Question

design a theoretical drug that will act on the physiological pathway (e.g. production, action, termination) of Neuropeptide Y (NPY) and improve learning and memory. Focusing on which part of that peptide pathway you will target to create a theoretical drug that will enhance learning and memory and How will your drug affect that target?

Answer 1

1.Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the mammalian central nervous system, which consists of the brain and spinal cord. It is secreted alongside other neurotransmitters such as GABA and glutamate.

In the autonomic system it is produced mainly by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue. In the brain, it is produced in various locations including the hypothalamus, and is thought to have several functions, including: increasing food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures.

• 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.
• Neuropeptides are small protein-like molecules (peptides) used by neurons to communicate with each other. They are neuronal signalling molecules that influence the activity of the brain and the body in specific ways.

2. Cross-talk between the nervous, endocrine and immune systems exists via regulator molecules, such as neuropeptides, hormones and cytokines. A number of neuropeptides have been implicated in the genesis of inflammation, such as tachykinins and calcitonin gene-related peptide. Development of their receptor antagonists could be a promising approach to anti-inflammatory pharmacotherapy. Anti-inflammatory neuropeptides, such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin, somatostatin, cortistatin, ghrelin, galanin and opioid peptides, are also released and act on their own receptors on the neurons as well as on different inflammatory and immune cells.

• Despite strong evidence showing substantive functional roles for many neuropeptides, at the cellular level a number of mysteries remain. Even seemingly straightforward questions can be complicated, such as: How far from a neuronal neuropeptide release site does a peptide act? For the amino acid neurotransmitters GABA, glycine, and glutamate, release occurs to a large degree at a presynaptic active zone, the transmitter diffuses a few tens of nanometers, activates receptors on the postsynaptic neuron, and then the transmitter is rapidly degraded or transported intracellularly. Amino acid transmitters act rapidly at ionotropic receptors, and at very discrete and spatially adjacent synaptic sites.
• A second possibility that has received considerable attention is that the peptide can diffuse long distances to act far from the release site. Very long distance signaling has been found for a number of neuroactive peptides/proteins. For instance, leptin from adipose tissue, ghrelin from the stomach, and insulin from the pancreas are released a long distance from the brain, but act on receptors within the CNS as signals of energy homeostasis. The blood brain barrier may prohibit entrance into the brain for many blood borne peptides; on the other hand, some regions of the brain such as the median eminence/arcuate nucleus may maintain a weak blood brain barrier which permits blood borne signals to enter the brain. Enhanced transport mechanisms may also exist for facilitating movement of some peptides into the brain.
• That peptides released by most neurons may act within a few microns of the release site does not negate the fact that some peptides can be released in large quantities and can act at longer distances. This may be the exception rather than the rule. For instance, considering the multiple subtypes of highly specialized NPY or somatostatin interneurons in the hippocampus or cortex, coupled with the multiple peptide responses reported in nearby cells and the highly specialized functions of different nearby interneurons, often with restricted functional microdomains .

(NOTE : Effects of neuropeptide Y on appetite. ... Stimulation of the NPY-ergic arcuate - paraventricular nucleus (ARC-PVN) pathway by exercise, fasting, energy loss (glucosuria) is followed by increased appetite and food intake and increased parasympathetic activity, but suppression of sympathetic activity and energy expenditure.)