Inhibition of Fatty Acid β-Oxidation in Rat Brain Cultured Astrocytes Exposed to the Neurotoxin 3-Nitropropionic Acid

Abstract

We describe the effects of the neurotoxin 3-nitropropionic acid (3-NPA) on fatty acid oxidation in neonatal rat brain astrocytes in primary culture, using a sensitive assay for β-oxidation which depends on the release of ³H₂O from [9,10(n)-³H]palmitic acid. 3-NPA is a suicide inhibitor of succinate dehydrogenase, a constituent of both Krebs cycle and complex II of the mitochondrial respiratory chain. It is widely distributed in plants and fungi. Neurotoxicity of 3-NPA to humans and animals, leading to selective neuronal cell death, appears mediated by the reduced level of ATP induced by the toxin. We demonstrated that 3-NPA can also impair energy metabolism in astrocytes. Exposure of astroglial cells in culture to 3-NPA leads to inhibition of the release of ³H₂O from [9,10(n)-3H]palmitic acid. Addition of 2 mM 3-NPA to the culture medium caused a rapid decrease in β-oxidation activity, which reached a plateau after 90 min. This inhibition was concentration-dependent. Concentration as low as 0.05 mM for 5 h significantly decreased β-oxidation activity (25% inhibition). Half-maximal inhibition was obtained after treatment with 0.5 mM 3-NPA, and 3 mM induced a maximal response (63% inhibition). 3-NPA is clearly a potent inhibitor of β-oxidation activity. We also show that 3-NPA 3 mM inhibits partially complex II (succinate ubiquinone reductase) and aspartate aminotransferase by 60 and 49% after 4 h treatment respectively. It has been shown that fatty acid is the preferred substrate for energy production in cultured astrocytes from developing brain. As astrocytes may also provide substrate alternative for energy metabolism in neurons and oligodendrocytes, it is likely that the inhibition of β-oxidation by 3-NPA may contribute significantly to the damage induced by this toxin in the central nervous system.

Cytochrome c oxidase isoform IV‐2 is involved in 3‐nitropropionic acid‐induced toxicity in striatal astrocytes

“…ATP levels were correlated to the number of viable cells surviving the treatment rather than the total number of cells initially used for the experiment or the protein amount determined after NPA treatment which are used in other studies. An observation made by Esfandiari et al demonstrating that SDH is only partially inhibited in astrocytes treated with 3 mM NPA for 4 h indicates that mitochondrial energy metabolism is not completely blocked by NPA and supports our data (Esfandiari et al, 1997). Taken into account that electrons enter the respiratory chain of mitochondria also at complex I, higher energy production can be assumed.…”

Opening of Mitochondrial ATP-Sensitive Potassium Channels Is a Trigger of 3-Nitropropionic Acid–Induced Tolerance to Transient Focal Cerebral Ischemia in Rats

“…22 However, 3-NPA itself is reported to inhibit ␤-oxidation in the central nervous system. 23 Therefore, our present results using 5-HD, together with those involving glibenclamide administration, suggest a key role of mitoK ATP as a trigger in the development of ischemic tolerance induced by 3-NPA in brain.…”

Altered cholesterol and fatty acid metabolism in Huntington disease

“…However, ethyl-EPA can stabilize membranes important in oxidative metabolism,26; modulate mitochondrial metabolism by increasing beta oxidation 27 and prevent mitochondrial apoptosis. 28 Ethyl-EPA has been shown to suppress apoptosis by affecting the phosphorylation of p38 MAPK 29 30 and the activation of p53 30. Ethyl-EPA also has direct effects on COX-2, PPAR receptors, and prostaglandin synthesis31 which may also lead to beneficial effects on the cellular metabolism of the central nervous system.…”