The Atypical Antidepressants Mianserin and Mirtazapine Inhibit TNF‐α‐Induced Apoptosis via LPA1 in Mouse HT22 Hippocampal Cells.

Abstract

Several studies have proposed that pro‐inflammatory cytokines, such as TNF‐α, contribute to the pathophysiology of major depression through different mode of actions, including direct impairment of hippocampal neural progenitor cell development and survival. However, little is known on the mechanisms by which drugs effective in treating major depression may counteract the deleterious effect of pro‐inflammatory cytokines on neural cells. We have recently reported that different antidepressants activate the lysophosphatidic acid receptor LPA1 to induce growth factor receptor transactivation, cell proliferation and neuroprotection [1,2]. In the present study we show that in mouse HT22 hippocampal cells, which display a neuroblast‐like phenotype, the atypical antidepressants mianserin and mirtazapine inhibit the apoptotic cell death induced by TNF‐α and that this protective action involves the activation of LPA1. Thus, prolonged exposure of HT22 cells to TNF‐α increased caspases 8, 7 and 3 activities, proteolytic cleavage of poly ADP‐ribose polymerase and DNA fragmentation. Co‐treatment with antidepressants markedly attenuated the activation of the apoptotic cascade induced by TNF‐α. Blockade of the LPA1 receptor with the selective antagonists AM966 and Ro6842262 antagonized the anti‐apoptotic activity of the antidepressants. Analysis of intracellular signalling showed that through activation of LPA1 antidepressants transactivated the fibroblast growth factor receptor and triggered the phosphorylation of ERK1/2 and CREB, two key regulators of neural survival and differentiation. Collectively, the data indicate that in HT22 hippocampal cells LPA1 is a critical mediator of the neuroprotective effects of mianserin and mirtazapine against the pro‐apoptotic action exerted by TNF‐α.Support or Funding InformationSupported by University of Cagliari. Italy