title: The protective effect of tianeptine on Gp120-induced apoptosis in astroglial cells: role of GS and NOS, and NF-κB suppression.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Human 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 κB (NF-κB) pathway were determined by Western blot analysis. The respective activities were assessed indirectly by measuring glutamine and nitrite concentrations or by luciferase reporter assays.
  
  
  RESULTS
  Tianeptine 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 IκB-α 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-κB transcriptional activity.
  
  
  CONCLUSIONS
  Tianeptine 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.
authors.affiliation: Department of Pharmacobiological Sciences, University Magna Graecia, Catanzaro, Italy.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Janda
authors.forename: Valeria
authors.initials: V
authors.lastname: Visalli
authors.forename: Carmela
authors.initials: C
authors.lastname: Colica
authors.forename: Serafina
authors.initials: S
authors.lastname: Aprigliano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Musolino
authors.forename: Nuria
authors.initials: N
authors.lastname: Vadalà
authors.forename: Carolina
authors.initials: C
authors.lastname: Muscoli
authors.forename: Iolanda
authors.initials: I
authors.lastname: Sacco
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Iannone
authors.forename: Domenicantonio
authors.initials: D
authors.lastname: Rotiroti
authors.forename: Michael
authors.initials: M
authors.lastname: Spedding
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mollace
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D015699:HIV Envelope Protein gp120; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011994:Recombinant Proteins; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D015699:HIV Envelope Protein gp120; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D018696:Neuroprotective Agents; D009573:Nitrites; D011994:Recombinant Proteins; D013841:Thiazepines; D005973:Glutamine; C050504:tianeptine; D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase; D053148:Caspase 3; D005974:Glutamate-Ammonia Ligase