Pyruvate protects against experimental stroke via an anti-inflammatory mechanism

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 NF-kB activation. Animals given LPS showed increased microglial and NF-kB 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.

Microglial Activation in Stroke: Therapeutic Targets

“…A final metabolite in glycolysis, pyruvate has recently been shown to have salutary effects in brain ischemia. [197][198][199][200] The mechanism of this protective effect is unclear, but it has been correlated with reduction in microglial activation and suppression of proinflammatory cytokines following focal cerebral ischemia. At the in vitro level, ethyl pyruvate (a prodrug form of pyruvate with improved brain penetrance) was found to inhibit NF-B activation in both cultured microglia and RAW 264.7 cells through a modification of the p65 subunit.…”

“…202 Further, pyruvate was also shown to inhibit microglial NF-B activation in rats given bacterial lipopolysaccharide, which causes transient microglial activation independent of any cell death. 200 Thus, pyruvate may directly inhibit microglial activation.…”

Anti-inflammatory mechanism of taurine against ischemic stroke is related to down-regulation of PARP and NF-κB

“…Active NF-jB is translocated into the nucleus and stimulates transcriptional activation of potentially deleterious pro-inflammatory genes, such as TNF-a, IL-1b, iNOS, and ICAM-1 (Kumar et al 2004;Ridder and Schwaninger 2009). In rodents, activation of NF-jB occurs after experimental stroke, and inhibiting the NF-jB signaling pathway due to pharmacological and genetic approaches has been reported to be neuroprotective in the model of experimental stroke (Schneider et al 1999;Williams et al 2006;Ridder and Schwaninger 2009;Wang et al 2009). …”

Global impairment and therapeutic restoration of visual plasticity mechanisms after a localized cortical stroke

“…One likely candidate, which might modify brain plasticity following stroke, are inflammatory reactions: stroke initiates a cerebral inflammatory reaction. Antagonizing this inflammation might reduce lesion size (17,18), although this has not been proved in patients yet. Furthermore, no systematic data are available on how an anti-inflammatory treatment regime might modify brain plasticity.…”