Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Motoneurons require neurotrophic factors for their survival and their differentiation. Xaliproden (SR57746A) is a synthetic compound that exhibits in vivo and in vitro neurotrophic effects in several experimental studies. Here we demonstrate that neuroprotective effects of Xaliproden on motoneuron cultures are mediated by the activation of the mitogen activated protein kinase pathway. It is inhibited by PD98059, a selective and irreversible inhibitor of MEK1. The activation of this pathway seems to involve two different proteins, the protein kinase C and the Ras. Indeed, we show that Xaliproden is able to activate the MAP kinases ERK1/2 and PKC in motoneurons. In addition, the use of a 5-hydroxytryptamine 1A receptor antagonist, Pindobind and pertussis toxin, inhibits the effect of Xaliproden on motoneuron survival, suggesting the involvement of this G-protein coupled receptor. Morever, 8-OH-DPAT, an agonist of 5-hydroxytryptamine 1A receptor, increases the survival of mouse motoneurons but not by the same extent as BDNF or xaliproden. Since 8-OH-DPAT does not act synergistically with Xaliproden, it is likely that their neuroprotective properties involve a similar pathway. Taken together, these results indicate that neuroprotective effects of Xaliproden on mouse motoneurons are dependent on the mitogen-activated protein kinase activation via 5-hydroxytryptamine 1A receptor.
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PMID:MAPK activation via 5-hydroxytryptamine 1A receptor is involved in the neuroprotective effects of xaliproden. 1569 8

Neurotrophic growth factors are involved in cell survival. However, natural growth factors have a very limited therapeutic use because of their short half-life. In the present study, we investigated the mechanism of action of a non-peptidic neurotrophic drug, Xaliproden, a potential molecule for the treatment of motoneuron diseases, since the transduction pathways of this synthetic 5-HT1A agonist are very poorly understood. Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the ERK1 and ERK2 isoforms of MAP kinase, which then rapidly decrease to the basal level. We demonstrate that isoforms of the SHC adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden-induced MAP kinases activation. The inhibitor of Ras farnesylation, FPT-1, and the protein kinase C inhibitors, GF 109203X and chelerythrine, inhibited the Xaliproden-induced MAP kinase activation, suggesting p21Ras and PKC involvement. Moreover, the observations that the 5-HT1A antagonist, pindobind, and pertussis toxin abolished the Xaliproden-induced ERK stimulation suggested that Xaliproden activates the MAP kinase pathways by stimulating the G protein-coupled receptor, 5-HT1A. These results demonstrate clearly that the non-peptidic compound, Xaliproden, exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins. These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by MAP kinase pathway by a pertussis toxin-sensitive mechanism involving 5-HT1A receptors, p21 Ras and MEK-1 and by PKC and Akt pathways.
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PMID:Xaliproden (SR57746A) induces 5-HT1A receptor-mediated MAP kinase activation in PC12 cells. 1588 46