Abstract
Reactive oxygen species (ROS) are produced in enzymatic and non-enzymatic reactions and have important roles in cell signalling but also detrimental effects. ROS-induced damage has been implicated in a number of neurological diseases; however, antioxidant therapies targeting brain diseases have been unsuccessful. Such failure might be related to inhibition of ROS-induced signalling in the brain. Using direct kinetic measures of lipid peroxidation in astrocytes and measurements of lipid peroxidation products in brain tissue, we here show that phospholipase C (PLC) preferentially cleaves oxidised lipids. Because of this, an increase in the rate of lipid peroxidation leads to increased Ca(2+) release from endoplasmic reticulum (ER) stores in response to physiological activation of purinoreceptors with ATP. Both vitamin E and its water-soluble analogue Trolox, potent ROS scavengers, were able to suppress PLC activity, therefore dampening intracellular Ca(2+) signalling. This implies that antioxidants can compromise intracellular Ca(2+) signalling through inhibition of PLC, and that PLC plays a dual role - signalling and antioxidant defence.
Keywords:
Astrocyte; Ca2+; Lipid peroxidation; Phospholipase C.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Adenosine Triphosphate / pharmacology
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Animals
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Antioxidants / pharmacology
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Astrocytes / cytology
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Astrocytes / drug effects*
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Astrocytes / metabolism
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Calcium / metabolism*
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Calcium Signaling / drug effects*
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Cerebral Cortex / cytology
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Chromans / pharmacology
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Coculture Techniques
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / metabolism
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Inositol 1,4,5-Trisphosphate / metabolism*
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Lipid Metabolism / drug effects
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Lipid Peroxidation
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Male
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Mesencephalon / cytology
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Mesencephalon / drug effects
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Mesencephalon / metabolism
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Neurons / cytology
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Neurons / drug effects*
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Neurons / metabolism
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Primary Cell Culture
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Receptors, Purinergic
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Type C Phospholipases / antagonists & inhibitors
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Type C Phospholipases / metabolism*
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Vitamin E / pharmacology
Substances
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Antioxidants
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Chromans
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Reactive Oxygen Species
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Receptors, Purinergic
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Vitamin E
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Inositol 1,4,5-Trisphosphate
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Adenosine Triphosphate
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Type C Phospholipases
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6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
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Calcium