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.
Highlights
Omega-6 linoleic acid (LA, 18:2 n-6) is the most consumed polyunsaturated fatty acid (PUFA) in the US diet, accounting for approximately 7% of daily calories[1]
Instead of incorporating into membrane phospholipids, up to 59% of the Linoleic acid (LA) entering the brain is converted into relatively polar compounds[29], which include LA-derived oxylipins[31] produced non-enzymatically or via the same LOX, COX, cytochrome P450 (CYP450) and soluble epoxide hydrolase (sEH) enzymes that act on arachidonic acid (AA) and DHA17, 32–34
LA itself is low in brain compared to AA and DHA28, its metabolites were abundant
Summary
Omega-6 linoleic acid (LA, 18:2 n-6) is the most consumed polyunsaturated fatty acid (PUFA) in the US diet, accounting for approximately 7% of daily calories[1]. LA was reported to raise seizure threshold in rats[50, 51], and to increase the number and duration of spontaneous wave discharges in a rat model of absence seizures[51], suggesting its involvement in neurotransmission It is not known whether the effects of LA in brain are mediated by LA itself or its oxidized metabolites, LA-metabolites have been detected in brain tissue[31, 52] and are known to activate pain-gating transient receptor potential vanilloid (TRPV) channels and inflammatory pathways in rodent spinal cord[53] and hindpaw[54], and to reduce retinal epithelial cell growth[55]. Understanding the conditions that increase the formation of LA-derived metabolites and whether they are bioactive in brain may inform on new pathways that could be targeted
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