The Specific FKBP38 Inhibitor N-(N′,N′-Dimethylcarboxamidomethyl)cycloheximide Has Potent Neuroprotective and Neurotrophic Properties in Brain Ischemia

• Published in: The Journal of biological chemistry Vol. 281; no. 21; pp. 14961 - 14970
• Main Authors: Edlich, Frank, Weiwad, Matthias, Wildemann, Dirk, Jarczowski, Franziska, Kilka, Susann, Moutty, Marie-Christine, Jahreis, Günther, Lücke, Christian, Schmidt, Werner, Striggow, Frank, Fischer, Gunter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.05.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Brain - pathology; Brain Ischemia - pathology; Calcium - metabolism; Cell Line, Tumor; Cycloheximide - analogs & derivatives; Cycloheximide - chemistry; Cycloheximide - pharmacology; Humans; Kinetics; Ligands; Models, Chemical; Nerve Growth Factors - metabolism; Neurodegenerative Diseases; Neurons - metabolism; Neuroprotective Agents - pharmacology; Tacrolimus Binding Proteins - antagonists & inhibitors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M600452200

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 remainsed unknown so far. Here we show that neurotrophic FKBP ligands, such as GPI1046 and N-[methyl(ethoxycarbonyl)]cycloheximide, inhibit the calmodulin/Ca2+ (CaM/Ca2+)-regulated FKBP38 with up to 80-fold higher affinity than FKBP12. In contrast, the non-neurotrophic rapamycin inhibits FKBP38·CaM/Ca2+ 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/Ca2+ 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 μg/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.