Linoleic acid participates in the response to ischemic brain injury through oxidized metabolites that regulate neurotransmission

Abstract

Linoleic acid (LA; 18:2 n-6), the most abundant polyunsaturated fatty acid in the US diet, is a precursor to oxidized metabolites that have unknown roles in the brain. Here, we show that oxidized LA-derived metabolites accumulate in several rat brain regions during CO2-induced ischemia and that LA-derived 13-hydroxyoctadecadienoic acid, but not LA, increase somatic paired-pulse facilitation in rat hippocampus by 80%, suggesting bioactivity. This study provides new evidence that LA participates in the response to ischemia-induced brain injury through oxidized metabolites that regulate neurotransmission. Targeting this pathway may be therapeutically relevant for ischemia-related conditions such as stroke.

Brain oxylipin concentrations following hypercapnia/ischemia: effects of brain dissection and dissection time

“…This study shows that several PUFA metabolites, including those derived from LNA, DGLA, and ALA, are also involved in the response to hypercapnia/ischemia and dissection. This is consistent with our recent study showing increased oxylipins derived from multiple PUFA precursors in various brain regions following hypercapnia/ischemia/dissection (29). Collectively, these findings suggest that LNA, DGLA, and ALA are involved in the response to ischemia-related brain injury similar to ARA and DHA, despite accounting for less than 2% of brain total fatty acids.…”

“…Brains (500 mg) obtained from nonmicrowave-irradiated rats were homogenized in 400 µl extraction solvent containing antioxidants and surrogate standard. The brain samples used were remaining parts following the removal of the cortex, cerebellum, hippocampus, and brainstem for oxylipin analysis in a separate study (29). Homogenized samples were split into two: one sample was extracted directly, while the other was kept overnight at 80°C (with the brain homogenate) prior to extraction.…”

“…Some oxylipin extraction protocols, including ours, involve overnight incubation of homogenized samples in organic solvent at 80°C because this is thought to optimize oxylipin extraction from tissues (29,68). Prolonged incubation in an extraction mixture containing acetone-saline (2:1; v:v) at room temperature has been reported to increase the concentration of PGs and TXB 2 in nonmicrowaved brains, suggesting that COX or other lipid metabolic enzymes might be active in extraction solvents such as acetone (55).…”

“…The sample size of seven to eight rats per group was based on a previous experiment comparing brain oxylipin profiles of rats subjected to CO 2 -induced ischemia to those euthanized with head-focused microwave fixation (29). This sample size was sufficient to detect significant effects of CO 2 -induced ischemia on brain oxylipin concentrations at a significance level  of 0.05 and a statistical power (1  ) of 0.8.…”

Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment

“…Shifts in LA metabolism in the post-ischemic brain were described recently in a rat model. [29] In that study, an LA oxylipin was found to regulate neurotransmission, and the cytochrome p450-derived LA Transl. Stroke Res.…”