Neuropeptides in learning and memory

Dementia conditions and memory deficits of different origins (vascular, metabolic and primary neurodegenerative such as Alzheimer's and Parkinson's diseases) are getting more common and greater clinical problems recently in the aging population. Since the presently available cognitive enhancers have very limited therapeutical applications, there is an emerging need to elucidate the complex pathophysiological mechanisms, identify key mediators and novel targets for future drug development. Neuropeptides are widely distributed in brain regions responsible for learning and memory processes with special emphasis on the hippocampus, amygdala and the basal forebrain. They form networks with each other, and also have complex interactions with the cholinergic, glutamatergic, dopaminergic and GABA-ergic pathways. This review summarizes the extensive experimental data in the well-established rat and mouse models, as well as the few clinical results regarding the expression and the roles of the tachykinin system, somatostatin and the closely related cortistatin, vasoactive intestinal polypeptide (VIP) and pituitary adenylate-cyclase activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), opioid peptides and galanin. Furthermore, the main receptorial targets, mechanisms and interactions are described in order to highlight the possible therapeutical potentials. Agents not only symptomatically improving the functional impairments, but also inhibiting the progression of the neurodegenerative processes would be breakthroughs in this area. The most promising mechanisms determined at the level of exploratory investigations in animal models of cognitive disfunctions are somatostatin sst4, NPY Y2, PACAP-VIP VPAC1, tachykinin NK3 and galanin GALR2 receptor agonisms, as well as delta opioid receptor antagonism. Potent and selective non-peptide ligands with good CNS penetration are needed for further characterization of these molecular pathways to complete the preclinical studies and decide if any of the above described targets could be appropriate for clinical investigations.