Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effect of Creatine

Mol Neurobiol (2016) 53:29542968 DOI 10.1007/s12035-015-9192-4

Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effectof Creatine

Mauricio P. Cunha1 & Josiane Budni1,2 & Fabiana K. Ludka1,3 & Francis L. Pazini1 &

Julia Macedo Rosa1 & gatha Oliveira1 & Mark W. Lopes1 & Carla I. Tasca1 &

Rodrigo B. Leal1 & Ana Lcia S. Rodrigues1

Received: 2 February 2015 /Accepted: 22 April 2015 /Published online: 6 May 2015 # Springer Science+Business Media New York 2015

Abstract Creatine has been proposed to exert beneficial effects in the management of depression, but the cell signaling pathways implicated in its antidepressant effects are not well established. This study investigated the involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. The acute treatment of mice with creatine (1 mg/kg, po) increased the Akt and P70S6K phosphorylation, and HO-1, GPx and PSD95 immunocontents. The pretreatment of mice with LY294002 (10 nmol/mouse, icv, PI3K inhibitor), wortmannin(0.1 g/mouse, icv, PI3K inhibitor), ZnPP (10 g/mouse, icv, HO-1 inhibitor), or rapamycin (0.2 nmol/mouse, icv, mTOR inhibitor) prevented the antidepressant-like effect of creatine (1 mg/kg, po) in the TST. In addition, the administration of subeffective dose of either the selective GSK3 inhibitor ARA014418 (0.01 g/mouse, icv), the nonselective GSK3 inhibitor lithium chloride (10 mg/kg, po), or the HO-1 inductor CoPP (0.01 g/mouse, icv), in combination with a subeffective dose of creatine (0.01 mg/kg, po) reduced the immobility time in the TST as compared with either drug alone. No treatment caused significant changes in the locomotor activity of mice. These results indicate that the antidepressant-like effect of creatine in the TST depends on

the activation of Akt, Nrf2/HO-1, GPx, and mTOR, and GSK3 inhibition.

Keywords Antidepressant . Akt . Creatine . Glycogen kinase 3 . Heme oxygenase-1 . mTOR

AbbreviationsARA014418 N-(4-Methoxybenzyl)-N-(5-nitro-1,3-thiazol-2-yl)ureaARE Antioxidant response elementCoPP Protoporphyrin IX cobalt chlorideERK 1/2 Extracellular-signal-regulated kinases 1/2 DMSO Dimethyl sulfoxideGPx Glutathione peroxidaseGSK3 Glycogen synthase kinase-3HO-1 Heme oxygenase-1icv IntracerebroventricularmTOR Mammalian target of rapamycinNMDA N-Methyl-D-aspartateNrf2 Nuclear factor-erythroid-derived 2-related factor-2PI3K Phosphatidylinositol 3-kinasePKA cAMP-dependent protein kinasePKC Protein kinase Cpo per osRapamycin 23,27-epoxy-3H-pyrido[2,1c][1,4] oxaazacyclohentriacontine solutionTST Tail suspension testLY294002 2-(4-Morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochlorideZnPP Protoporphyrin IX zinc(II)

* Mauricio P. Cunha [email protected]

1 Department of Biochemistry, Center of Biological Sciences,Universidade Federal de Santa Catarina, 88040-900 Florianpolis, SC, Brazil

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