Pituitary Adenlylate Cyclase Activating Peptide Protects Adult Neural Stem Cells from a Hypoglycaemic milieu

PLoS One. 2016 Jun 15;11(6):e0156867. doi: 10.1371/journal.pone.0156867. eCollection 2016.


Hypoglycaemia is a common side-effect of glucose-lowering therapies for type-2 diabetic patients, which may cause cognitive/neurological impairment. Although the effects of hypoglycaemia in the brain have been extensively studied in neurons, how hypoglycaemia impacts the viability of adult neural stem cells (NSCs) has been poorly investigated. In addition, the cellular and molecular mechanisms of how hypoglycaemia regulates NSCs survival have not been characterized. Recent work others and us have shown that the pituitary adenylate cyclase-activating polypeptide (PACAP) and the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 stimulate NSCs survival against glucolipoapoptosis. The aim of this study was to establish an in vitro system where to study the effects of hypoglycaemia on NSC survival. Furthermore, we determine the potential role of PACAP and Exendin-4 in counteracting the effect of hypoglycaemia. A hypoglycaemic in vitro milieu was mimicked by exposing subventricular zone-derived NSC to low levels of glucose. Moreover, we studied the potential involvement of apoptosis and endoplasmic reticulum stress by quantifying protein levels of Bcl-2, cleaved caspase-3 and mRNA levels of CHOP. We show that PACAP via PAC-1 receptor and PKA activation counteracts impaired NSC viability induced by hypoglycaemia. The protective effect induced by PACAP correlated with endoplasmic reticulum stress, Exendin-4 was ineffective. The results show that hypoglycaemia decreases NSC viability and that this effect can be substantially counteracted by PACAP via PAC-1 receptor activation. The data supports a potential therapeutic role of PAC-1 receptor agonists for the treatment of neurological complications, based on neurogenesis impairment by hypoglycaemia.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Blotting, Western
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Endoplasmic Reticulum Stress / drug effects
  • Exenatide
  • Gene Expression / drug effects
  • Glucose / metabolism
  • Glucose / pharmacology*
  • Hypoglycemic Agents / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Peptides / pharmacology*
  • Pituitary Adenylate Cyclase-Activating Polypeptide / pharmacology*
  • Protective Agents / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor CHOP / genetics
  • Venoms / pharmacology*


  • Ddit3 protein, mouse
  • Hypoglycemic Agents
  • Peptides
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Protective Agents
  • RNA, Messenger
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
  • Venoms
  • Transcription Factor CHOP
  • Exenatide
  • Caspase 3
  • Glucose

Grants and funding

This work was supported by Novo Nordisk foundation [Grant number 5421], (http://www.novonordiskfonden.dk/en/grantrecipients?field_date_value%5Bvalue%5D&field_date_value_1%5Bvalue%5D&field_related_center_tid=All&keys=&page=1), Diabetesfonden [Grant number DIA2013-010], (http://www.diabetesfonden.se/Forskning/Beviljade-projekt/), The Swedish Heart and Lung Foundation [grant number:20130523, (http://www.hjartlungfonden.se/Forskning/), The fighting stroke project (Uppdrag Besegra Stroke). This work has also been supported by grants from: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, The foundations Magnus Bergvalls, Syskonen Svensson, Åhlén, STROKE Riksförbundet, Gamla Tjänarinnor. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.