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)

The aim of this study was to evaluate the neurotrophic and neuroprotective properties of a series of immunophilin ligands and to assess the potential involvement of FK506 Binding Protein 12 kDa (FKBP12) rotamase inhibition in this activity. Both FK506 and rapamycin induced a potent inhibition of the FKBP12 rotamase activity (pIC(50) values of 7.3 and 7.4, respectively) but only a modest inhibition was observed with 1-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2-carboxylic acid S-3-pyridin-3-yl-propyl ester (GPI 1046) (5.8), its N-oxide (5.4) and thioester (6.3) analogues. Compared to nerve growth factor, all these immunophilin ligands only induced marginal increases in neurite outgrowth of rat dissociated newborn dorsal root ganglia cells. Furthermore, systemic administration of GPI 1046 and its N-oxide and thioester analogues failed to prevent striatal dopamine depletion induced by acute or chronic i.p. treatment with 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP). These results suggest that inhibition of FKBP12 rotamase activity is not predictive for neurotrophic and neuroprotective properties of immunophilin ligands and question their therapeutic utility in neurodegenerative diseases like Parkinson's disease.
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PMID:Failure of GPI compounds to display neurotrophic activity in vitro and in vivo. 1127 96

The immunophilin receptors implicated in generating the neurotrophic effects of FK506 and rapamycin (RM) are unknown. Our studies are directed at (1) characterizing the effects of FK506 and RM on human fetal neurons and glia (2) revealing the role played by the immunophilin FKBP receptors and downstream effectors in mediating the effects of FK506 and RM on human brain cells and (3) clarifying the role of immunophilins (IP) in the normal and degenerating human brain. These studies provide the basis for the implementation of the FDA-approved immunophilin ligands (IPL) in the pharmacologic treatment of Parkinson's disease (PD). Additionally, they establish a potential link to pathogenetic and repair mechanisms associated with neurodegeneration and propose FKBP12 and FKBP52 as substrates that can be targeted by future drug design endeavors. Our studies also show for the first time that the immunophilin FKBP is present in the human brain and that its levels are altered in the brain of patients with neurodegenerative diseases. The increased levels of FKBP12 in neurons situated in areas of degeneration suggest that it may become a novel marker of pathology. Although the precise role of this immunophilin in the normal and degenerating brain awaits further clarification, this study suggests that FKBP might play a role in neuroprotection against abnormal protein aggregation, as well as participate in axonal transport and synaptic vesicle assembly. The rotamase activity of FKBP is likely to underlie these functions. If this hypothesis is confirmed, therapeutic attempts using rotamase activity-inhibiting immunophilin ligand administration in neurodegenerative disease patients need to be carefully designed.
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PMID:Immunophilins and their ligands: insights into survival and growth of human neurons. 1252 84

Aggregation of alpha-synuclein (alpha-SYN) plays a key role in Parkinson's disease (PD). We have used fluorescence correlation spectroscopy (FCS) to study alpha-SYN aggregation in vitro and discovered that this process is clearly accelerated by addition of FK506 binding proteins (FKBPs). This effect was observed both with E. coli SlyD FKBP and with human FKBP12 and was counteracted by FK506, a specific inhibitor of FKBP. The alpha-SYN aggregates formed in the presence of FKBP12 showed fibrillar morphology. The rotamase activity of FKBP apparently accelerates the folding and subsequent aggregation of alpha-SYN. Since FK506 and other non-immunosuppressive FKBP inhibitors are known to display neuroregenerative and neuroprotective properties in disease models, the observed inhibition of rotamase activity and alpha-SYN aggregation, may explain their mode of action. Our results open perspectives for the treatment of PD with immunophilin ligands that inhibit a specific member of the FKBP family.
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PMID:The aggregation of alpha-synuclein is stimulated by FK506 binding proteins as shown by fluorescence correlation spectroscopy. 1641 Mar 43

Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.
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PMID:Design, synthesis, and biological activity of novel polycyclic aza-amide FKBP12 ligands. 1645 Oct 85