Intranasal Insulin and Orexins to Treat Age-related Cognitive Decline

The intranasal (IN) administration of neuropeptides, such as insulin and orexins, has been suggested as a treatment strategy for age-related cognitive decline (ARCD). Because dysfunctional neuropeptide signaling is an observed characteristic of ARCD, it has been suggested that IN delivery of insulin and/or orexins may restore endogenous peptide signaling and thereby preserve cognition. IN administration is particularly alluring as it is a relatively non-invasive method that directly targets peptides to the brain. Several laboratories have examined the behavioral effects of IN insulin in young, aged, and cognitively impaired rodents and humans. These studies demonstrated improved performance on various cognitive tasks following IN insulin administration. Fewer laboratories have assessed the effects of IN orexins; however, this peptide also holds promise as an effective treatment for ARCD through the activation of the cholinergic system and/or the reduction of neuroinflammation. Here, we provide a brief overview of the advantages of IN administration and the delivery pathway, then summarize the current literature on IN insulin and orexins. Additional preclinical studies will be useful to ultimately uncover the mechanisms underlying the pro-cognitive effects of IN insulin and orexins, whereas future clinical studies will aid in the determination of the most efficacious dose and dosing paradigm. Eventually, IN insulin and/or orexin administration may be a widely used treatment strategy in the clinic for ARCD.