MAP Kinase Activation by Fluoxetine and Its Relation to Gene Expression in Cultured Rat Astrocytes

Abstract

Chronic treatments with antidepressants active on major depressive disorders influence pathways involved in cell survival and plasticity. As astrocytes seem to play a key role in the protection of brain cells, we investigated in these cells the rapid effects of the antidepressant fluoxetine (Prozac) on signaling cascades and gene induction, which probably play a role in neuroprotection. We show here that fluoxetine alone activates the extracellular signal-regulated-protein kinase (Erk) and p38 mitogen-associated protein (MAP) kinase cascades. RT-PCR revealed that genes, modulated in brain by long-term fluoxetine treatment, are rapidly induced by fluoxetine in cultured astrocytes: brain-derived nerve factor (BDNF) and its receptors, glial-derived nerve factor (GDNF) and deiodinase 3 (D3). Induction of D3 by fluoxetine is inhibited by U0126 and SB203580, suggesting that Erk and p38 MAP kinases are involved. Glial-derived nerve factor (GDNF) induction by fluoxetine is prevented by U0126, suggesting that Erk is implicated. Brain-derived nerve factor (BDNF) induction seems mediated by other signaling pathways. In conclusion, we show that fluoxetine alone rapidly activates mitogen activated protein (MAP) kinase cascades in rat astrocytes and that genes involved in neuroprotection are induced in a few hours in a MAP kinase-dependent or -independent manner.

Pharmacologically Diverse Antidepressants Rapidly Activate Brain-Derived Neurotrophic Factor Receptor TrkB and Induce Phospholipase-Cγ Signaling Pathways in Mouse Brain

“…This observation is consistent with the lack of alteration in the autophosphorylation of the TrkB Shc binding site, which mediates the activation of these signaling pathways (Saarelainen et al, 2003;Rantamäki et al, 2006). Previous studies on the role of MAPK pathway in the mechanism of antidepressant action have yielded conflicting results (Mercier et al, 2004;Tiraboschi et al, 2004;Fumagalli et al, 2005). The role of the pathways initiated by the TrkB Shc binding site have been extensively studied in vitro (Huang and Reichardt, 2001), but the replacement of the tyrosine 515 with a phenylalanine (which abolished the shc binding) in transgenic mice produced an unexpectedly mild phenotype (Minichiello et al, 2002), suggesting that other signaling pathways can largely compensate for the lack of MAPK pathway activation in vivo.…”

Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex

“…Earlier studies have shown that phosphorylation at serine 505 of cPLA 2 protein by mitogenactivated protein kinase (MAPK p38) resulted in cPLA 2 activation. 53,54 Another study reported that fluoxetine activates MAPK p38 activity in cultured rat astrocytes, 55 which could account for the increased phosphorylation of cPLA 2 by chronic fluoxetine. The difference in the percent increase of cPLA 2 protein level (54%) compared to the percent increase in phosphorylated cPLA 2 (serine 505) level (27%) may represent differences in MAPK activity 54 and cPLA 2 protein half-life.…”

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

“…The current study indicates that decreased p38 MAPK activity is involved in functional changes observed in n-3 PUFA deprived rats. 15 Fluoxetine also activates the p38 MAPK cascade, 80 suggesting that the depressive symptoms observed in n-3 PUFA deprived rats are related to decreased p38 MAPK activity. Constitutive p38 MAPK activity maintains the expression of rat brain dopamine 81,82 and serotonin transporters 83 and n-3 PUFA deprivation upregulates D1 and D2 receptors 84 and decreases stimulated serotonin release, 85 all of which are believed to be involved in depression.…”