A NEW TARGET FOR FUTURE ANTIEMETICS: INHIBITION of GLYCOGEN SYNTHASE KINASE 3 (GSK‑3)
N. Darmani1, W. Zhong1 
1COMP/WUHS, Basic Medical Sciences, Pomona CA, USA

Introduction:
GSK-3 is a mutifunctional kinase involved in a variety of diseases. Its two isoforms GSK-3alpha and GSK-3beta are constitutively active and upon cellular stimuli turns into its catalytic inactivation by phosphorylation at ser 21 and 9. Our preliminary findings suggest a pivotal role for GSK-3 in vomiting. To investigate a role for GSK-3 in vomiting we examined: i) least shrew brainstem GSK-3α/β phosphorylation following exposure to diverse emetogens, and ii) whether GSK-3 inhibition exerts antiemetic efficacy.
 Methods
Shrews were treated with fully effective emetic doses of diverse emetogens and brainstem GSK-3α/β phosphorylation at Ser21/9 was examined at several time-points post-treatment via Western blots. Other groups of shrews were pretreated with the GSK-3α/β inhibitor SB216763 (0.25 mg/kg, i.p.) to determine its antiemetic potential against different emetogens.  
Results
Increases in brainstem GSK-3α/β phosphorylation at Ser21/9 were observed following administration of the serotonergic 5-HT3 (5-HT or 2-Me-5-HT, 5 mg/kg)-, tachykinin NK1 (GR73632, 5 mg/kg)-, dopamine D2 (apomorphine or quinpirole, 2 mg/kg)-, cholinergic M1 (McN-A343, 2 mg/kg)-receptors, the L-type calcium channel agonist (FPL 64176, 10 mg/kg) and proposed chemotherapeutic thapsigargin (0.5 mg/kg, 0.5 mg/kg). This increase was further confirmed through immunostaining brainstem sections of FPL64176-treated least shrews. Moreover, the GSK-3 inhibitor SB216763 exerted potent and broad-spectrum antiemetic efficacy against vomiting evoked by the above discussed emetogens. 
Conclusions
Our findings demonstrate a pivotal role for GSK-3 in vomiting and implies targeting signals up and/or downstream of GSK-3 enzyme may provide powerful novel avenues for developing new and potent antiemetics.

19 - A NEW TARGET FOR FUTURE ANTIEMETICS: INHIBITION OF GLYCOGEN SYNTHASE KINASE 3 (GSK‑3)