Signaling Pathways Relevant to Cognition-Enhancing Drug Targets

Abstract

Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.

Identification of a Short Cell-Penetrating Peptide from Bovine Lactoferricin for Intracellular Delivery of DNA in Human A549 Cells

“…One possible reason is that calcium chloride condenses nascent plasmid DNA to form stable and small nanoparticles with 100–140 nm in diameter, leading to the enhancement of gene expression [ 48 ]. Another possible reason is that calcium ion may activate transcription factors to facilitate gene expression through its downstream signaling effectors; for instance, calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), and cAMP response element-binding protein (CREB) [ 50 ].…”

A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation

“…ERK activation has also been shown to be involved in learning of various hippocampus-dependent tasks (Menard et al, 2015; Peng et al, 2010; Xia and Storm, 2012). A previous study indicated that training in novel object recognition or in fear conditioning resulted in SCOP degradation and ERK activation in hippocampus 5 min after training (Shimizu et al, 2007).…”

(D-Ser2)Oxm[Lys38- and #947;-glu-PAL] improves hippocampal gene expression and cognition in a mouse model of type 1 diabetes

“…As such, defective IRS-1 dependent insulin signaling in the hippocampus has been associated with severe cognitive deterioration [15]. Interestingly, hippocampal expression of mTOR, a protein kinase involved in the insulin signaling pathway [16], was prominently enhanced by (d-Ser 2 ) Oxm[Lys 38 -γ-glu-PAL] treatment. These observations suggest that the improvement of peripheral insulin sensitivity noted with (d-Ser 2 )Oxm[Lys 38 -γ-glu-PAL] also extends to its central actions.…”