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Keap1/Nrf2/HO-1 signaling pathway contributes to p-chlorodiphenyl diselenide antidepressant-like action in diabetic mice

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Abstract

Rationale

The association between depression and diabetes has been recognized for many years, but the nature of this relationship remains uncertain.

Objectives

This study investigated the antidepressant-like effect of (p-ClPhSe)2 on mice made diabetic by streptozotocin (STZ) and the contribution of cerebral cortical Keap1/Nrf2/HO-1 signaling pathway for this effect.

Methods

Male adult Swiss mice received streptozotocin (STZ, 200 mg/kg, i.p.) to induce diabetes (glycemia ≥ 200 mg/dl) or citrate buffer (5 ml/kg, control group). The mice were treated with (p-ClPhSe)2 at the dose of 5 mg/kg, i.g., for 7 days. Mice performed behavior tests, tail suspension (TST), and forced swimming tests (FST), to evaluate depressive-like phenotype.

Results

Diabetic mice showed an increase in immobility time in the TST and FST when compared to the control group. The protein contents of Keap1/Nrf2/HO-1 pathway were decreased in the cerebral cortex of diabetic mice. Diabetic mice had an increase in the relative adrenal weight and a decrease in the protein content of glucocorticoid receptor. The levels of TBARS and RS and SOD activity were found altered in the cerebral cortex of diabetic mice. The number of FJC-positive cells was increased in the cerebral cortex of diabetic mice. Treatment with (p-ClPhSe)2 was effective against depressive-like phenotype, oxidative stress, and FJC-positive cells of diabetic mice. (p-ClPhSe)2 did not reverse the parameters of HPA axis evaluated in this study. (p-ClPhSe)2 modulated the cerebral cortical Keap1/Nrf2/HO-1 pathway in diabetic mice.

Conclusions

This study demonstrates the contribution of cerebral cortical Keap1/Nrf2/HO-1 pathway in the (p-ClPhSe)2 antidepressant-like action in diabetic mice.

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Funding

Universidade Federal de Santa Maria (UFSM), Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS, Grant number 17/2551-0000), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Grant number 407118/2018-7), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PROEX #23038.005848/2018-31) provided financial support. C.W.N is recipient of CNPq fellowship (#304864/2015-3).

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Correspondence to Cristina W. Nogueira.

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Zborowski, V.A., Heck, S.O., Vencato, M. et al. Keap1/Nrf2/HO-1 signaling pathway contributes to p-chlorodiphenyl diselenide antidepressant-like action in diabetic mice. Psychopharmacology 237, 363–374 (2020). https://doi.org/10.1007/s00213-019-05372-3

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Keywords

  • Depressive-like
  • Organoselenium
  • Selenium
  • Keap1/Nrf2/HO-1
  • Diabetes