Revisited case for intranasal neuropeptide Y based therapeutics: From preclinical to clinical

Compelling evidence from a variety of approaches attributes manifold benefits to NPY in the brain. NPY can reduce stress, depressive symptoms, pain, neuroinflammation, seizures, and is implicated in attenuating alcohol use disorder and neurodegenerative diseases, such as Alzheimer's, Machado-Joseph and Huntington Disease. NPY enhances immune regulation, neuro-proliferation, memory and cognition. However, its therapeutic potential has not yet been realized. Intranasal nose to brain (N2B) delivery is a non-invasive approach that can provide high bioavailability with limited side effects. Here we discuss therapeutic opportunities and challenges of N2B administration of NPY and related agonists. Preclinical N2B administration of NPY, either alone or with other compounds, to experimental animals has been very successful. For example, a single NPY intranasal infusion to male rats was able to prevent, as well as reverse, many behavioral impairments triggered by Single Prolonged Stress model for PTSD. Females were found to require higher doses of NPY, or pretreatment with a DPPIV inhibitor, to provide resilience. In humans, limited studies found that intranasal administration of NPY in saline was well tolerated and showed promise for PTSD or depression at highest dose administered. However, saline should be avoided in favor of water for aqueous delivery, and each sex should be analyzed separately. Overall, these findings call for further work to enhance N2B delivery of NPY or selective agonists to human brain to harness NPY's exciting therapeutic potential.