Melatonin alleviates asphyxial cardiac arrest-induced cerebellar Purkinje cell death by attenuation of oxidative stress

Exp Neurol. 2019 Oct:320:112983. doi: 10.1016/j.expneurol.2019.112983. Epub 2019 Jun 26.

Abstract

Although multiple reports using animal models have confirmed that melatonin appears to promote neuroprotective effects following ischemia/reperfusion-induced brain injury, the relationship between its protective effects and activation of autophagy in Purkinje cells following asphyxial cardiac arrest and cardiopulmonary resuscitation (CA/CPR) remains unclear. Rats used in this study were randomly assigned to 6 groups as follows; vehicle-treated sham operated group, vehicle-treated asphyxial CA/CPR operated group, melatonin-treated sham operated group, melatonin-treated asphyxial CA/CPR operated group, PDOT (a MT2 melatonin receptor antagonist) plus (+) melatonin-treated sham operated group and PDOT+melatonin-treated asphyxial CA/CPR operated group. Melatonin (20 mg/kg, i.p., 4 times before CA and 3 times after CA) treatment significantly improved survival rate and neurological deficit compared with the vehicle-treated asphyxial CA/CPR rats (survival rates ≥40% vs 10%), showing that melatonin treatment exhibited protective effect against asphyxial CA/CPR-induced Purkinje cell death. The protective effect of melatonin against CA/CPR-induced Purkinje cell death paralleled a remarkable attenuation of autophagy-like processes (Beclin-1, Atg7 and LC3), as well as a dramatic reduction in superoxide anion radical (O2·-), intense enhancements of CuZn superoxide dismutase (SOD1) and MnSOD (SOD2) expressions. Furthermore, the protective effect was notably reversed by treatment with PDOT, which is a selective MT2 antagonist. In brief, melatonin conferred neuroprotection against asphyxial CA/CPR-induced Purkinje cell death via inhibiting autophagic activation by reducing expressions of O2·- and increasing expressions of antioxidant enzymes, and suggests that MT2 is involved in neuroprotective effect of melatonin against Purkinje cell death caused by asphyxial CA/CPR.

Keywords: Antioxidant enzymes; Asphyxial cardiac arrest; Autophagy-like cell death; Melatonin; Melatonin receptor; Purkinje cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Asphyxia / etiology
  • Autophagy / drug effects
  • Heart Arrest / complications
  • Heart Arrest / pathology*
  • Male
  • Melatonin / pharmacology*
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects*
  • Purkinje Cells / drug effects*
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Melatonin, MT2 / metabolism

Substances

  • Antioxidants
  • Neuroprotective Agents
  • Receptor, Melatonin, MT2
  • Melatonin