抄録
Background. The lysophosphatidic acid (LPA) receptor LPA1 is a critical regulator of neural development and survival, and dysregulation of LPA1 signaling has been associated with distinct neuropsychiatric disorders. We first reported that in non-neuronal cells different classes of antidepressants induce intracellular signaling and growth factor receptor trans-activation through LPA1, indicating that this receptor constitutes a novel molecular target of these psychoactive drugs. In the present study we investigated whether antidepressant-induced LPA1 activation could oppose the neuronal damage by pro-inflammatory cytokines, which are considered key factors in the pathogenesis of major depression.
Methods. Experiments were conducted in mouse HT22 immortalized hippocampal cells and mouse primary hippocampal neurons. The effects of antidepressants on cytokine-induced apoptosis were examined by using western blot, immunofluorescence and cytofluorimetry. The involvement of LPA1 was assessed by using selective antagonists and gene silencing. Pharmacological inhibitors were used to study ERK1/2 and FGF receptor (FGF-R) signaling.
Results. We found that in HT22 cells the tricyclic antidepressants amitriptyline and imipramine and the tetracyclic antidepressants mianserin and mirtazapine stimulated ERK1/2 signaling through LPA1. Prolonged exposure of HT22 cells to TNF-alpha triggered apoptotic cascade, as indicated by activation of caspases 8, 9, and 3, increased cleavage of poly ADP-ribose polymerase (PARP), and enhanced DNA fragmentation. Antidepressants prevented TNF-alpha-induced apoptosis by acting on LPA1. IL-1a, IL-6, IFN-beta and IFN-gamma did not affect PARP cleavage per se, but potentiated the TNF-alpha stimulation. Antidepressants attenuated the enhanced apoptotic response elicited by the combination of TNF-alpha with either IL-1a or IFN-beta. TNF-alpha also activated a pro-survival signaling by activating NF-kB, but this response was not affected by mianserin. Conversely, mianserin counteracted TNF-alpha-induced cytochrome c release from mitochondria and ERK1/2 inhibition. Blockade of FGF-R and ERK1/2 activities prevented the neuroprotective effect of mianserin. In mouse primary hippocampal neurons TNF-alpha induced apoptotic cell death, which was inhibited by mianserin and mirtazapine through LPA1.
Conclusions. These data indicate that certain antidepressants acting through LPA1 coupled to FGF-R trans-activation protect from TNF-alpha-induced neuronal death by enhancing ERK1/2-dependent suppression of the pro-apoptotic cascade, while sparing TNF-alpha-induced pro-survival signaling via NF-kB.
