Figure 1
From: Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression
Oxidative stress in vulnerability to depression. Restoration of redox homeostasis and reversion of the phenotype of vulnerability with antioxidant treatment. (a) The experimental 'double-hit' design involved subjecting rats to SD (D-3-D0) followed, 4 weeks later, by CMS. Evaluation of redox parameters was performed 5 days (D5), 11 days (D11) and 4 weeks (D31) after the end of the social defeat procedure. Neuroanatomical parameters were measured at D11 and D31. Depression-like phenotype (helplessness behavior, decrease in sweet water consumption, HPA, body weight) was evaluated at D31 and at the end of the double-hit procedure, at D53. Animals were treated with 7,8-DHF or with Tempol: 1- for 7,8-DHF treatment, administrations were performed at D5, D7 and D9; 2- a 15-day-long treatment with Tempol started 11 days after SD (D11). (b) Oxidative stress results in lipid oxidative damage (lipid peroxidation, MDA) and in decreased activity of the sensitive redox aconitase in vulnerable (V, n=6–8) rats, but not in NV (n=7–8) animals, 31 days after the end of the SD procedure (D31). (c) The quantity and activity of SOD, which catalyzes the ROS hydrogen peroxide (H2O2) production and of the antioxidant systems involved in the reduction of ROS H2O2 to water, peroxiredoxin-2 (Prx-2) and its inactive form (Prx-sulfinic [SO2]/sulfonic [SO3]), glutathione peroxidase (GPx) and catalase activities, were evaluated in V animals and NV animals. The peroxiredoxin-2 antibody targets both the active and inactive forms of the enzyme (total). The Prx-SO2/SO3 antibody targets the inactive form of enzyme. SOD activity and the inactive form of Prx-2 were increased in V animals indicating oxidative stress. (d) Effects of a 15-day-long treatment with Tempol starting 11 days after SD (D11), when vulnerable (V) could be identified based on serum BDNF levels. Tempol normalized all signs of oxidative stress in V animals to control and NV levels. Tempol prevented lipid oxidative damage, decrease in aconitase, increase in SOD, and restored the active form of peroxiredoxin-2 (Prx-2). Glutathione peroxidase (GPx) and catalase activities were not affected (C: n=5–6; NV: n=6–8; V: n=5–6). (e) Tempol restored anatomical integrity (total apical dendrite length and spine density) of CA3 hippocampal neurons in V animals (n=4–5). (f) Tempol prevented the appearance of a depression-like phenotype of V animals after CMS as assessed by immobility time in the forced swim test, sweet water consumption and activity of HPA axis (C: n=6–8; NV: n=10; V: n=7–9). See also Supplementary Figure S1d for proteomic analysis 31 days after SD. The results of statistical analyses are presented in Supplementary Table S1A1-2. *P<0.05 vs C animals; aP<0.05 vs NV group; †P<0.05 vs the corresponding Tempol-treated group. BDNF, brain-derived neurotrophic factor; CMS, chronic mild stress; DHF, dihydroxyflavone; HPA, hypothalamic–pituitary–adrenal hyperactivity; NV, non-vulnerable; ROS, reactive oxygen species; SD, social defeat; SOD, superoxide dismutase.
