Neuroprotective effect of ethyl pyruvate against Zn(2+) toxicity via NAD replenishment and direct Zn(2+) chelation

Neuropharmacology. 2016 Jun;105:411-419. doi: 10.1016/j.neuropharm.2016.02.001. Epub 2016 Feb 3.

Abstract

Ethyl pyruvate (EP) is a simple aliphatic ester of pyruvic acid and has been shown to have robust protective effect in various pathological conditions. A variety of mechanisms have been reported to underlie the protective effects of EP, which include anti-inflammatory, anti-oxidative, and anti-apoptotic functions. Recently, we reported that EP suppressed high mobility group box 1 (HMGB1) release from primary microglial cells via direct Ca(2+) chelation. In the present study, we investigated whether and how EP chelates Zn(2+) in neurons when it is present at toxic levels. In cortical neurons treated with 40 μM of Zn(2+) for 24 h, both EP and pyruvate significantly suppressed neuronal cell death, although the potency of pyruvate was greater than that of EP, and that NAD replenishment contributed to the neuroprotective effects of both pyruvate and EP. However, when cortical neurons were exposed to acute treatment of Zn(2+) (400 μM, 15 min), EP, but not pyruvate, significantly suppressed neuronal death, despite the fact that NAD replenishment by EP was weaker than that by pyruvate. Spectrophotometric studies revealed that EP directly chelates Zn(2+), and this was confirmed in physiological contexts, such as, NMDA-treated primary cortical cultures and OGD-subjected hippocampal slice cultures, in which EP suppressed intracellular Zn(2+) elevation and neuronal cell death. In addition, EP markedly reduced the expressions of PARP-1 and of the NADPH oxidase subunit in Zn(2+)-treated primary cortical neurons, well known Zn(2+)-induced downstream processes. Together, these results show EP suppresses Zn(2+) induced neurotoxicity via dual functions, chelating Zn(2+) and promoting NAD replenishment.

Keywords: Chelation; Ethyl pyruvate; NAD; Neuroprotection; Zinc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Chelating Agents / pharmacology*
  • Glucose / deficiency
  • Hypoxia / prevention & control
  • N-Methylaspartate / metabolism
  • NAD / metabolism*
  • Neurons / drug effects
  • Neuroprotective Agents / pharmacology*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Primary Cell Culture
  • Pyruvates / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species
  • Zinc / metabolism
  • Zinc / toxicity*

Substances

  • Chelating Agents
  • Neuroprotective Agents
  • Pyruvates
  • Reactive Oxygen Species
  • ethyl pyruvate
  • NAD
  • N-Methylaspartate
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Glucose
  • Zinc