Elsevier

Neurobiology of Disease

Volume 36, Issue 1, October 2009, Pages 223-231
Neurobiology of Disease

Pyruvate protects against experimental stroke via an anti-inflammatory mechanism

https://doi.org/10.1016/j.nbd.2009.07.018Get rights and content

Abstract

Pyruvate, a key intermediate in glucose metabolism, was explored as a potential treatment in models of experimental stroke and inflammation. Pyruvate was administered to rodents after the onset of middle cerebral artery occlusion (MCAO). Since the extent of inflammation is often proportional to the size of the infarct, we also studied a group of animals given lipopolysaccharide (LPS) to cause brain inflammation without cell death. Following MCAO, pyruvate did not affect physiological parameters but significantly reduced infarct volume, improved behavioral tests and reduced numbers of neutrophils, microglial and NFκB activation. Animals given LPS showed increased microglial and NFκB activation which was almost completely abolished by pyruvate. Lactate, a major metabolite of pyruvate, was increased after pyruvate administration. However, administration of lactate itself did not have any anti-inflammatory effects. Pyruvate protects against ischemia possibly by blocking inflammation, but lactate itself does not appear to explain pyruvate's anti-inflammatory properties.

Introduction

Pyruvate, a final metabolite in glycolysis, has recently been shown to have salutary effects in brain ischemia (Lee et al., 2001, Yi et al., 2007, Yu et al., 2005). The precise mechanism of pyruvate's protective effect is unclear, but has been correlated to a reduction in microglial activation and the suppression of pro-inflammatory cytokines following focal cerebral ischemia. In related models of cardiac ischemia, pyruvate was also shown to have both cardioprotective and anti-oxidant properties (Woo et al. 2004). At the in vitro level, ethyl pyruvate was found to inhibit nuclear factor-kappa B (NFκB) activation in both cultured microglia (Kim et al. 2005) and RAW 264.7 cells (Han et al., 2005, Ulloa et al., 2002) through a modification of its p65 subunit. In models of lethal sepsis, ethyl pyruvate also reduced mortality and reduced circulating levels of HMBG1 (Ulloa et al. 2002). Post ischemic inflammation, including activation of NFκB and inhibition of downstream immune mediators, has been established to contribute to ischemic progression (Wang et al. 2007). Thus, this anti-inflammatory property of ethyl pyruvate may be an important factor in its protective effect.

However, the ethyl group of ethyl pyruvate may itself have pharmacological actions which could have influenced prior observations. Whether pyruvate itself, an endogenous metabolic intermediate, also has anti-inflammatory effects is less clear. In order to study pyruvate in its more endogenous state, we study similar properties in sodium pyruvate. Further, whether sodium pyruvate has similar protective and anti-inflammatory properties is less clear, and the existing literature is conflicting (Gonzalez-Falcon et al., 2003, Kim et al., 2005, Lee et al., 2001). We explore here whether sodium pyruvate protects against experimental stroke, and whether it does so via an anti-inflammatory mechanism using a model of brain inflammation that does not cause brain cell death. Since pyruvate can be rapidly metabolized to lactate, we also explored whether any anti-inflammatory effect of pyruvate may be mediated through this metabolite.

Section snippets

Stroke model

All experiments were performed following an institutionally approved protocol in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Measures were taken, in accordance with the above guidelines to minimize pain and discomfort. Male Sprague–Dawley rats (Charles River) weighing between 270–300 g were anesthetized using isoflurane with a face mask and maintained with 1.5% isoflurane in 150 ml/min oxygen and 850 ml/min air. Rectal temperature and

Pyruvate did not affect physiologic parameters or mortality in MCAO

No significant differences were found among any of the physiological parameters monitored between control and pyruvate treated groups (Table 1). Mortality was less than 15% in each group, and not statistically different between groups. One animal died before the end of the experiments in the vehicle treated control group, and none among those given pyruvate.

Serum pyruvate and lactate levels after systemic administration

Blood pyruvate and lactate were evaluated at serial time points after the i.p. pyruvate injections. Blood pyruvate peaked 15 min after

Discussion

We show here that treatment of experimental stroke with systemically administered sodium pyruvate leads to reduction in infarct size and improved neurological deficits. This effect was associated with less inflammation and decreased activation of the inflammatory transcription factor, NFκB. Furthermore, we suggest a direct anti-inflammatory property of pyruvate, as administration led to similar decreases in microglial and NFκB activation in a model of pure brain inflammation that does not cause

Acknowledgments

This project was funded in part by the Dept. of Veterans Affairs (MAY, RAS) and grants: NIH NINDS R01 NS 40516 (MAY), AHA Established Investigator Award #0540066N (MAY), P50 NS14543 (RAS and MAY) and P01 NS37520 (MAY).

References (34)

  • ConnA.R. et al.

    Transport of alpha-keto analogues of amino acids across blood–brain barrier in rats

    Am. J. Physiol.

    (1982)
  • De RyckM. et al.

    Photochemical stroke model: flunarizine prevents sensorimotor deficits after neocortical infarcts in rats

    Stroke

    (1989)
  • DengH. et al.

    Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation

    Stroke

    (2003)
  • DesagherS. et al.

    Pyruvate protects neurons against hydrogen peroxide-induced toxicity

    J. Neurosci.

    (1997)
  • FongJ.J. et al.

    NXY-059: review of neuroprotective potential for acute stroke

    Ann. Pharmacother.

    (2006)
  • HanH.S. et al.

    Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation

    J. Neurosci.

    (2002)
  • HanH.S. et al.

    Mild hypothermia inhibits nuclear factor-kappaB translocation in experimental stroke

    J. Cereb. Blood Flow Metab.

    (2003)
  • Cited by (74)

    • The potential use of lactate blockers for the prevention of COVID-19 worst outcome, insights from exercise immunology

      2021, Medical Hypotheses
      Citation Excerpt :

      Implications of lactate blockers in COVID-19 To conclude, all of the previously mentioned approaches are considered promising therapeutic targets in preventing acute lung injury and in combating the fatal deteriorations of COVID-19 manifestations [39]. To date, there is no single study exploring the effect of beta-blockers on the rate of complications and mortality from COVID-19.

    View all citing articles on Scopus
    View full text