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. 2015 Feb 17:9:17.
doi: 10.3389/fnins.2015.00017. eCollection 2015.

A unique array of neuroprotective effects of pyruvate in neuropathology

Yuri Zilberter  1 , Olena Gubkina  1 , Anton I Ivanov  1
Affiliations

A unique array of neuroprotective effects of pyruvate in neuropathology

Yuri Zilberter et al. Front Neurosci. .
No abstract available

Keywords: NAD; PARP-1; energy metabolism; neurodegeneration; neuroinflammation; oxidative stress; pyruvate.

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Figures

Figure 1
Figure 1
Pyruvate and lactate in normal and pathological conditions. (A) In normal conditions, glucose enters the cell via glucose transporters (GluT) and is metabolized in a 10-step glycolysis. Endogenous pyruvate is a final product of glycolysis and the main energy substrate for ATP generation in mitochondria. Excessive for mitochondria pyruvate can be transformed to lactate by lactate dehydrogenase (LDH) in the presence of NADH. Extracellular lactate can enter the cell via monocarboxylate transporters (MCT). Lactate then is converted to pyruvate by LDH in the presence of NAD+ (green arrows). This explains why extracellular lactate may serve efficiently as the energy fuel for brain cells. (B) The situation is changed radically under pathological conditions. A number of neurological disorders are characterized by the oxidative stress and increased level of interstitial glutamate—both factors inducing strong excitotoxicity. Oxidative stress results from excessive presence of ROS, while glutamate induces cellular overload with Ca2+ ions. ROS induce DNA damage leading to the overactivation of poly-ADP ribose polymerase-1 (PARP-1) that results in depletion of cytosolic NAD+. ROS also activate the pro-inflammatory transcription factor NF-kB inducing neuroinflammation. Depletion of NAD+ induces inhibition of glycolysis since the glycolysis step 6, conversion of glyceraldehyde 3-phosphate to 3-phosphoglycerate, requires two molecules of NAD+. This results in the insufficient outcome of pyruvate and decline in the mitochondrial ATP production. Moreover, NAD+ depletion makes ineffectual the conversion of lactate to pyruvate (dashed green arrows) and lactate cannot serve as the energy substrate anymore. (C) Exogenous pyruvate is able to ameliorate many impaired cellular functions described in (B). In blood, pyruvate activates a blood resident enzyme glutamate–pyruvate transaminase which transforms glutamate into 2-ketoglutarate and thus lowers the blood glutamate level. This results in an enhanced efflux of glutamate from brain parenchyma that reduces neuronal overload with Ca2+ ions. Pyruvate reacts directly with H2O2 producing acetate, H2O and CO2 and thus reducing oxidative stress. Pyruvate inhibits PARP-1 overactivation that prevents depletion of NAD+ and thus promotes glycolysis (glyceraldehyde-3-phosphate depending step). It also inhibits expression of several pro-inflammatory proteins, such as tumor necrosis factor (TNF), interleukin 6 (IL-6) and others. All these effects explain the neuroprotective properties of pyruvate.
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