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Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress

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Abstract

Studies indicated that mammalian target of rapamycin (mTOR), oxidative stress, and inflammation are involved in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has been identified as a novel MDD therapy; however, the antidepressant mechanism is not fully understood. In addition, the effects of ketamine after mTOR inhibition have not been fully investigated. In the present study, we examined the behavioral and biochemical effects of ketamine in the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens after inhibition of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol) or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). Immobility was assessed in forced swimming tests, and then oxidative stress parameters and inflammatory markers were evaluated in the brain and periphery. mTOR activation in the PFC was essential to ketamine’s antidepressant-like effects. Ketamine increased lipid damage in the PFC, hippocampus, and amygdala. Protein carbonyl was elevated in the PFC, amygdala, and NAc after ketamine administration. Ketamine also increased nitrite/nitrate in the PFC, hippocampus, amygdala, and NAc. Myeloperoxidase activity increased in the hippocampus and NAc after ketamine administration. The activities of superoxide dismutase and catalase were reduced after ketamine administration in all brain areas studied. Inhibition of mTOR signaling pathways by rapamycin in the PFC was required to protect against oxidative stress by reducing damage and increasing antioxidant enzymes. Finally, the TNF-α level was increased in serum by ketamine; however, the rapamycin plus treatment group was not able to block this increase. Activation of mTOR in the PFC is involved in the antidepressant-like effects of ketamine; however, the inhibition of this pathway was able to protect certain brain areas against oxidative stress, without affecting inflammation parameters.

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Acknowledgments

Laboratory of Neurosciences (Brazil) is a center within the National Institute for Molecular Medicine (INCT-MM) and a member of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (JQ and GZR), FAPESC (JQ), and Instituto Cérebro e Mente, UNESC (JQ). JQ, FP, and AFC are CNPq Research Fellows. HMA has CAPES studentship. Center for Translational Psychiatry (USA) is funded by the Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston.

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Authors and Affiliations

  1. Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil

    Helena M. Abelaira, Gislaine Z. Réus, Zuleide M. Ignácio, Maria Augusta B. dos Santos, Airam B. de Moura, Danyela Matos, Júlia P. Demo, Júlia B. I. da Silva & João Quevedo

  2. Laboratory of Clinical and Experimental Pathophysiology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina (UNISUL), Tubarão, SC, Brazil

    Lucineia G. Danielski & Fabricia Petronilho

  3. Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil

    André F. Carvalho

  4. Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    João Quevedo

  5. Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    João Quevedo

  6. Neuroscience Graduate Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA

    João Quevedo

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  1. Helena M. Abelaira
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  2. Gislaine Z. Réus
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  3. Zuleide M. Ignácio
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  4. Maria Augusta B. dos Santos
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  5. Airam B. de Moura
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  8. Júlia B. I. da Silva
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  9. Lucineia G. Danielski
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Correspondence to Gislaine Z. Réus.

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Abelaira, H.M., Réus, G.Z., Ignácio, Z.M. et al. Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress. Mol Neurobiol 54, 5335–5346 (2017). https://doi.org/10.1007/s12035-016-0071-4

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