic for Parkinson's disease, stroke, and motor neuron disease. However, GDNF does not cross the blood-brain barrier (BBB). Human GDNF was re-engineered by fusion of the mature GDNF protein to the carboxyl terminus of the chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb-GDNF fusion protein is bi-functional, and both binds the HIR, to trigger receptor-mediated transport across the BBB, and binds the GDNF receptor (GFR)-alpha1, to activate GDNF neuroprotection pathways behind the BBB. COS cells were dual transfected with the heavy chain (HC) and light chain fusion protein expression plasmids, and the HC of the fusion protein was immunoreactive with antibodies to both human IgG and GDNF. The HIRMAb-GDNF fusion protein bound with high affinity to the extracellular domain of both the HIR, ED(50) = 0.87 +/- 0.13 nM, and the GFRalpha1, ED(50) = 1.68 +/- 0.17 nM. The HIRMAb-GDNF fusion protein activated luciferase gene expression in human neural SK-N-MC cells dual transfected with the c-ret kinase and a luciferase reporter gene under the influence of the rat tyrosine hydroxylase promoter, and the ED(50), 1.68 +/- 0.45 nM, was identical to the ED(50) in the GFRalpha1 binding assay. The fusion protein was active in vivo in a rat middle cerebral artery occlusion model, where the stroke volume was reduced 77% (P < 0.001). In conclusion, these studies describe the re-engineering of GDNF, to make this neurotrophin transportable across the human BBB.
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PMID:GDNF fusion protein for targeted-drug delivery across the human blood-brain barrier. 1808 Mar 33

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.
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PMID:A new generation of neurobiological drugs engineered to overcome the challenges of brain drug delivery. 1918 Feb 67

To maintain a physical organization and a different composition of its surroundings environment, living beings use a great part of the energy that they produce. Vital processes require an elevated number of reactions which are regulated and integrated by chemical messengers. They use autocrine, paracrine, endocrine and synaptic signals through receptors of cell surface, nuclear or associated with ionic chanels, enzymes, trimeric G proteins and to intracellular kinases. Through these mechanisms pheromones play an important role in the relationships between different individuals, and hormones are able to regulate the integrative functions of our organism. In the nervous system, neurotransmitters, neuromodulators, sensors and receptors between other messengers, play functions of great relevance, while growth factors stimulate cell proliferation and cytokines have many effects but the most important is the ones related with the control of the immflamatory process. Alterations of these messengers permit us a better understanding of the diseases and possibly of its treatments in a near future. Modifications of the expression of genes from the nuclear and mitochondrial genomas are responsible of monogenic, polygenic and mitochondrial diseases, while alterations in the activities of dopamine and serotonin neurotransmitters are related with schizophrenia, Parkinson disease and depression, respectively. Other example is the hyperthyroidism of the Graves-Bassedow disease due to the competitive interference of the LATS immunoglobulin with TSH at the level of the folicular cells producing thyroid hormones Twenty five years ago in the reviews on the mechanisms of insulin action, there was presentations in which the insulin receptor was located in the plasma membrane of the target cells while in the cytoplasm only a big interrogative was observed, that at present is replaced by chemical mediators cascades responsible of the multiple effects of insulin. This finding is similar to many other processes, and all together constitute a new approach for a better knowledge of the biological processes and as a consequence of the diseases.
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PMID:[Pathophysiological implications of the chemical messengers]. 2043 62


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