Involvement of PI3K, GSK-3β and PPARγ in the antidepressant-like effect of folic acid in the forced swimming test in mice.
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.
Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Josiane
J
Budni
Kelly R
KR
Lobato
Ricardo W
RW
Binfaré
Andiara E
AE
Freitas
Ana Paula
AP
Costa
Maria Dolores
MD
Martín-de-Saavedra
Rodrigo B
RB
Leal
Manuela G
MG
Lopez
Ana Lúcia S
AL
Rodrigues
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism; D005492:Folic Acid / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D013550:Swimming
D000928:Antidepressive Agents; D047495:PPAR gamma; D005492:Folic Acid; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3