title: Ketamine Exhibits Different Neuroanatomical Profile After Mammalian Target of Rapamycin Inhibition in the Prefrontal Cortex: the Role of Inflammation and Oxidative Stress.
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.
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.
authors: Helena M
authors: HM
authors: Abelaira
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil. gislainezilli@hotmail.com.
authors: Gislaine Z
authors: GZ
authors: Réus
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.
authors: Zuleide M
authors: ZM
authors: Ignácio
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.
authors: Maria Augusta B
authors: MAB
authors: Dos Santos
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.
authors: Airam B
authors: AB
authors: de Moura
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.
authors: Danyela
authors: D
authors: Matos
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.
authors: Júlia P
authors: JP
authors: Demo
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.
authors: Júlia B I
authors: JBI
authors: da Silva
authors: Laboratory of Clinical and Experimental Pathophysiology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina (UNISUL), Tubarão, SC, Brazil.
authors: Lucineia G
authors: LG
authors: Danielski
authors: Laboratory of Clinical and Experimental Pathophysiology, Postgraduate Program in Health Sciences, University of Southern Santa Catarina (UNISUL), Tubarão, SC, Brazil.
authors: Fabricia
authors: F
authors: Petronilho
authors: Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: André F
authors: AF
authors: Carvalho
authors: Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, 88806-000, Brazil.|Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.|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.|Neuroscience Graduate Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: João
authors: J
authors: Quevedo
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D004660:Encephalitis / Q000517:prevention & control*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D000975:Antioxidants; D007649:Ketamine; D020123:Sirolimus
keywords: Animal model; Inflammation; Ketamine; Major depressive disorder; Oxidative stress; mTOR