Lithium and tamoxifen modulate cellular plasticity cascades in animal model of mania.
Lithium (Li) is the main mood stabilizer and acts on multiple biochemical targets, leading to neuronal plasticity. Several clinical studies have shown that tamoxifen (TMX) - a protein kinase C (PKC) inhibitor - has been effective in treating acute mania. The present study aims to evaluate the effects of TMX on biochemical targets of Li, such as glycogen synthase kinase-3β (GSK-3β), PKC, PKA, CREB, BDNF and NGF, in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were treated with d-AMPH (2mg/kg, once a day) or saline (Sal; NaCl 0.9%, w/v), Li (47.5 mg/kg, intraperitoneally (i.p.), twice a day) or TMX (1 mg/kg i.p., twice a day) or Sal in protocols of reversion and prevention treatment. Locomotor behavior was assessed using the open-field task, and protein levels were measured by immunoblot. Li and TMX reversed and prevented d-AMPH-induced hyperactivity. Western blot showed that d-AMPH significantly increased GSK-3 and PKC levels, and decreased pGSK-3, PKA, NGF, BDNF and CREB levels in the structures analyzed. Li and TMX were able to prevent and reverse these changes induced by d-AMPH in most structures evaluated. The present study demonstrated that the PKC inhibitor modulates the alterations in the behavior, neurotrophic and apoptosis pathway induced by d-AMPH, reinforcing the need for more studies of PKC as a possible target for treatment of bipolar disorder.
Laboratory of Neurosciences, National Institute for Translational Medicine, and Center of Excellence in Applied Neurosciences of Santa Catarina, Postgraduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil.
Kelen
K
Cechinel-Recco
Samira S
SS
Valvassori
Roger B
RB
Varela
Wilson R
WR
Resende
Camila O
CO
Arent
Marcelo F
MF
Vitto
Gabrielle
G
Luz
Claudio T
CT
de Souza
João
J
Quevedo
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001714:Bipolar Disorder / Q000188:drug therapy*; D015153:Blotting, Western; D003913:Dextroamphetamine / Q000633:toxicity; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000494:pharmacology*
D018692:Antimanic Agents; D013629:Tamoxifen; D008094:Lithium; D011493:Protein Kinase C; D003913:Dextroamphetamine