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

Frank Edlich, Matthias Weiwad, Dirk Wildemann, Franziska Jarczowski, Susann Kilka, Marie-Christine Moutty, Günther Jahreis, Christian Lücke, Werner Schmidt, Frank Striggow, Gunter Fischer
2006 Journal of Biological Chemistry  
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
more » ... 6 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 FKBP38⅐CaM/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 FKBP38⅐CaM/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 g/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. Members of the enzyme class of peptidyl prolyl cis/trans-isomerases (PPIases 2 ; EC 5.2.1.8) are the cytosolic receptors of the immunosuppressive drugs FK506 (tacrolimus), rapamycin (sirolimus), and cyclosporine A (1, 2). With the exception of cyclosporine A these drugs reversibly
doi:10.1074/jbc.m600452200 pmid:16547004 fatcat:u7qxnk2whfdufgwg7ednegc5ue