A Novel Octapeptide Derived From G Protein-Coupled Receptor 124 Improves Cognitive Function Via Pro-Angiogenesis In A Rat Model Of Chronic Cerebral Hypoperfusion-Induced Vascular Dementia

Abstract

Purpose

The lack of effective therapies mandates the development of new treatment strategies for vascular dementia (VaD). G protein-coupled receptor 124 (GPR124) may be a therapeutic target for angiogenesis-related diseases of CNS, including VaD. The GCPF peptide is a truncated and screened fragment of the GPR124 extracellular domain. The potential use of GCPF for VaD treatment, angiogenesis and targeting of integrin αvβ3 are evaluated.

Methods and results

First, the in vivo results indicated that the GCPF peptide could decrease mean escape latency and increase platform crossing times in BCCAO rats. Second, the in vitro and ex vivo results indicated that the GCPF peptide was an active angiogenic peptide and could promote hCMEC/D3 cell migration and adhesion to ECM molecules. Third, in silico analyses predicted that GCPF could specifically interact with integrin αvβ3; the ∆G of GCPF binding to the binding pocket was −16.402 KJ/mol. The molecular characteristics indicated that highly hydrophilic GCPF with a pI of 11.70 had a short half-life in mammals (~1 hr). Finally, the ELISA experiments indicated that low dissociation constant (K_d= 2.412±0.455 nM) corresponds to the high affinity of GCPF for integrin αvβ3.

Conclusion

The data indicate that adhesion of GCPF immobilized on ECM surface to endothelial cells via integrin αvβ3 modulates cellular functions to promote angiogenesis and improve cognitive function. This is the first report to prove that GCPF, a novel octapeptide, may be an effective strategy for VaD therapy.

Keywords:

• G-protein coupled receptor 124
• vascular dementia
• chronic cerebral hypoperfusion
• angiogenesis
• integrin
• protein therapy

Acknowledgments

We thank China Pharmaceutical University for providing access to the Sybyl and MOE software packages. We also thank ELSEVIER author services for language editing.

Author Contributions

All authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.