NEUROPROTECTIVE EFFECT OF FK506 AGAINST OXIDATIVE STRESS

ROSBACO, M.E., DANERI-BECERRA C., GALIGNIANA M.D., RAMOS-HRYB, A.B.

Congreso; XXXIV Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2019

SAN

Immunophilins FKBP51 and FKBP52 bind the macrolide FK506. Previously, we reported that FK506 favours neurodifferentiation and the neuroregeneration. Here, we analyzed whether FK506 also shows neuroprotective action to oxidative stress. A rapid neuritogenesis was observed in undifferentiated N2a cells treated with 1 µM FK506 in the absence of trophic factors, including serum. Then, 250 µm slices from prefrontal cortexes from Balb-C mice (60 d) were prestabilized for 72 h and incubated for 4 h with 200 µM H2O2. Western blots revealed the induction of Hsp90, Hsp70, FKBP52 and p23, which was prevent by 1 h pretreatment with 1 M FK506. While controls showed three phosphorylated isoforms of FKBP51, treatment with H2O2 only exhibited the least phosphorylated band. In turn, pretreatment with FK506 protected the phosphorylated isoforms, and treatments with FK506 alone showed the intermediate phosphorylated band (reactive to anti-P-Tyr IgG), suggesting that this isoform may be responsible for the mechanism of action of the drug. Hypoxia was generated by stereotactic injection of 2 l 50 mM CoCl2 in the prefrontal cortex of the right hemisphere, and the contralateral was used as control. The overexpression of chaperones was partially impaired by pretreatment with FK506. Rotarod and open field (AnyMaze) studies evidenced better and faster recovery of FK506-treated mice. This study shows for the first time the neuroprotective effect of FK506 against oxidative stress in nervous tissue.