Effects of venlafaxine on p90Rsk activity in rat C6-gliomas and brain.
The intracellular actions of the antidepressant, venlafaxine, were studied in C6-gliomas using a phosphoproteomics approach. Long-term pre-treatment of C6-gliomas with venlafaxine followed by an acute challenge with isoproterenol (a beta-adrenoceptor agonist), resulted in increased p90Rsk phosphorylation (three-fold) versus control levels (isoproterenol alone). The effect of venlafaxine pre-treatment on p90Rsk activity was dose-dependent (EC(50)=3.75nM) in C6 gliomas. In rat brain sections, intense immunoreactive phospho-p90Rsk labeling was observed for both neurons and glia, especially in cortical layers II/III and hippocampal formations. In vivo studies demonstrated an intense but similar distribution pattern of phospho-p90Rsk staining after chronic venlafaxine dosing of rats compared to naives and no region-specific drug effect was observed in vivo. In conclusion, our findings suggest that some of the centrally-mediated benefits of venlafaxine in depression may be due to its intracellular properties especially on the neuro-glial circuitry and MAPK/p90Rsk-dependent pathways at an early stage.
Khawaja
Xavier Z
XZ
Wyeth Neuroscience, CN 8000, Princeton, NJ, USA. khawajx@wyeth.com
Storm
Stephen
S
Liang
Jin-Jun
JJ
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D003511:Cyclohexanols / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D000069470:Venlafaxine Hydrochloride
D003511:Cyclohexanols; D000069470:Venlafaxine Hydrochloride; D038744:Ribosomal Protein S6 Kinases, 90-kDa