The Potential of the Nose-to-Brain Delivery of PACAP for the Treatment of Neuronal Disease

Abstract

Research on the neuroprotective effect of pituitary adenylate cyclase-activating polypeptide (PACAP) and its use as a therapeutic agent has grown over the past 30 years. Both in vitro and in vivo experiments have shown that PACAP exerts a strong neuroprotective effect in many central and peripheral neuronal diseases. Various delivery routes have been employed from intravenous (IV) injections to intracerebroventricular (ICV) administration, leading either to systemic or topical delivery of the peptide. Over the last decade, a growing interest in the use of intranasal (IN) administration of PACAP and other therapeutic agents has emerged as an alternative delivery route to target the brain. The aim of this review is to summarize the findings on the neuroprotective effect of PACAP and to discuss how the IN administration of PACAP could contribute to target the effects of this pleiotropic peptide.

Recent Uses of Lipid Nanoparticles, Cell-Penetrating and Bioactive Peptides for the Development of Brain-Targeted Nanomedicines against Neurodegenerative Disorders

“…Many publications have suggested that some bioactive peptides with neuroprotective effects (e.g., PACAP) can exert a potential therapeutic role in the prevention and treatment of neurodegenerative diseases. PACAP (Table 1) was originally isolated from ovine hypothalamic extracts in view of its capacity to stimulate cyclic adenosine monophosphate formation in rat anterior pituitary cells [115]. Over the past three decades, PACAP has been shown to exert neurotrophic and neuroprotective effects in both in vitro and in vivo models of various neuropathologies [116].…”

“…The treatment of neuronal diseases presents a significant challenge owing to the BBB, which limits the delivery of most biomolecules in therapeutic quantities to the CNS. In addition to the challenge posed by the BBB, many neuroprotective agents, such as PACAP, have short half-lives [115]. Specifically, when PACAP is administered intravenously (IV), it exhibits a remarkably brief half-life of less than 5 min due to its rapid degradation by dipeptidylpeptidase IV (DPP IV) (an exopeptidase responsible for cleaving X-proline or While CPP-functionalized nanoparticles are still being investigated, there are obstacles for their widespread use in the treatment of NDs.…”

“…In addition to the challenge posed by the BBB, many neuroprotective agents, such as PACAP, have short half-lives [115]. Specifically, when PACAP is administered intravenously (IV), it exhibits a remarkably brief half-life of less than 5 min due to its rapid degradation by dipeptidylpeptidase IV (DPP IV) (an exopeptidase responsible for cleaving X-proline or X-alanine dipeptides from the N-terminals of the polypeptides) [115]. In addition to IV administration, direct injection into the brain is not considered a readily available translational option due to its highly invasive nature and impractical clinical application.…”