Epoxyeicosatrienoic acids pretreatment improves amyloid β-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes

Pallabi Sarkar, Ivan Zaja, Martin Bienengraeber, Kevin R. Rarick, Maia Terashvili, Scott Canfield, J R Falck, David R. Harder

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Amyloid-β (Aβ) has long been implicated as a causative protein in Alzheimer's disease. Cellular Aβ accumulation is toxic and causes mitochondrial dysfunction, which precedes clinical symptoms of Alzheimer's disease pathology. In the present study, we explored the possible use of epoxyeicosatrienoic acids (EETs), epoxide metabolites of arachidonic acid, as therapeutic target against Aβ-induced mitochondrial impairment using cultured neonatal hippocampal astrocytes. Inhibition of endogenous EET production by a selective epoxygenase inhibitor, MS-PPOH, caused a greater reduction in mitochondrial membrane potential in the presence of Aβ (1, 10 μM) exposure versus absence of Aβ. MS-PPOH preincubation also aggravated Aβ-induced mitochondrial fragmentation. Preincubation of the cells with either 14,15- or 11,12-EET prevented this mitochondrial depolarization and fragmentation. EET pretreatment also further improved the reduction observed in mitochondrial oxygen consumption in the presence of Aβ. Preincubation of the cells with EETs significantly improved cellular respiration under basal condition and in the presence of the protonophore, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). The uncoupling of ATP synthase from the electron transfer chain that occurred in Aβ-treated cells was also prevented by preincubation with EETs. Lastly, cellular reactive oxygen species production, a hallmark of Aβ toxicity, also showed significant reduction in the presence of EETs. We have previously shown that Aβ reduces EET synthesis in rat brain homogenates and cultured hippocampal astrocytes and neurons (Sarkar P, Narayanan J, Harder DR. Differential effect of amyloid beta on the cytochrome P450 epoxygenase activity in rat brain. Neuroscience 194: 241-249, 2011). We conclude that reduction of endogenous EETs may be one of the mechanisms through which Aβ inflicts toxicity and thus supplementing the cells with exogenous EETs improves mitochondrial dynamics and prevents metabolic impairment.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume306
Issue number4
DOIs
StatePublished - Feb 15 2014

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Amyloid
Astrocytes
Acids
Alzheimer Disease
Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Mitochondrial Dynamics
Cell Respiration
Mitochondrial Membrane Potential
Poisons
Epoxy Compounds
Brain
Neurosciences
Arachidonic Acid
Oxygen Consumption
Cytochrome P-450 Enzyme System
Reactive Oxygen Species
Adenosine Triphosphate
Electrons
Pathology
Neurons

Keywords

  • EETs
  • Mitochondrial fragmentation
  • Mitochondrial membrane potential
  • Oxygen consumption
  • ROS

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Epoxyeicosatrienoic acids pretreatment improves amyloid β-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes. / Sarkar, Pallabi; Zaja, Ivan; Bienengraeber, Martin; Rarick, Kevin R.; Terashvili, Maia; Canfield, Scott; Falck, J R; Harder, David R.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 306, No. 4, 15.02.2014.

Research output: Contribution to journalArticle

Sarkar, Pallabi ; Zaja, Ivan ; Bienengraeber, Martin ; Rarick, Kevin R. ; Terashvili, Maia ; Canfield, Scott ; Falck, J R ; Harder, David R. / Epoxyeicosatrienoic acids pretreatment improves amyloid β-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes. In: American Journal of Physiology - Heart and Circulatory Physiology. 2014 ; Vol. 306, No. 4.
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