Curcumin-induced degradation of PKCδ is associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats

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 (PKC delta) to be associated with increased polysialyltransferase (PST) activity, suggesting inhibitors of this kinase might ameliorate cognitive deficits. Using a rottlerin template, a drug previously considered an inhibitor of PKC delta, we searched the Compounds Available for Purchase (CAP) database with the Accelrys" Catalyst programme for structurally similar molecules and, using the available crystal structure of the phorbol-binding domain of PKC delta, 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 PKC delta protein expression. Curcurnin did not directly inhibit PKC delta activity but formed a tight complex with the enzyme. With increasing doses of curcumin, the Tyr(131) residue of PKC delta, which is known to direct its degradation, became progressively phosphorylated and this was associated with numerous Tyr(131)-phospho-PKC delta fragments. Chronic administration of curcumin in vivo 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 PKC delta in regulating PST and NCAM PSA expression and provide evidence that drug modulation of this system enhances the process of memory consolidation. (C) 2009 Elsevier Inc. All rights reserved.