Neuroprotective effect of pharmacological postconditioning on cerebral ischaemia-reperfusion-induced injury in mice

J Pharm Pharmacol. 2019 Jun;71(6):956-970. doi: 10.1111/jphp.13073. Epub 2019 Feb 27.

Abstract

Objectives: To investigate the mechanism of neuroprotection rendered via pharmacological postconditioning in cerebral ischaemia-reperfusion-induced injury in mice.

Methods: Pharmacological postconditioning is strategy which either involves hindering deleterious pathway or inducing modest stress level which triggers intracellular defence pathway to sustain more vigorous insult leading to conditioning. Hence, in current research we explored the potentiality of CGS21680 (0.5 mg/kg; i.p), an adenosine A2 A receptor agonist and PTEN inhibitor, SF1670 (3 mg/kg; i.p.) to trigger postconditioning after inducing cerebral global ischaemia (17 min) and reperfusion (24 h)-induced injury via occlusion of both carotid arteries. Mice were also given treatment with LY294002 (1.5 mg/kg; i.p.), a PI3K inhibitor and adenosine A2 A receptor antagonist, Istradefylline (2 mg/kg; i.p.), to establish the precise mechanism of postconditioning. Various biochemical and behavioural parameters were assessed to examine the effect of pharmacological postconditioning.

Key findings: Pharmacological postconditioning induced with CGS21680 and SF1670 attenuated the infarction along with improved behavioural and biochemical parameters in comparison with ischaemia-reperfusion control group. The outcome of postconditioning with CGS21680 and SF1670 was significantly reversed by LY294002 and Istradefylline, respectively.

Conclusions: The neuroprotective effects of CGS21680 and SF1670 postconditioning on cerebral ischaemia-reperfusion injury may be due to PI3K/Akt pathway activation.

Keywords: LY294002; PI3K; global cerebral ischaemia; istradefylline; pharmacological postconditioning.

MeSH terms

  • Adenosine / administration & dosage
  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosine A2 Receptor Agonists / administration & dosage
  • Adenosine A2 Receptor Agonists / pharmacology
  • Animals
  • Brain Ischemia / prevention & control*
  • Chromones / pharmacology
  • Male
  • Mice
  • Morpholines / pharmacology
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology*
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • Phenanthrenes / administration & dosage
  • Phenanthrenes / pharmacology
  • Phenethylamines / administration & dosage
  • Phenethylamines / pharmacology*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Purines / administration & dosage
  • Purines / pharmacology
  • Reperfusion Injury / prevention & control*
  • Time Factors

Substances

  • Adenosine A2 Receptor Agonists
  • Chromones
  • Morpholines
  • Neuroprotective Agents
  • Phenanthrenes
  • Phenethylamines
  • Purines
  • SF1670
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • istradefylline
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Adenosine