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

被引：12

作者：

Abelaira, Helena M. ^{[1
]}

Reus, Gislaine Z. ^{[1
]}

Ignacio, Zuleide M. ^{[1
]}

dos Santos, Maria Augusta B. ^{[1
]}

de Moura, Airam B. ^{[1
]}

Matos, Danyela ^{[1
]}

Demo, Julia P. ^{[1
]}

da Silva, Julia B. I. ^{[1
]}

Danielski, Lucineia G. ^{[2
]}

Petronilho, Fabricia ^{[2
]}

Carvalho, Andre F. ^{[3
,4
]}

Quevedo, Joao ^{[1
,5
,6
,7
]}

机构：

[1] Univ Southern Santa Catarina, Hlth Sci Unit, Grad Program Hlth Sci, Lab Neurosci, BR-88806000 Criciuma, SC, Brazil

[2] Univ Southern Santa Catarina UNISUL, Lab Clin & Expt Pathophysiol, Postgrad Program Hlth Sci, Tubarao, SC, Brazil

[3] Univ Fed Ceara, Fac Med, Dept Clin Med, Fortaleza, CE, Brazil

[4] Univ Fed Ceara, Fac Med, Translat Psychiat Res Grp, Fortaleza, CE, Brazil

[5] Univ Texas Hlth Sci Ctr Houston, Ctr Translat Psychiat, Dept Psychiat & Behav Sci, Sch Med, Houston, TX 77030 USA

[6] Univ Texas Hlth Sci Ctr Houston, Ctr Excellence Mood Disorders, Dept Psychiat & Behav Sci, Sch Med, Houston, TX 77030 USA

[7] Univ Texas Hlth Sci Ctr Houston, Neurosci Grad Program, Grad Sch Biomed Sci, Houston, TX 77030 USA

来源：

MOLECULAR NEUROBIOLOGY | 2017年 / 54卷 / 07期

关键词：

mTOR; Oxidative stress; Inflammation; Ketamine; Animal model; Major depressive disorder; FORCED SWIMMING TEST; CHRONIC MILD STRESS; METHYL-D-ASPARTATE; NEGATIVE T-CELLS; WORKING-MEMORY; ANTIDEPRESSANT DRUGS; NEUROTROPHIC FACTOR; ANIMAL-MODEL; ACTIVATION; RATS;

D O I：

10.1007/s12035-016-0071-4

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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-alpha 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.

引用

页码：5335 / 5346

页数：12

共 98 条

[11]

Chaturvedi H. K., 1999, Indian Journal of Experimental Biology, V37, P952

[12] Efferent projections of infralimbic and prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca fuscata [J].