PMID- 30840161
OWN - NLM
STAT- MEDLINE
DCOM- 20200505
LR  - 20200505
IS  - 1573-675X (Electronic)
IS  - 1360-8185 (Linking)
VI  - 24
IP  - 5-6
DP  - 2019 Jun
TI  - Inhibition of TNF-alpha-induced neuronal apoptosis by antidepressants acting through 
      the lysophosphatidic acid receptor LPA(1).
PG  - 478-498
LID - 10.1007/s10495-019-01530-2 [doi]
AB  - Tumor necrosis factor-alpha (TNF-alpha), 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-alpha-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 LPA(1). Mianserin failed to affect TNF-alpha-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 LPA(1), mianserin 
      also attenuated the enhanced pro-apoptotic response induced by the combination of 
      TNF-alpha with other pro-inflammatory cytokines. TNF-alpha 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 
      LPA(1) signalling, protect HT22 hippocampal cells from TNF-alpha-induced apoptosis 
      through a mechanism involving, at least in part, the potentiation of the 
      pro-survival pathways activated by the cytokine.
FAU - Olianas, Maria C
AU  - Olianas MC
AUID- ORCID: 0000-0002-4041-641X
AD  - Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, 
      Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
FAU - Dedoni, Simona
AU  - Dedoni S
AUID- ORCID: 0000-0002-7330-2179
AD  - Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, 
      Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
FAU - Onali, Pierluigi
AU  - Onali P
AUID- ORCID: 0000-0002-9733-460X
AD  - Laboratory of Cellular and Molecular Pharmacology, Section of Neurosciences, 
      Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. 
      onali@unica.it.
AD  - Department of Biomedical Sciences, University of Cagliari, Cittadella 
      Universitaria, 09042, Monserrato, CA, Italy. onali@unica.it.
LA  - eng
GR  - L.R. n degrees 7 / 2007-CRP10810/2012-FIR 2017 Universita' degli Studi di 
      Cagliari/Regione Autonoma della Sardegna/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Apoptosis
JT  - Apoptosis : an international journal on programmed cell death
JID - 9712129
RN  - 0 (Antidepressive Agents)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - 0 (Receptors, Lysophosphatidic Acid)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Tnfrsf1a protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Gene Silencing
MH  - Humans
MH  - MAP Kinase Signaling System/drug effects
MH  - Mice
MH  - Neurons/drug effects/metabolism/*pathology
MH  - Phosphorylation/drug effects
MH  - Receptors, Fibroblast Growth Factor/antagonists & inhibitors/metabolism
MH  - Receptors, Lysophosphatidic Acid/antagonists & inhibitors/genetics/*metabolism
MH  - Receptors, Tumor Necrosis Factor, Type I/metabolism
MH  - Tumor Necrosis Factor-alpha/*pharmacology
OTO - NOTNLM
OT  - Antidepressants
OT  - Apoptosis
OT  - HT22 hippocampal cells
OT  - LPA1
OT  - TNF-alpha
EDAT- 2019/03/07 06:00
MHDA- 2020/05/06 06:00
CRDT- 2019/03/07 06:00
PHST- 2019/03/07 06:00 [pubmed]
PHST- 2020/05/06 06:00 [medline]
PHST- 2019/03/07 06:00 [entrez]
AID - 10.1007/s10495-019-01530-2 [pii]
AID - 10.1007/s10495-019-01530-2 [doi]
PST - ppublish
SO  - Apoptosis. 2019 Jun;24(5-6):478-498. doi: 10.1007/s10495-019-01530-2.