Inhibition of TNF- α-induced neuronal apoptosis by antidepressants acting through the lysophosphatidic acid receptor LPA 1

AbstractTumor 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 atten uated 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 cytoki ne. 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 stabi...
Source: Apoptosis - Category: Molecular Biology Source Type: research