The protective effect of tianeptine on Gp120‐induced apoptosis in astroglial cells: role of GS and NOS, and NF‐κB suppression

Abstract

Tianeptine is an antidepressant affecting the glutamatergic system. In spite of its proven clinical efficacy, molecular effects of tianeptine are not entirely clear. Tianeptine modulates cytokine expression in the CNS and protects the hippocampus from chronic stress effects. HIV infection is associated with inflammation and neuronal loss, causing HIV-associated dementia (HAD). The human immunodeficiency virus type-1 glycoprotein gp120 has been proposed as a likely aetiological agent of HAD. In this study, we determined whether tianeptine protects astroglial cells from the neurodegenerative effects of gp120. EXPERIMENTAL APPROACHHuman astroglial cells were treated with gp120 and tianeptine, and viability and apoptosis was monitored by TUNEL, annexin V, and activated caspase-3 staining and flow cytometry. Protein levels of glutamine synthase (GS), inducible and constitutive nitric oxide synthases (iNOS, cNOS) and nuclear factor kB (NF-kB) pathway were determined by Western blot analysis. The respective activities were assessed indirectly by measuring glutamine and nitrite concentrations or by luciferase reporter assays. KEY RESULTSTianeptine showed an anti-apoptotic effect and prevented caspase-3 activation by gp120. The mechanism of tianeptine's action involved GS and cNOS stabilization and iNOS suppression. Moreover, tianeptine increased IkB-a levels in the absence of gp120 and blocked its degradation in response to gp120. This correlated with the suppression of basal and gp120-induced NF-kB transcriptional activity. CONCLUSIONS AND IMPLICATIONSTianeptine clearly exerts neuroprotective effects in vitro by suppressing the molecular pro-inflammatory effects of gp120. Studies in animal models should be performed to evaluate the potential of tianeptine as a treatment for HAD. BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 1590 British Journal of Pharmacology (2011) AbbreviationsAbs, antibodies; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CMV, cytomegalovirus; cNOS, constitutive nitric oxide synthase; FITC, fluorescein isothiocyanate; GLT1, glutamate transporter 1; Gp120, glycoprotein 120; GS, glutamine synthase; HIV, human immunodeficiency virus; IkB, inhibitor of nuclear factor

Oxidized LDL attenuates protective autophagy and induces apoptotic cell death of endothelial cells: Role of oxidative stress and LOX-1 receptor expression

“…Furthermore, recent evidence also shows that ROS overproduction blocks PI-3-kinase/Akt pathway causing an early impairment of constitutive endothelial NOS (eNOS) activity through the inhibition of its phosphorylation/activation, an effect due to LOX-1 activation [22][23][24][25]. This event was clearly observed also in our experimental settings as the incubation of BAECs with oxyLDL elicited a time-dependent decrease in serine 1179 phosphorylation of eNOS suggesting that its inactivation affects physiological NO-operated the suppression of iNOS gene expression normally caused by inactivated transcriptional factor Nuclear Factor kB (NF-kB) [5,[26][27][28][29][30][31]. ONOO − overproduction, derived by high O 2 − levels on the one hand and by iNOS-induced NO overproduction on the other hand, has been correlated with endothelial cell death via apoptosis [32][33][34].…”

Retracted: Anti‐inflammatory properties of tianeptine on lipopolysaccharide‐induced changes in microglial cells involve toll‐like receptor‐related pathways

“…Many findings indicate that NF-jB performs a pivotal role in inflammation due to its ability to induce the transcription of proinflammatory genes and the consequent up-regulation of cytokines including TNF-a and IL-6 (Majumder et al 1998;Lee 2013). Furthermore, several studies have shown that NF-jB is also one of the most important signaling pathways mediating the expression of iNOS after the addition of a variety of extracellular mediators, including endotoxin and proinflammatory cytokines (Janda et al 2011).…”

Glutamate metabolism and HIV-associated neurocognitive disorders

“…The antidepressant tianeptine, that interferes with the effects on glutamatergic transmission (Piroli et al , 2013; Reagan et al , 2004; Svenningsson et al , 2007) and decreases the production of inflammatory cytokines (Castanon et al , 2004; Mutlu et al , 2012), increased cell viability and prevented the loss of astrocytic GS levels caused by gp120. Further examination of the mechanism of protection of tianeptine revealed that it prevented the activation of NF-κB by controlling the levels of IκB-α and thus in turn modulating the expression of inducible nitric oxide synthase (iNOS) and the stabilization of constitutive nitric oxide synthase (cNOS) (Janda et al , 2011). Collectively, these data demonstrate that HIV-mediated glutamate toxicity results from the combination of persistent inflammatory stimuli, unresolved oxidative damage, and direct damage by viral proteins (i.e.…”

“…According to various groups, blocking the enzymatic activity of glutaminase (Erdmann et al , 2009; Erdmann et al , 2006; Ye et al , 2013; Zhao, 2004; Zhao L, 2012) or promoting the conversion of glutamate to glutamine via GS (Janda et al , 2011; Kleinkauf-Rocha et al , 2013; Muscoli et al , 2005; Visalli et al , 2007) may be an alternative strategy in preventing HIV-1 neuropathology. ROS and RNS are known to influence glutamate handling, as antioxidant compounds are able to restore glutamatergic homeostasis that may result from viral replication or protein-mediated oxidative effects on CNS cultures and murine models of HIV-1.…”

“…Despite the need to unravel molecular mechanisms whereby the antioxidant/oxidant balance correlates with glutamate dysregulation, in a similar fashion that involves overcoming oxidative stress levels, the clinically approved antidepressant tianeptine also shows potential for reducing the development of the neurotoxic effects of HIV CNS pathology. Tianeptine protects astrocytic cultures from the pro-apoptotic and neurodegenerative effects of HIV-1 gp120 IIIB through a mechanism that involves the inactivation of NF-κB, suppression of iNOS, and stabilization of cNOS, which final process results in reduced nitric oxide levels (Janda et al , 2011). Similar findings show the involvement of iNOS and GS pathway as a link between glutamate-mediated insults and the response to inflammatory stimulus by pro-inflammatory cytokines (Muscoli et al , 2005).…”