More Than Three Decades After Discovery of the Neuroprotective Effect of PACAP, What Is Still Preventing Its Clinical Use?

Abstract

Discovered in 1989, pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with strong neuroprotective properties, as shown in various neurodegenerative preclinical models of Parkinson, Alzheimer, or Huntington diseases. PACAP neuroprotection has also been reported in animal models of cerebral ischemia and traumatic brain injury. The neuroprotective effect of PACAP occurs through its capacity to modulate most of the multiphasic aspects of neuronal diseases, such as oxidative stress, neuronal cell death, and inflammation. However, more than three decades after its discovery, and although PACAP neurotrophic and neuroprotective activities have now been largely documented, its clinical use is still awaited. Thus, the aim of this manuscript is to discuss the main reasons which limit the use of PACAP as a therapeutic agent for the treatment of neuronal diseases. To achieve this objective, an opinion survey has been conducted among experts in the field of PACAP, and a bibliographic investigation was carried out.

Keywords: Clinical use; Neurodegenerative diseases; Neuroprotection; PACAP.

Fig. 1

Number of studies addressing the PACAP neuroprotective effects from 1990 to December 2024 in PubMed

Fig. 2

Specialists’ response by percentage regarding potential clinical studies with PACAP

Fig. 3

Response to the survey regarding the PACAP metabolic instability and low bioavailability

Fig. 4

Specialists surveyed response regarding the three PACAP receptors’ activation

Fig. 5

Specialists’ answers regarding the interest to develop PACAP analogs

Fig. 6

Body temperature variations after PACAP administration intranasally (10 µg in 10 µl; IN; n = 7), intravenously (200 μl at a concentration of 0.02 μg/kg with 100 μl in the form of a bolus and then 100 μl by infusion over a 30-min period; IV; n = 7), or intraperitoneally (200 μl in the form of a bolus at a concentration of 0.02 μg/kg; IP; n = 8) in tMCAO mice. The control group represents mice with tMCAO treated 10 min after the reperfusion by intranasal administration of NaCl (0.9%; Ctrl; n = 7)