The Increase in TNF-α Levels Is Implicated in NF-κB Activation and Inducible Nitric Oxide Synthase Expression in Brain Cortex after Immobilization Stress

Abstract

The underlying mechanisms by which physical or psychological stress causes neurodegeneration are still unknown. We have demonstrated that the high-output and long-lasting synthesizing source of nitric oxide (NO), inducible NO synthase (iNOS), is expressed in brain cortex after three weeks of repeated stress and that its overexpression accounts for the neurodegenerative changes found in this situation. Now we have found that a short duration of stress (immobilization for 6 h) also induces the expression of iNOS in brain cortex in adult male rats. In order to elucidate the possible mechanisms involved in iNOS expression, we have studied the role of the cytokine tumor necrosis factor-␣ (TNF-␣ ) released in brain during stress. We have shown that there is an increase in soluble TNF-␣ levels after 1 h of stress in cortex and that this is preceded by an increase in TNF-␣ -convertase (TACE) activity in brain cortex as soon as 30 min after immobilization. Stress-induced increase in both TACE activity and TNF-␣ levels seems to be mediated by excitatory amino acids since they can be blocked by MK-801 (dizocilpine) (0.2 mg/kg i.p.), an antagonist of the N-methyl-D-aspartate subtype of glutamate receptor. In order to study the role of TACE and TNF-␣ in iNOS induction, a group of animals were i.p. injected with the preferred TACE inhibitor BB1101 (2 and 10 mg/kg). Indeed, BB1101 inhibited iNOS expression induced by six hours of stress. In addition, we studied the role of the transcription factor nuclear factor B (NF-B), which is Gross and Wolin 1995). In this context, we have demonstrated that restrain stress induces a generalized increase in NO production (Leza et al. 1998) and that iNOS is expressed in brain cortex of rats exposed to stress (Olivenza et al. 2000). In support of the idea that iNOS is one of the mechanisms responsible for the functional damage in this condition, we have also demonstrated that aminoguanidine, a preferred inhibitor of iNOS, protects against cell damage produced by immobilization stress in rats (Olivenza et al. 2000; Madrigal et al. 2000), an experimental procedure used as a model of stress disorders in humans (Bremner et al. 1991).These evidences indicate that stress-induced iNOS expression in brain may mediate, at least in part, the anatomical and clinical features of neurotoxic damage found in animals and humans after exposure to uncontrollable stress (Sheline et al. 1996;Sapolsky 1996;Kim and Yoon 1998). This emphasizes the interest of the study of the mechanisms of iNOS expression after stress exposure. iNOS, as an inducible protein, is mainly regulated at the transcriptional level and is expressed after exposure of cells to several noxious agents such as cytokines and/or lipopolysaccharide (rev. in Nathan and Xie 1994). Although a considerable amount of evidence has shown that physical and psychological stress elevates plasma levels of several cytokines in animals and humans (i.e. TNF-␣ , IL-6, IFN ␥ ), the physiological significance of such elevation remains to be elucidated (Yamasu et a...

In VitroIschemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-α Pathway

“…Analysis of TACE protein by Western blot demonstrates its presence in control cortical cultures, consistently with the demonstration of TACE mRNA in rat and mouse adult brain (Kärkkäinen et al, 2000) and with our work demonstrating the presence of TACE protein in rat CNS (Hurtado et al, 2001;Cárdenas et al, 2002;Hurtado et al, 2002;Madrigal et al, 2002). Moreover, our present results indicate that TACE expression is increased in cultures exposed to IPC, also in agreement with our previous data showing TACE upregulation after IPC in in vivo models of cerebral ischemia (Cárdenas et al, 2002).…”

Stress-induced neuroinflammation: mechanisms and new pharmacological targets

“…One of these activators is TNF-α (31). The implication of TACE and TNF-α in stressinduced activation of NFκB was confirmed after finding that the pharmacological inhibition of TACE also blocked the stress-induced activation of NFκB (27).…”

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

“…Rodents exhibiting depression-like behaviors also have elevated brain cytokine levels (Goshen et al, 2008;Kreisel et al, 2014), and administration of inflammatory cytokines causes depressionlike behaviors in rodents (Bluthé et al, 2000;De la Garza et al, 2005;Dantzer and Kelley 2007;Palin et al, 2008;Fu et al, 2010). Acute inescapable tail shocks, acute or chronic restraint stress, and social defeat stress, all of which induce depressive-like behaviors in rodents, activate the inflammatory transcription factor nuclear factor-κB (NF-κB) and increase levels of the cytokines IL-1β, TNFα, IL-6 and IL-10 in rodent brains (Nguyen et al, 2000;Madrigal et al, 2002;O'Connor et al, 2003;Deak et al, 2003;Deak et al, 2005;Blandino et al, 2006;Blandino et al, 2009;Audet et al, 2011;Wohleb et al, 2011;You et al, 2011). In addition to inducing neuroinflammation, stress amplified the increases of inflammatory cytokines (e.g., IL-1β, TNFα) in rodent brains induced by peripheral administration of the inflammatory Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) (Quan et al, 2001;Johnson et al, 2002;Johnson et al, 2003;Johnson et al, 2004;Munhoz et al, 2006;De Pablos et al, 2006;Frank et al, 2007;Espinosa-Oliva et al, 2009;Wohleb et al, 2012).…”