Restauration of injured nervous system by immunophilin ligands

DANERI-BECERRA C, GALIGNIANA MD

Congreso; The 8th International Conference on the Hsp90 Chaperone Machinery; 2016

Immunophilins (IMMs) are proteins classified as cyclophilins (CyP) when they bind cyclosporine A (CsA), or FK506-Binding Proteins (FKBPs) when they bind the macrolide FK506. The nervous system expresses high levels of IMMs, but their biological roles are poorly understood. Previously, we reported that FK506 favours neurodifferentiation in an FKBP52-dependent fashion, whereas FKBP51 is an antagonistic factor. Organotypic prefrontal brain slices and spinal cord slices treated with FK506 showed high induction of FKBP52 expression, whereas treatments with CsA induced the expression of CyP17 in brain, but not in spinal cord. To test the neuroregenerative properties of both IMM ligands, in this study we subjected mice to surgical transection of the mid thoracic spinal cord. Locomotion recovery was evaluated according to the BMS (Basso Mouse Scale) test for three weeks of treatment with daily (s.c.) doses of 0.1 mg/kg CsA or FK506. In both cases, locomotor function was significantly recovered. No differences were observed in KO mice for FKBP51 or FKBP52 versus wild type controls. However FKBP51 KO mice showed stronger recovery, whereas FKBP52 KO mice recovered at lower rate, confirming in vivo that both IMMs are antagonistically related to neuroregeneration. Grip strength, balance and motor coordination were evaluated in drug-treated mice by Rotarod performance test, and locomotor behaviour was analyzed using ANY-Maze Video Tracking System by Stoelting Co. Results led to equal conclusions as the BMS test. To test the putative neuroprotective action of these drugs against neurocortical brain hypoxia, mice were injected with 2 µl 50 mM CoCl2 in the frontoparietal cortex using a stereotaxic apparatus. Rotarod tests showed recovery of motor coordination in both CsA- and FK506-treated mice, although the ANY-Maze analysis demonstrated that FK506-treated mice have a better performance. We conclude that IMMs activated by their specific ligands play key neurotrophic roles.