Creatine and Alpha-Lipoic Acid Antidepressant-Like Effect Following Cyclosporine A Administration

Cyclosporine A (CYA), is an immunosuppressant drug used to prevent graft rejection, but it may initiate neuropsychological problems such as depression. The aim was to evaluate the antidepressant-like effects of creatine (Crt), a mediator of oxidative phosphorylation, and alpha-lipoic acid (ALA), a cofactor for the mitochondrial respiratory chain following CYA administration.

Female mice (27 ± 2 g) were used, immobility time during the forced swimming test (FST) was measured, and hippocampal brain-derived neurotrophic factor (BDNF) level was evaluated. CYA 20 mg/kg, ALA 40 mg/kg, fluoxetine 20 mg/kg, and Crt 10 mg/kg (oral) were administered for 6 consecutive days, and the tests were performed on day 7.

ALA, but not Crt, treatment alone decreased immobility in the FST (i.e., decreases depression-like behavior). CYA administration increased immobility in the FST (175.1 ± 13.16 s, vs. vehicle 130.9 ± 13.5 s, p= 0.0364), and this depression-like behavior was prevented by co-administrating, ALA (100 ± 15.9 s, p= 0.020) or Crt (93.5 ± 16.6, p= 0.009) and the positive control, fluoxetine. Notably, there was a synergistic effect of Crt-ALA co-administration since CYA-induced immobility was lower in this group than in the groups pretreated with Crt or ALA. These behavioral changes were observed without treatment effects on locomotor activity in an open field. CYA treatment increased hippocampal BDNF protein levels prevented by co-administration of ALA (with or without Crt) or fluoxetine.

CYA-induced depression-like behavior might be related to hippocampal mitochondrial dysfunction as ALA and Crt prevented the development of this behavioral phenotype. ALA, similar to fluoxetine, prevented BDNF alteration and its possible neurological changes.