The common inositol-reversible effect of mood stabilizers on neurons does not involve GSK3 inhibition, myo-inositol-1-phosphate synthase or the sodium-dependent myo-inositol transporters.
We previously showed that the mood stabilizers lithium, valproate (VPA), and carbamazepine (CBZ) have a common, inositol-reversible effect on the dynamic behavior of sensory neurons, suggesting that they all inhibit phosphoinositide (PIns) synthesis. We now report similar effects of the drugs in cortical neurons and show by mRNA analysis that these neurons do not express myo-inositol-1-phosphate synthase (MIP-synthase) or the sodium-dependent myo-inositol transporters (SMIT1 and SMIT2), but they do express the H+/myo-inositol transporter (HMIT) mRNA and protein. We used glycogen synthase kinase-3 (GSK3) inhibitors and Western blotting of GSK3 targets to confirm that the common effects of the drugs on both sensory and cortical neuron growth cones are inositol-dependent and GSK3-independent. Moreover, the anti-convulsant drugs gabapentin and phenytoin do not mimic the mood stabilizers. These results confirm that the common inositol-reversible effect of mood stabilizers on neurons does not involve GSK3 and further show that the effects are independent of MIP-synthase and SMIT transporters.
Schizophrenia and Bipolar Neurophysiology and Pharmacology Research Department, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, Essex, CM19 5AW, UK. Elena.2.DiDaniel@gsk.com
Elena
E
Di Daniel
Lili
L
Cheng
Peter R
PR
Maycox
Anne W
AW
Mudge
D000818:Animals; D000831:Animals, Newborn; D018692:Antimanic Agents / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects* / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008094:Lithium / Q000494:pharmacology; D007296:Myo-Inositol-1-Phosphate Synthase / Q000235:genetics*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D027981:Symporters / Q000235:genetics*; D014635:Valproic Acid / Q000494:pharmacology
D018692:Antimanic Agents; D004791:Enzyme Inhibitors; D051246:Glucose Transport Proteins, Facilitative; D012333:RNA, Messenger; C508355:SLC5A3 protein, mouse; C486673:Slc2a13 protein, rat; D027981:Symporters; D002220:Carbamazepine; D014635:Valproic Acid; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D007296:Myo-Inositol-1-Phosphate Synthase