What are Neuropeptides? Neuropeptides are a class of signaling molecules in the brain. Signaling molecules are chemicals that transmit messages between neurons. The vast majority of signaling molecules in the brain are derived from peptides, which are small proteins. HOW DO NEUROPEPTIDES WORK IN THE BRAIN? Neuropeptides influence many of the systems that are disrupted in depression, such as emotional control (anxiety, aggression), sleep, eating, motivation, pleasure and arousal. Neuropeptides are modulatory compounds, meaning that they have effects over a longer time frame and over multiple interacting systems simultaneously. Current small-molecule therapies for affective disorders such as depression and anxiety target the pathways of 'classical' neurotransmitters serotonin, norepinephrine, dopamine and acetylcholine. However, it is estimated that the number of neuropeptide signaling systems in the brain are between 50 and 100 – and may be as high as 200. Thus, the role of neuropeptides remains a significantly understudied component in the understanding of affective disorders. Many of the side effects of current medications are related to the inability of the small-molecule therapies to bind to a single class of receptors or to specifically target the receptors involved in the illness. As a result, many other receptors will be affected, which can lead to side effects such as gastrointestinal and sexual dysfunction. With neuropeptides, side effects associated with systems unrelated to depression or anxiety are less likely because neuropeptides are much larger than small molecule-based drugs and, therefore, are more specific to their receptors and have less chance of binding receptors that are unrelated to the neuropeptide. In addition, neuropeptide degradation in the blood and tissues does not lead to the formation of toxic metabolic byproducts. EMERGENCE OF NEUROPEPTIDE-BASED THERAPIES The use of neuropeptide-based therapeutics has been limited in current therapeutic practices because many peptides are rapidly broken down in the body and are difficult to absorb across the gut (similar to reasons why insulin cannot be taken orally by diabetics). Also, scientists traditionally did not think that peptides could enter the brain, due to their relatively large size and perceived difficulty in crossing what is known as the blood-brain barrier. However, many peptides are, in fact, transported into the brain. PT00114 crosses the blood-brain barrier to exert its action in specific areas of the brain. For these reasons, investigations of peptide-based therapeutics may offer enormous potential.
POTENTIAL ADVANTAGES OF PEPTIDE-BASED THERAPIES Compared with small-molecule therapeutics, peptides may be safer because they have different pathways of metabolism. Peptides may also have less chance of side effects compared with small molecules, because many of the small molecules were designed to block receptors and reuptake mechanisms to modify the function of the neurotransmitter system. Most neuropeptides, on the other hand, are used to activate receptor systems. Peptides may also act more specifically than current treatments. Because neuropeptides are signaling molecules, they do not block receptors. By potentially acting more specifically than current treatments, a people may be able to retain the flexibility of emotion and feeling that is required to cope successfully in daily life and return to healthy levels of functioning. This is a key issue with current psychotropic medications, as people do not want to feel “drugged” or blunted emotionally.
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