Neuropeptide Y Y2 and Y5 receptors as promising targets for neuroprotection in primary neurons exposed to oxygen-glucose deprivation and in transient focal cerebral ischemia in rats

Neuroscience. 2017 Mar 6;344:305-325. doi: 10.1016/j.neuroscience.2016.12.040. Epub 2017 Jan 3.

Abstract

It was postulated that neuropeptide Y (NPY)-ergic system could be involved in the ischemic pathophysiology, however, the role of particular subtypes of NPY receptors (YRs) in neuroprotection against ischemia is still not well known. Therefore, we investigated the effect of NPY and YR ligands using in vitro and in vivo experimental ischemic stroke models. Our in vitro findings showed that NPY (0.5-1μM) and specific agonists of Y2R (0.1-1μM) and Y5R (0.5-1μM) but not that of Y1R produced neuroprotective effects against oxygen-glucose deprivation (OGD)-induced neuronal cell death, being also effective when given 30min after the end of OGD. The neuroprotective effects of Y2R and Y5R agonists were reversed by appropriate antagonists. Neuroprotection mediated by NPY, Y2R and Y5R agonists was accompanied by the inhibition of both OGD-induced calpain activation and glutamate release. Data from in vivo studies demonstrated that Y2R agonist (10μg/6μl; i.c.v.) not only diminished the infarct volume in rats subjected to transient middle cerebral artery occlusion (MCAO) but also improved selected gait parameters in CatWalk behavioral test, being also effective after delayed treatment. Moreover, we found that a Y5R agonist (10μg/6μl; i.c.v.) did not reduce MCAO-evoked brain damage but improved stride length, when it was given 30min after starting the occlusion. In conclusion, our studies indicate that Y5 and especially Y2 receptors may be promising targets for neuroprotection against ischemic damage.

Keywords: CatWalk; MCAO; NPY; OGD; Y receptors; neuroprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Calpain / metabolism
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / physiology
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gait / drug effects
  • Gait / physiology
  • Glucose / deficiency
  • Glutamic Acid / metabolism
  • Ischemic Attack, Transient / drug therapy
  • Ischemic Attack, Transient / metabolism
  • Ischemic Attack, Transient / pathology
  • Male
  • Mice
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotection / drug effects
  • Neuroprotection / physiology
  • Neuroprotective Agents / pharmacology*
  • Random Allocation
  • Rats, Sprague-Dawley
  • Receptors, Neuropeptide Y / agonists*
  • Receptors, Neuropeptide Y / antagonists & inhibitors
  • Receptors, Neuropeptide Y / metabolism

Substances

  • Neuroprotective Agents
  • Receptors, Neuropeptide Y
  • neuropeptide Y2 receptor
  • neuropeptide Y5 receptor
  • Glutamic Acid
  • Calpain
  • Glucose