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Inhibition of TNF-α-induced neuronal apoptosis by antidepressants acting through the lysophosphatidic acid receptor LPA1

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Abstract

Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine considered to be implicated in the pathogenesis of major depressive disorder, is a critical regulator of neuronal cell fate. In the present study we found that TNF-α-induced apoptosis of HT22 hippocampal cells, a neuroblast-like cell line, was markedly attenuated by the antidepressants mianserin, mirtazapine and amitriptyline. The anti-apoptotic effect of the antidepressants was blocked by either pharmacological inhibition or gene silencing of the lysophosphatidic acid receptor LPA1. Mianserin failed to affect TNF-α-induced caspase 8 activation, but inhibited the loss of mitochondrial membrane potential, the release of cytochrome c from mitochondria, procaspase 9 cleavage and downstream activation of caspase 3 in response to the cytokine. By acting through LPA1, mianserin also attenuated the enhanced pro-apoptotic response induced by the combination of TNF-α with other pro-inflammatory cytokines. TNF-α appeared to counterbalance its own pro-apoptotic response by activating NF-kB, ERK1/2 and JNK. Antidepressants had no significant effects on NF-kB activation, but potentiated the TAK-1-dependent phosphorylation of ERK1/2 and JNK elicited by the cytokine. This synergistic interaction was associated with enhanced JNK-mediated phosphorylation of Bcl-2 at Ser70 and increased ERK1/2-dependent mitochondrial accumulation of Mcl-1, two anti-apoptotic proteins that promote mitochondrial outer membrane stability. These results indicate that certain antidepressants, by activating LPA1 signalling, protect HT22 hippocampal cells from TNF-α-induced apoptosis through a mechanism involving, at least in part, the potentiation of the pro-survival pathways activated by the cytokine.

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Funding

This study was funded by Regione Autonoma della Sardegna, Italy. L.R. no. 7/2007 (CRP10810/2012) and by Universita’ degli Studi di Cagliari, Italy, FIR 2017.

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  1. Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    Maria C. Olianas, Simona Dedoni & Pierluigi Onali

  2. Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042, Monserrato, CA, Italy

    Pierluigi Onali

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  1. Maria C. Olianas
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Olianas, M.C., Dedoni, S. & Onali, P. Inhibition of TNF-α-induced neuronal apoptosis by antidepressants acting through the lysophosphatidic acid receptor LPA1. Apoptosis 24, 478–498 (2019). https://doi.org/10.1007/s10495-019-01530-2

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