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

Abstract

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 (PKCdelta) 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 PKCdelta, we searched the Compounds Available for Purchase (CAP) database with the Accelrys((R)) Catalyst programme for structurally similar molecules and, using the available crystal structure of the phorbol-binding domain of PKCdelta, 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 PKCdelta protein expression. Curcumin did not directly inhibit PKCdelta activity but formed a tight complex with the enzyme. With increasing doses of curcumin, the Tyr(131) residue of PKCdelta, which is known to direct its degradation, became progressively phosphorylated and this was associated with numerous Tyr(131)-phospho-PKCdelta 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 PKCdelta in regulating PST and NCAM PSA expression and provide evidence that drug modulation of this system enhances the process of memory consolidation.

Insulin Promotes Neuronal Survival via the Alternatively Spliced Protein Kinase CδII Isoform

“…PKC activation in the brain is essential for learning, synaptogenesis, and neuronal repair (8 -10). In particular, PKC␦ has been implicated in memory, neuronal survival, and proliferation and activates survival pathways in neurons (11,43,44). The two alternatively spliced variants of PKC␦ expressed in mouse neuronal cells are PKC␦I and PKC␦II.…”

“…Insulin signaling pathways activate PKC and its substrates, many of which are essential components of learning, memory, and cognition. In particular, PKC␦ (PRKCD) has been implicated in memory, neuronal survival, and proliferation (11)(12)(13). PKC␦ improves learning and memory by preventing neuronal loss and maintaining the synapses (14).…”

H3 Receptor Antagonism Enhances NCAM PSA-Mediated Plasticity and Improves Memory Consolidation in Odor Discrimination and Delayed Match-to-Position Paradigms

“…Agents, such as curcumin and a-tocopherol, which induce the degradation of PKCd, enhance PST activity and PSA of neurons in the infragranular zone of the dentate gyrus and the synaptic remodeling of their dendritic arbor (Conboy et al, 2009;Ferri et al, 2006;Zingg and Azzi, 2004). The ability of GSK189254 to increase dentate polysialylated cell frequency may, however, be related to its ability to augment the outflow of acetylcholine, as two other cholinergic agents, tacrine and nefiracetam, similarly increase cholinergic drive (Nishizaki et al, 2000;Irizarry and Hyman, 2001;Medhurst et al, 2007) and all three agents enhance NCAM PSA in a bell-shaped dose-dependent manner (Murphy et al, 2006).…”

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

“…Curcumin inhibits Aβ40 aggregation in vitro and reduces amyloid plaque burden in animal models of AD [246,247]. Recently, curcumin was shown to induce PKCδ degradation and enhance spatial learning in rats [248].…”