PACAP glycosides promote cell outgrowth in vitro and reduce infarct size after stroke in a preclinical model.

Autor: Bernard K; Physiological Sciences Graduate Program, The University of Arizona, Tucson, AZ 85724, United States., Dickson D; College of Nursing, The University of Arizona, Tucson, AZ 85724, United States., Anglin BL; Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, United States., Leandro Heien M; Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, United States., Polt R; Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, United States., Morrison HW; College of Nursing, The University of Arizona, Tucson, AZ 85724, United States., Falk T; Physiological Sciences Graduate Program, The University of Arizona, Tucson, AZ 85724, United States; Department of Neurology, The University of Arizona, Tucson, AZ 85724, United States; Department of Pharmacology, the University of Arizona, Tucson, AZ 85724, United States. Electronic address: tfalk@u.arizona.edu.
Jazyk: angličtina
Zdroj: Neuroscience letters [Neurosci Lett] 2024 Jul 27; Vol. 836, pp. 137883. Date of Electronic Publication: 2024 Jun 22.
DOI: 10.1016/j.neulet.2024.137883
Abstrakt: Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is a pleiotropic peptide known to promote many beneficial processes following neural damage and cell death after stroke. Despite PACAP's known neurotrophic and anti-inflammatory properties, it has not realized its translational potential due to a poor pharmacokinetic profile (non-linear PK/PD), and limited Blood-Brain Barrier Penetration (BBB) permeability. We have previously shown that glycosylation of PACAP increases stability and enhances BBB penetration. In addition, our prior studies showed reduced neuronal cell death and neuroinflammation in models of Parkinson's disease and Traumatic Brain Injury (TBI). In this study we show that a PACAP (1-27) glucoside retains the known neurotrophic activity of native PACAP (1-27) in vitro and a 5-day daily treatment regimen (100 nM) leads to neurite-like extensions in PC12 cells. In addition, we show that intraperitoneal injection of a PACAP (1-27) lactoside (10 mg/kg) with improved BBB-penetration, given 1-hour after reperfusion in a Transient Middle Cerebral Artery Occlusion (tMCAO) mouse model, reduces the infarct size after the ischemic injury in males significantly by ∼ 36 %, and the data suggest a dose-dependency. In conclusion, our data support further development of PACAP glycopeptides as promising novel drug candidates for the treatment of stroke, an area with an urgent clinical need.
Competing Interests: Declaration of Competing Interest MLH, TF, and RP hold patents related to the content. MLH, TF, and RP have equity in Teleport Pharmaceuticals, LLC, a UArizona biotech startup. This interest played no role in the design of the studies; in the collection, analyses, or interpretation of data; in the writing of the Paper, or in the decision to present the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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