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Artículo

Proof that the high molecular weight immunophilin FKBP52 mediates the in vivo neuroregenerative effect of the macrolide FK506

Daneri Becerra, Cristina del RosarioIcon ; Patiño Gaillez, Michelle Geraldine Sissel; Galigniana, Mario DanielIcon
Fecha de publicación: 12/2020
Editorial: Pergamon-Elsevier Science Ltd
Revista: Biochemical Pharmacology
ISSN: 0006-2952
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Bioquímica y Biología Molecular

Resumen

The immunosuppressant drug FK506 (or tacrolimus) is a macrolide that binds selectively to immunophilins belonging to the FK506-binding protein (FKBP) subfamily, which are abundantly expressed proteins in neurons of the peripheral and central nervous systems. Interestingly, it has been reported that FK506 increases neurite outgrowth in cell cultures, implying a potential impact in putative treatments of neurodegenerative disorders and injuries of the nervous system. Nonetheless, the mechanism of action of this compound is poorly understood and remains to be elucidated, with the only certainty that its neurotrophic effect is independent of its primary immunosuppressant activity. In this study it is demonstrated that FK506 shows efficient neurotrophic action in vitro and profound effects on the recovery of locomotor activity, behavioural features, and erectile function of mice that underwent surgical spinal cord injury. The recovery of the locomotor activity was studied in knock-out mice for either immunophilin, FKBP51 or FKBP52. The experimental evidence demonstrates that the neurotrophic actions of FK506 are the consequence of its binding to FKBP52, whereas FK506 interaction with the close-related partner immunophilin FKBP51 antagonises the function of FKBP52. Importantly, our study also demonstrates that other immunophilins do not replace FKBP52. It is concluded that the final biological response is the resulting outcome of the drug binding to both immunophilins, FKBP51 and FKBP52, the latter being the one that commands the dominant neurotrophic action in vivo.
Palabras clave: FKBP51 , FKBP52 , IMMUNOPHILINS , NEUROREGENERATION , SPINAL CORD INJURY , TACROLIMUS
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info:eu-repo/semantics/restrictedAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/132948
DOI: http://dx.doi.org/10.1016/j.bcp.2020.114204
Colecciones
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Citación
Daneri Becerra, Cristina del Rosario; Patiño Gaillez, Michelle Geraldine Sissel; Galigniana, Mario Daniel; Proof that the high molecular weight immunophilin FKBP52 mediates the in vivo neuroregenerative effect of the macrolide FK506; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 182; 12-2020; 1-10
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