Changes in hippocampal gene expression by 7‐nitroindazole in rats submitted to forced swimming stress

Abstract

Nitric oxide (NO) is an atypical neurotransmitter that has been related to the pathophysiology of major depression disorder. Increased plasma NO levels have been reported in depressed and suicidal patients. Inhibition of neuronial nitric oxide synthase (nNOS), on the other hand, induces antidepressant effects in clinical and pre-clinical trials. The mechanisms responsible for the antidepressant-like effects of nNOS inhibitors, however, are not completely understood. In this study, genomic and proteomic analyses were used to investigate the effects of the preferential nNOS inhibitor 7-nitroindazole (7-NI) on changes in global gene and protein expression in the hippocampus of rats submitted to forced swimming test (FST). Chronic treatment (14 days, i.p.) with imipramine (15 mg/kg daily) or 7-NI (60 mg/kg daily) significantly reduced immobility in the FST. Saturation curves for Serial analysis of gene expression libraries showed that the hippocampus of animals submitted to FST presented a lower number of expressed genes compared to non-FST stressed groups. Imipramine, but not 7-NI, reverted this effect. GeneGo analyses revealed that genes related to oxidative phosphorylation, apoptosis and survival controlled by HTR1A signaling and cytoskeleton remodeling controlled by Rho GTPases were significantly changed by FST. 7-NI prevented this effect. In addition, 7-NI treatment changed the expression of genes related to transcription in the cAMP response element-binding pathway. Therefore, this study suggests that changes in oxidative stress and neuroplastic processes could be involved in the antidepressant-like effects induced by nNOS inhibition.

Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats

“…NO has been involved in many signaling pathways related to stress and MDD, as well as to the antidepressant activity of classical drugs (Wegener et al, 2003;Joca & Guimarães, 2006;Wegener & Volke, 2010;Hiroaki-Sato et al, 2014). Corroborating the results from the present study, pharmacological inhibition of NOS induces antidepressant-like effects in the learned helplessness paradigm (Stanquini et al, 2017) and other models, such as forced swimming test (Ferreira et al, 2012;Montezuma et al, 2012;Sales et al, 2017) and unpredictable chronic stress (Yazir et al, 2012). Furthermore, activation and expression levels of NOS is attenuated by treatment with antidepressant drugs (Finkel et al, 1996;Wegener et al, 2003;Dhir & Kulkarni, 2007Zomkowski et al, 2010;Zhou et al, 2011;Bollinger et al, 2017).…”

Antidepressant action via the nitric oxide system: A pilot study in an acute depressive model induced by arginin.

“…The non-selective NOS inhibitor, l-N G -nitroarginine methyl ester (l-NAME), and the selective neuronal NOS inhibitor, 7-nitroindazole, induce dose-dependent antidepressant-like effects in the forced swimming test [7][8][9]. Furthermore, hippocampal NOS expression is significantly increased in depressed patients [10].…”

Chemically Bonding of Amantadine with Gardenamide A Enhances the Neuroprotective Effects against Corticosterone-Induced Insults in PC12 Cells

“…In depressed patients, hippocampal NOS expression is significantly increased [ 23 ]. Interestingly, it was found that the non-selective NOS inhibitor, L- N G -nitroarginine methyl ester (L-NAME), and the nNOS selective inhibitor 7-NI, induce dose-dependent antidepressant-like effects in the forced swimming test [ 24 , 25 , 26 ]. Another report showed that the clinical antidepressant Fluoxetine raises brain eNOS expression in the arginine depressive rat model [ 27 ].…”