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In an effort to decipher the precise signaling mechanisms through which traditional antidepressants confer neuroprotection, Yang et al. (2012, this issue of EJN) used nutrient deprivation stress as an in vitro model of the neural pathology of hippocampal neurons. Nutrient deprivation resulting in decreased survival has previously been reported in cortical (Tong et al., 2004) and hippocampal (Zheng & Quirion, 2009; Patel et al., 2010) neurons in culture. Prolonged stress causes depression and mood disorders, leading to neuronal degeneration and atrophy in the prefrontal cortex and hippocampus.These effects can be reversed by antidepressants, but not without a long lag time (Ota & Duman, 2012). This delayed treatment response suggests that there are slow-onset adaptations of downstream signaling pathways, including target genes that have therapeutic actions. The authors tested antidepressant drugs that acutely inhibit the reuptake or breakdown of norepinephrine and serotonin, and activate signaling cascades such as those involving phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and protein kinase A (PKA). These intracellular pathways downstream of antidepressants are believed to converge to cAMP response element-binding protein (CREB) activation. Phosphorylation of CREB then promotes transcription of a number of pro-survival genes, as well as genes that regulate multiple physiological processes, including neuroplasticity, neuroprotection, and neurogenesis.

Moreover, several studies have provided strong evidence that brain-derived neurotrophic factor (BDNF) and phospho-CREB are mediators of antidepressant drug action (Nibuya et al., 1996; Conti et al., 2002). BDNF exerts its effects through its tyrosine kinase receptor, trkB, which undergoes dimerization and autophosphorylation, resulting in the activation of various survival-promoting cascades, such as the MAPK–extracellular signal-related kinase (ERK) and PI3K–Akt kinase cascades. In vitro studies have shown that these intracellular pathways promote neuronal growth and regeneration, as well as inhibiting cell death (Voleti & Duman, 2012). In line with these findings, Yang et al. (2012) provide evidence indicating that the advantages of the antidepressants outweigh the benefits provided by the nutrients in neuronal cultures. Furthermore, blocking of signaling pathways appeared to be more harmful to neuronal survival than depriving the hippocampal neurons of the nutrient supplement N2. In addition, they found that the noradrenaline reuptake inhibitors were more effective in supporting neuronal survival than the serotonin reuptake inhibitors. The convergence to BDNF through CREB phosphorylation via PI3K activation was found to be independent of the presence of N2; however, the other two pro-survival pathways, MAPK and PKA, required N2 for neuronal survival, demonstrating the dependence of neuronal health on nutrients.

Earlier studies by these authors have shown that the triad BDNF/CREB/PI3K plays a major role in neuronal survival, and can be activated by antidepressants (Perkinton et al., 2002; Donati & Rasenick, 2003; Chen & Russo-Neustadt, 2005, 2007). The results of the present study suggest a positive feedback loop: the inhibitors of PKA, even in the presence of N2, suppressed the increased BDNF expression through CREB activation by antidepressants. Given the role of PI3K in a multitude of physiological functions, it is very likely that there is crosstalk between other signaling kinases. The evidence described in Yang et al. (2012) suggests such signaling pathway crosstalk. They demonstrated that when PI3K was inhibited, the level of phosphorylated MAPK was increased, and vice versa. Others have shown possible crosstalk with ERK signaling (Bondeva et al., 1998; Pandey et al., 1999) and MAPK (Ou & Gean, 2006). By use of an in vitro model of nutrient deprivation stress, the present study clearly demonstrates that antidepressants activate different intracellular signaling pathways, which then possibly interact in a coordinated manner to protect neurons and enhance their survival even in the presence of nutrient deprivation stress.

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