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. 2014 Jun:71:362-367.
doi: 10.1016/j.freeradbiomed.2014.03.022. Epub 2014 Mar 24.

α-Lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice

Sylvia Hiller  1 , Robert DeKroon  2 , Longquan Xu  1 , Jennifer Robinette  3 , Witold Winnik  4 , Oscar Alzate  5 , Stephen Simington  1 , Nobuyo Maeda  1 , Xianwen Yi  6
Affiliations

α-Lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice

Sylvia Hiller et al. Free Radic Biol Med. 2014 Jun.

Abstract

Hypothermia is a key symptom of sepsis, but the mechanism(s) leading to hypothermia during sepsis is largely unknown and thus no effective therapy is available for hypothermia. Therefore, it is important to investigate the mechanism and develop effective therapeutic methods. Lipopolysaccharide (LPS)-induced hypothermia accompanied by excess nitric oxide (NO) production leads to a reduction in energy production in wild-type mice. However, mice lacking inducible nitric oxide synthase did not suffer from LPS-induced hypothermia, suggesting that hypothermia is associated with excess NO production during sepsis. This observation is supported by the treatment of wild-type mice with α-lipoic acid (LA) in that it effectively attenuates LPS-induced hypothermia with decreased NO production. We also found that LA partially restored ATP production, and activities of the mitochondrial enzymes involved in energy metabolism, which were inhibited during sepsis. These data suggest that hypothermia is related to mitochondrial dysfunction, which is probably compromised by excess NO production and that LA administration attenuates hypothermia mainly by protecting mitochondrial enzymes from NO damage.

Keywords: Antioxidant; Body energy; Free radicals; Lipoic acid; Mitochondria.

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Figures

Figure 1
Figure 1
Time course of hypothermia in wild type (WT) and iNOS−/− mice induced by lipopolysaccharides (LPS). A). α-lipoic acid (LA) was given at 30 min prior to LPS injection. Animal number: WT+LA=17; WT-LA=14; iNOS−/−+LA=10; iNOS−/−-LA=10. B). LA or ascorbate were administered at 30 min after LPS injection. Data are expressed as means ± SEM. Animal number: WT+LA=12; WT-LA=13; iNOS−/−+LA=10; iNOS−/−-LA=10; and WT+ascrobate=4.
Figure 1
Figure 1
Time course of hypothermia in wild type (WT) and iNOS−/− mice induced by lipopolysaccharides (LPS). A). α-lipoic acid (LA) was given at 30 min prior to LPS injection. Animal number: WT+LA=17; WT-LA=14; iNOS−/−+LA=10; iNOS−/−-LA=10. B). LA or ascorbate were administered at 30 min after LPS injection. Data are expressed as means ± SEM. Animal number: WT+LA=12; WT-LA=13; iNOS−/−+LA=10; iNOS−/−-LA=10; and WT+ascrobate=4.
Figure 2
Figure 2
Total plasma nitrate/nitrite (NOx) immediately before, and 4 hours after LPS injection in septic mice. Values are the mean ± SEM. Statistical analysis are by one-way ANOVA.
Figure 3
Figure 3
Effects of LA on energy production during sepsis. ATP content in the livers of the WT (A) and iNOS−/− mice (B) at 4 hours following LPS treatment. Control mice were injected with PBS. (C) Glutathione (GSH) levels in mitochondria isolated from liver of LPS-treated mice. All results are expressed as mean ± SEM. The numbers inside the bars indicate the number of animals used for each measurement.
Figure 3
Figure 3
Effects of LA on energy production during sepsis. ATP content in the livers of the WT (A) and iNOS−/− mice (B) at 4 hours following LPS treatment. Control mice were injected with PBS. (C) Glutathione (GSH) levels in mitochondria isolated from liver of LPS-treated mice. All results are expressed as mean ± SEM. The numbers inside the bars indicate the number of animals used for each measurement.
Figure 4
Figure 4
Activities of complex III and alpha-ketoglutarate dehydrogenase (KDH) in mitochondria isolated from liver of LPS-treated WT mice (A and C) and iNOS−/− mice (B and D) in the presence or absence of LA or ascorbate. (A and B) Complex III activity was expressed as nmole of reduced cytochrome C/minute per mg of protein. (C and D) KDH activity was determined by monitoring NAD+ reduction at 340 nm. The activities of two enzymes shown are the means ± SEM.
Figure 4
Figure 4
Activities of complex III and alpha-ketoglutarate dehydrogenase (KDH) in mitochondria isolated from liver of LPS-treated WT mice (A and C) and iNOS−/− mice (B and D) in the presence or absence of LA or ascorbate. (A and B) Complex III activity was expressed as nmole of reduced cytochrome C/minute per mg of protein. (C and D) KDH activity was determined by monitoring NAD+ reduction at 340 nm. The activities of two enzymes shown are the means ± SEM.
Figure 5
Figure 5
Serum concentrations of (A) prostaglandin E2 (PGE2), (B) tumor necrosis factor alpha (TNF-α), and (C) interleukin-6 (IL-6) at 2 hours and 4 hours after intraperitoneal injection of LPS in mice supplemented with LA compared to controls. Error bars represent SEM.
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