Curcumin-induced degradation of pkc( is associated with enhanced dentate ncam psa expression and spatial learning in adult and aged wistar rats.

Lisa Conboy , Andrew G. Foley , Noel M. O'Boyle , Marie Lawlor , Helen C. Gallagher , Keith J. Murphy , Ciaran M. Regan

Polysialylation of the neural cell adhesion molecule (NCAM PSA) is necessary for the consolidation processes of hippocampus-based learning. Previously, we have found inhibition of protein kinase C delta (PKCδ) to be associated with increased polysialyltransferase activity (PST), suggesting inhibitors of this kinase might ameliorate cognitive deficits. Using a rottlerin template, a drug previously considered an inhibitor of PKCδ, we searched the CAP database with the Accelrys Catalyst programme for structurally similar molecules and, using the available crystal structure of the phorbol-binding domain of PKCδ, found that diferuloylmethane (curcumin) docked effectively into the phorbol site. Curcumin increased NCAM PSA expression in cultured neuro-2A neuroblastoma cells and this was inversely related to PKCδ protein expression. Curcumin did not directly inhibit PKCδ activity but formed a tight complex with the enzyme. With increasing doses of curcumin, the Tyr residue of PKCδ, which is known to direct its degradation, became progressively phosphorylated and this was associated with numerous Tyr-phospho-PKCδ fragments. Chronic administration of curcumin also increased the frequency of polysialylated cells in the dentate infragranular zone and significantly improved the acquisition and consolidation of a water maze spatial learning paradigm in both adult and aged cohorts of Wistar rats. These results further confirm the role of PKCδ in regulating PST and NCAM PSA expression and provide evidence that drug modulation of this system enhances the process of memory consolidation.

Mots clés: PKCδ; PST; NCAM PSA; Curcumin; Spatial learning

Lisa Conboy, Andrew G. Foley, Noel M. O'Boyle, Marie Lawlor, Helen C. Gallagher, et al.. Curcumin-induced degradation of pkc( is associated with enhanced dentate ncam psa expression and spatial learning in adult and aged wistar rats.. Biochemical Pharmacology, 2009, 77 (7), pp.1254. ⟨10.1016/j.bcp.2008.12.011⟩. ⟨hal-00493480⟩