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Dear Colleagues,

Prostaglandins are a series of unsaturated fatty acids that play critical roles in regulating various neuronal signals. Endoperoxide H synthases-1/2 (cyclooxygenases-1/2, COX-1/2) catalyze the commitment step in prostaglandin synthesis.　Moreover, prostaglandins (PGD₂, PGE₂, PGF_2α), prostacyclin (PGI₂), and thromboxane A₂ (TXA₂) form the prostanoid family of lipid mediators.

Alterations in their biosynthesis are accompanied by a wide range of pathological conditions. Prostaglandin E2 (PGE2) is a membrane-derived lipid signaling molecule that has an important role in neuronal development. Abnormal PGE2 function, possibly due to environmental insult during prenatal development, has been linked to brain pathologies such as autism spectrum disorder (ASD). PGE2 may destabilize the actin cytoskeleton at various stages of neuronal differentiation, causing changes in neuronal morphology. Moreover, PGE2 is a lipid signaling molecule important for brain development and function in neuronal cell lines. Prenatal exposure to PGE2 affects the Wnt pathway at the level of β-catenin, the major downstream regulator of Wnt-dependent gene transcription. After maternal exposure, PGE2 signaling converges with the Wnt canonical pathway in the developing mouse brain. All affected genes have been previously associated with disorders of the central nervous system, including ASD. Additionally, the addition of PGE2 to neuronal cells leads to changes in the expression of Wnt genes and the activation of non-phospho β-catenin abnormal PGE2 levels in the mouse brain during development, which may interfere with the Wnt pathway via the phosphorylation of β-catenin at multiple sites, leading to a differential expression of crucial neurodevelopmental genes.

Prostaglandin H synthases or cyclooxygenases (COX -1 and COX-2) play a central role in the inflammatory cascade by converting arachidonic acid into bioactive prostanoids, which is relevant to the pathophysiology of ASD. COX-2 activity is linked to anti-inflammatory and neuroprotective actions and is involved in the generation of novel lipid mediators with pro-resolution properties.

The investigation of links between the various types of prostaglandins, Wnt signaling, and the role of COX -1 and COX-2 are important issues in the pathophysiology of ASD.

Prof. Dr. Kunio Yui
Guest Editor

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Keywords

autism spectrum disorder
prostaglandins
prostaglandin E2
cyclooxygenases
signaling mediator

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16 pages, 885 KiB

Open AccessArticle

Lipid Peroxidation via Regulating the Metabolism of Docosahexaenoic Acid and Arachidonic Acid in Autistic Behavioral Symptoms

by Kunio Yui, George Imataka and Tadashi Shiohama

Curr. Issues Mol. Biol. 2023, 45(11), 9149-9164; https://doi.org/10.3390/cimb45110574 - 15 Nov 2023

Cited by 1 | Viewed by 910

Abstract

The association between the lipid peroxidation product malondialdehyde (MDA)-modified low-density lipoprotein (MDA-LDL) and the pathophysiology of autism spectrum disorder (ASD) is unclear. This association was studied in 17 children with ASD and seven age-matched controls regarding autistic behaviors. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC). To compensate for the small sample size, adaptive Lasso was used to increase the likelihood of accurate prediction, and a coefficient of variation was calculated for suitable variable selection. Plasma MDA-LDL levels were significantly increased, and plasma SOD levels were significantly decreased in addition to significantly increased plasma docosahexaenoic acid (DHA) levels and significantly decreased plasma arachidonic acid (ARA) levels in the 17 subjects with ASD as compared with those of the seven healthy controls. The total ABC scores were significantly higher in the ASD group than in the control group. The results of multiple linear regression and adaptive Lasso analyses revealed an association between increased plasma DHA levels and decreased plasma ARA levels, which were significantly associated with total ABC score and increased plasma MDA-LDL levels. Therefore, an imbalance between plasma DHA and ARA levels induces ferroptosis via lipid peroxidation. Decreased levels of α-linolenic acid and γ-linolenic acid may be connected to the total ABC scores with regard to lipid peroxidation. Full article

(This article belongs to the Special Issue The Role of Prostaglandins in Autism)

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