Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FK506 and FK506-derived inhibitors of the FK506-binding protein (FKBP)-type peptidylprolyl cis/trans-isomerases (PPIase) display potent neuroprotective and neuroregenerative properties in various neurodegeneration models, showing the importance of neuroimmunophilins as targets for the treatment of acute and chronic neurodegenerative diseases. However, the PPIase activity targeted by active site-directed ligands remains unknown so far. Here we show that neurotrophic FKBP ligands, such as GPI1046 and N-[methyl(ethoxycarbonyl)]cycloheximide, inhibit the calmodulin/Ca(2+) (CaM/Ca(2+))-regulated FKBP38 with up to 80-fold higher affinity than FKBP12. In contrast, the non-neurotrophic rapamycin inhibits FKBP38.CaM/Ca(2+) 500-fold less affine than other neuroimmunophillins. In the context of the high expression of FKBP38 in neuroblastoma cells, these data suggest that FKBP38.CaM/Ca(2+) inhibition can mediate neurotrophic properties of FKBP ligands. The FKBP38-specific cycloheximide derivative, N-(N',N'-dimethylcarboxamidomethyl)cycloheximide (DM-CHX) was synthesized and used in a rat model of transient focal cerebral ischemia. Accordingly, DM-CHX caused neuronal protection as well as neural stem cell proliferation and neuronal differentiation at a dosage of 27.2 mug/kg. These effects were still dominant, if DM-CHX was applied 2-6 h post-insult. In parallel, sustained motor behavior deficits of diseased animals were improved by drug administration, revealing a potential therapeutic relevance. Thus, our results demonstrate that FKBP38 inhibition by DM-CHX regulates neuronal cell death and proliferation, providing a promising strategy for the treatment of acute and/or chronic neurodegenerative diseases.
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PMID:The specific FKBP38 inhibitor N-(N',N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. 1654 4

Immunophilins consist of a family of highly conserved proteins binding with immunosuppressive drugs such as FK506, rapamycin and cyclosporin A. FK506-binding protein (FKBP) is one of two major immunophilins and most of FKBP family members bind FK506 and show peptidylprolyl cis/trans isomerase (PPIase) activity. Small size FKBP family members contain only FK506-binding domain, while FKBPs with large molecular weights possess extra domains such as tetratricopeptide repeat domains, calmodulin binding and transmembrane motifs. FKBPs are involved in several biochemical processes including protein folding, receptor signaling, protein trafficking and transcription. FKBP family proteins play important functional roles in the T-cell activation, when complexed with their ligands. The roles of immunophilins in protein transportation and apoptosis through their molecular interactions with receptors or proteins have emerged recently. Moreover, therapeutic implications of immunophilin ligands in treating neurodegenerative disorders have been accumulating. FK506 and its derivatives with no immunosuppressive activities bind to the conserved active sites of the canonical FKBP members such as FKBP12, which shows PPIase activity. These immunophilin ligands show variable efficacy in animal models for Parkinson's disease, dementia, and spinal cord injury, where the canonical immunophilins function as chaperones and are associate with the protein folding and modulation of oxidative stress. On the other hand, in the noncanonical FKBP members such as FKBP38, FK506-binding site is not conserved and shows neither PPIase activity nor affinity to FK506. Interestingly, the small molecule-mediated inhibition of the noncanonical member of FKBP family appears to cause neuronal protection and induce proliferation of neuronal stem cells in a rat focal cerebral ischemia model. Currently, the mechanisms of actions remain unclear. This review focuses on molecular characteristics of the canonical and noncanonical FKBP family members and the biological functions of their ligands in performing neuroprotective and neurotrophic activities.
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PMID:FKBP family proteins: immunophilins with versatile biological functions. 1863 47