5-Lipoxygenase inhibitor MK-886 increases GluR1 phosphorylation in neuronal cultures in vitro and in the mouse cortex in vivo

• Published in: Brain research 2007-05, Vol.1147, p.148-153
• Main Authors: Imbesi, Marta, Zavoreo, Iris, Uz, Tolga, Sharma, Rajiv P, Dimitrijevic, Nikola, Manev, Hari, Manev, Radmila
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase (5-LOX, 5-LO); 5-Lipoxygenase activating protein (FLAP); AMPA; Animals; Arachidonate 5-Lipoxygenase - metabolism; Biological and medical sciences; Cells, Cultured; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Fundamental and applied biological sciences. Psychology; Glutamate; Indoles - pharmacology; Lipoxygenase Inhibitors - pharmacology; Male; Mice; Mice, Inbred C57BL; Neurology; Neurons - drug effects; Neurons - metabolism; Phosphorylation; Prefrontal Cortex - cytology; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Receptors, AMPA - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2007.02.012

Abstract Modifications of AMPA glutamate receptor GluR1 phosphorylation are critical for neuroplastic mechanisms. Previous in vitro studies in brain slices employed MK-886, a functional inhibitor of the enzyme 5-lipoxygenase (5-LOX), and found increased GluR1 phosphorylation. Since slice preparations have accompanying postmortem phosphorylation changes, e.g., decreased GluR1 phosphorylation, it remains to be clarified whether MK-886 can affect GluR1 phosphorylation in intact neurons and in the brain in vivo. We used primary neuronal cultures prepared from embryonic mouse brain and in vivo drug administration to investigate the effects of MK-886 on GluR1 phosphorylation using quantitative Western immunoblotting assays. In vitro, MK-886 increased GluR1 phosphorylation at both serine 831 and serine 845. In vivo, repeated but not a single MK-886 injection increased GluR1 phosphorylation in the prefrontal cortex. These findings indicate that MK-886 has an intrinsic effect on neuronal phosphorylation both in vitro and in vivo and support the use of MK-886 as a pharmacological tool in studies of not only the 5-LOX pathway but also neuronal GluR1 functioning.