Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke

Can J Physiol Pharmacol. 2020 Sep;98(9):659-666. doi: 10.1139/cjpp-2020-0164. Epub 2020 Jun 23.

Abstract

Stimulation of endothelin B receptors by its agonist IRL-1620 (INN, sovateltide) provides neuroprotection and neurological and motor function improvement following cerebral ischemia. We investigated the effect of sovateltide on stem and progenitor cells mediated neural regeneration and its effect on the cerebral tissue repair and restoration of neurological and motor function. Sovateltide (5 μg/kg) was injected intravenously in permanent middle cerebral artery occluded (MCAO) rats at 4, 6, and 8 h at days 0, 3, and 6. Neurological and motor function tests were carried out pre-MCAO and at day 7 post-MCAO. At day 7, significantly reduced expression of neuronal differentiation markers HuC/HuD and NeuroD1 was seen in MCAO + vehicle than sham rats. Sovateltide treatment upregulated HuC/HuD and NeuroD1 compared to MCAO + vehicle and their expression was similar to sham. Expression of stem cell markers Oct 4 and Sox 2 was similar in rats of all of the groups. Significantly reduced infarct volume and DNA damage with recovery of neurological and motor function was observed in sovateltide-treated MCAO rats. These results indicate that sovateltide initiates a regenerative response by promoting differentiation of neuronal progenitors and maintaining stem cells in an equilibrium following cerebral ischemic stroke.

Keywords: AVC; IRL-1620; cellules progénitrices neuronales; endothelin; endothelin receptors; endothéline; ischemia; ischémie; neuronal progenitors; regeneration; récepteurs de l’endothéline; régénérescence; stroke.

MeSH terms

  • Animals
  • Brain / drug effects*
  • Brain / pathology
  • Cell Differentiation / drug effects
  • DNA Damage / drug effects
  • Disease Models, Animal
  • Endothelins / administration & dosage*
  • Humans
  • Infarction, Middle Cerebral Artery / complications
  • Infarction, Middle Cerebral Artery / drug therapy*
  • Infarction, Middle Cerebral Artery / pathology
  • Injections, Intravenous
  • Ischemic Stroke / drug therapy*
  • Ischemic Stroke / etiology
  • Ischemic Stroke / pathology
  • Male
  • Nerve Regeneration / drug effects
  • Neurons / drug effects
  • Neurons / pathology
  • Peptide Fragments / administration & dosage*
  • Rats
  • Receptor, Endothelin B / agonists
  • Receptor, Endothelin B / metabolism
  • Stem Cells / drug effects*
  • Stem Cells / pathology

Substances

  • Endothelins
  • Peptide Fragments
  • Receptor, Endothelin B
  • ednrb protein, rat
  • sovateltide