Immunophilin FKBP52 mediates the in vivo neuroregenerative effect of the macrolide FK506

GALIGNIANA MD; DANERI C; PATIÑO M

Congreso; LXV Reunión Anual de SAIC; 2020

SAIC

The immunosuppressant drug FK506 (or tacrolimus) is a macrolide that binds selectively to immunophilinsbelonging to the FK506-binding protein (FKBP) subfamily, which are abundantly expressed proteins in neuronsof the peripheral and central nervous systems. Interestingly, it has been reported that FK506 increases neuriteoutgrowth in cell cultures, implying a potential impact in putative treatments of neurodegenerative disordersand injuries of the nervous system. Nonetheless, the mechanism of action of this compound is poorly understoodand remains to be elucidated, with the only certainty that its neurotrophic effect is independent of its primaryimmunosuppressant activity. In this study it is demonstrated that FK506 shows efficient neurotrophic action invitro and profound effects on the recovery of locomotor activity, behavioural features, and erectile function ofmice that underwent surgical spinal cord injury. The recovery of the locomotor activity was studied in knock-outmice for either immunophilin, FKBP51 or FKBP52. The experimental evidence demonstrates that the neurotrophicactions of FK506 are the consequence of its binding to FKBP52, whereas FK506 interaction with theclose-related partner immunophilin FKBP51 antagonises the function of FKBP52. Importantly, our study alsodemonstrates that other immunophilins do not replace FKBP52. It is concluded that the final biological responseis the resulting outcome of the drug binding to both immunophilins, FKBP51 and FKBP52, the latter being theone that commands the dominant neurotrophic action in vivo.