Neurotrophic Effects of Tianeptine on Hippocampal Neurons: A Proteomic Approach

Abstract

Tianeptine, an atypical tricyclic antidepressant with unique characteristics, can improve memory and prevent stress-induced hippocampal damage. It has neuroplastic and neurotrophic effects on hippocampal neurons and can prevent dendritic atrophy of the hippocampus in certain pathological conditions. To obtain a better understanding of the underlying mechanisms, we performed a proteomic analysis on tianeptine-treated hippocampal neurons. Primary hippocampal neurons were prepared from fetal Sprague-Dawley rats, eliminating glia cells by addition of cytosine beta-D-arabinofuranoside at day 2 in vitro (DIV2). The neurons were treated with tianeptine (10 microg/mL) or vehicle at DIV3, then harvested at DIV4 or DIV9 for immunocytochemical analysis of, respectively, neurite outgrowth or synapse formation. A proteomics analysis was performed on DIV4 neurons and the data were confirmed by Western blot analysis. Using specific markers, we demonstrated that tianeptine can augment neurite growth and promote synaptic contacts in cultured hippocampal neurons. The proteomics analysis identified 11 differentially expressed proteins, with roles in neurite growth, metabolism of neurotrophic substances, synaptogenesis, and synaptic activity homeostasis. The data shed light on the mechanisms underlying the neurotrophic effect of tianeptine observed in both animal studies and the clinic.

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

“…In a proteomics study intended to uncover protein changes in primary mammalian neurons exposed to the atypical antidepressant and anxiolytic drug tianeptine [(RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c, f] [1,2]thiazepin-11-ylamino) heptanoic acid S,S-dioxide; Stablon or Coaxil], Chu et al found a highly selective drug-induced increase in CRMP2. Tianeptine increased CRMP2 expression up to 4-fold, with a concomitant promotion of neurite elongation and especially, axon extension [14]. Our group has independently observed and confirmed this phenomenon (Fig.…”

“…Similarly, knockdown of Sra1 and WAVE1 cancels CRMP2-induced axon outgrowth [10] indicating that proper connection of CRMP2 to Sra1/WAVE1 is essential to preserve integrity of distal actin networks. In normal rodent neuron culture CRMP2 concentration seems to be limiting in neurite outgrowth because increasing CRMP2 by transfection or treatment with the CRMP2 expression-inducing compound tianeptine (discussed below) is sufficient to stimulate neurite extension [1][2][3]14].…”

“…Lanthionine ketimine (LK; 2H-1,4-thiazine-5,6-dihydro-3,5-dicarboxylic acid) is a natural brain sulfur amino acid metabolite probably derived from non-canonical reactions catalyzed by the transsulfuration enzyme cystathionine-β-synthase [14,[64][65][66]. Our group recently discovered that LK possesses various biological activities including the ability to potentiate growth factor-mediated neurite outgrowth, and another ability to antagonize the activation of microglia and macrophages by pro-inflammatory cytokines [13,[66][67][68].…”

“…CRMP2 is expressed most heavily in highly plastic areas of the adult brain such as the hippocampus, olfactory bulb and cerebellum [6]. In neurons, CRMP2 normally is concentrated within the distal portions of neurites, in synapses and in growth cones [3,4,14]. Multiple CRMP2 isoforms result from alternative splicing of the N terminus, with predominant forms being a 75 kDa CRMP2A variant that is important during embryonic development and a 62-66 kDa CRMP2B variant (multiple sub-isoforms) that appears most commonly expressed in adult CNS [15].…”

The impact of mitochondrial aldehyde dehydrogenase (ALDH2) activation by Alda-1 on the behavioral and biochemical disturbances in animal model of depression

“…Decrease of Drp2 expression in the frontal cortex was reported in patients with the bipolar disorder or depression by brain proteome-wide search (Johnston-Wilson et al, 2000). Interestingly, it has also been shown that an atypical antidepressant -tianeptine -increased Drp2 expression, with a concomitant promotion of neurite elongation and axon extension (Chu et al, 2010). Changes of the expression of the aforementioned proteins upon Alda-1 treatment may shed a new light on molecular mechanisms responsible for the beneficial effects of ALDH2 activation in prenatally stressed rats.…”