Involvement of PI3K, GSK-3β and PPARγ in the antidepressant-like effect of folic acid in the forced swimming test in mice

Abstract

Preclinical and clinical studies indicate that deficiency in folic acid plays a role in the pathophysiology of depression. Considering that alterations in the signaling pathways that regulate neuroplasticity and cellular survival are implicated in depressive disorders, the present study investigated the involvement of the phosphoinositide 3-kinase (PI3K), glycogen synthase kinase-3 (GSK-3β), and peroxisome proliferator-activated receptor-γ (PPARγ) in the antidepressant-like effect of folic acid in the forced swimming test (FST). The intracerebroventricular (i.c.v.) pre-treatment of mice with LY294002 (10 nmol/site, a PI3K inhibitor) or GW-9662 (1 µg/site, a PPARγ antagonist) prevented the antidepressant-like effect of folic acid (50 mg/kg, p.o.) in the FST. In addition, the administration of subeffective doses of the selective GSK-3β inhibitor, AR-A014418 (3 mg/kg, i.p.), a non-selective GSK-3β inhibitor, lithium chloride (10 mg/kg, p.o) or a PPARγ agonist, rosiglitazone (1 µg/site, i.c.v.) in combination with a subeffective dose of folic acid (10 mg/kg, p.o.) significantly reduced the immobility time in the FST as compared with either drug alone, without altering the locomotor activity. These results indicate that the antidepressant-like effect of folic acid in the FST might be dependent on inhibition of GSK-3β and activation of PPARγ, reinforcing the notion that these are important targets for antidepressant activity.

Akt Mediates GSK-3β Phosphorylation in the Rat Prefrontal Cortex during the Process of Ketamine Exerting Rapid Antidepressant Actions

“…1); however, they significantly downregulated mTOR signaling proteins, p-mTOR and p-p70S6K (p < 0.05; fig. 2, 3), which is consistent with a previous animal study [13]. …”

“…One hour later, rats were subjected to the FST for 10 min and the data on immobility time were recorded for analysis, as described above. A decrease in the immobility time is indicative of antidepressant-like effects [13,14]. …”

Glycine site N-methyl-D-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats

“…Further methodological details, including those for tissue sample preparation, 34 Western blot assays, intracerebral cannula implantation and intracranial injections, 35,36 together with detailed experimental design of the 6 main experiments performed [37][38][39] are included in Appendix 1 (available at cma.ca/jpn).…”

Akt2 Deficiency is Associated with Anxiety and Depressive Behavior in Mice

“…Akt phosphorylates and thus inhibits glycogen synthase 3 (GSK3). PI3K-Akt signaling has been discussed to mediate antidepressant effects and constitutes an important signaling pathway in the subcellular integration of synaptic neurotransmission [11,12]. This pathway also modulates neuronal cell proliferation, migration, and plasticity [12].…”