Physiological and Pathological Roles of 15-Deoxy-Δ12,14-Prostaglandin J2 in the Central Nervous System and Neurological Diseases

Abstract

Prostaglandins (PGs) are divided into conventional PGs, e.g., PGD, and cyclopentenone-type PGs, e.g., 15-deoxy-Δ prostaglandin J (15d-PGJ). PGD is non-enzymatically metabolized to PGJ, Δ-PGJ, and 15d-PGJ. In the central nervous system, 15d-PGJ differentiates embryonic midbrain cells into dopaminergic neuronal cells via its nuclear peroxysome proliferator-activated receptor-γ (PPARγ). 15d-PGJ exerts conflict actions: proinflammatory and anti-inflammatory activities. In the brain, 15d-PGJ possesses opposite functions as a neuroprotectant at low concentrations and a neurotoxicant at high concentrations in the brain. PPARγ contributes to the neuroprotective effect of 15d-PGJ but not to the neurotoxic effect. Its membrane receptor, chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2), is not also involved in the neurotoxicity of 15d-PGJ. 15d-PGJ induces neuronal apoptosis via inactivating ubiquitin proteasome pathway and activating caspase cascade. Alternatively, 15d-PGJ downregulates phosphoinositide 3-kinase (PI3K)-Akt pathway and suppresses neurite outgrowth. 15d-PGJ possesses α,β-unsaturated ketone moiety in its cyclopentenone ring and acts an endogenous electrophile. By the Michael addition reaction, 15d-PGJ is covalently bound to cellular nucleophiles, such as free cysteine residues of proteins that regulate intracellular signaling pathways. There are specific binding sites of [H]15d-PGJ in the plasma membrane of cerebral cortices. Besides CRTH2, plasmalemmal glycolytic enzymes, respiratory chain enzymes, molecular chaperones, adaptor proteins and cytoskeletons are identified as membrane targets for 15d-PGJ. In the present review, we provide evidences for pathophysiological roles of 15d-PGJ in the central nervous system and neurological diseases.

Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception

“…When activated by their ligands, which are mostly lipid metabolites, the PPARs can alter multiple physiological functions, including glucose absorption, lipid balance, cell growth, and inflammation, by inducing transcriptional regulation [235]. Interestingly, PGDs and cyclopentenone PGs, such as 15d-PGJ 2 , PGJ 2 , PGA 1 , and PGA 2 can activate PPARγ [236][237][238]. Among those examples, 15d-PGJ 2 has been investigated in the context of pain modulation.…”

4,4-Diisothiocyanatostilbene Disulfonic Acid Enhanced 15-Deoxy-Δ^12,14-prostaglandin J₂-Induced Neuronal Apoptosis

“…The VDAC inhibitor, DIDS, has been reported to protect cortical neurons against the oxygen-glucose deprivation. 29) However, we detected the neurotoxicity of DIDS, but not its neuroprotective effect, in the primary cortical neurons. In the immature culture, we focused direct effects of DIDS on neurons.…”

“…14) 15d-PGJ 2 induces neuronal differentiation 17) and neuroprotection 18) through its nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ) at low concentrations. In contrast, 15d-PGJ 2 induces neuronal cell death at high concentrations 10,19) independently of PPARγ or its membrane receptor chemoattractant receptor-homologous molecule expressed on T-helper 2 (Th2) cells. 20) VDACs have been reported as one of candidates targeted for 15d-PGJ 2 .…”

Metabolomics Analysis of Laparoscopic Surgery Combined with Wuda Granule to Promote Rapid Recovery of Patients with Colorectal Cancer Using UPLC/Q‐TOF‐MS/MS

“…Arachidonic acid, 11-HETE, and thromboxane B 2 in serum are products of arachidonic acid metabolism. Arachidonic acid is a major polyunsaturated fatty acid, is a precursor of many important eicosanoids (arachidonic acidderived inflammatory mediators) in mammals, and is abundant at the sn-2 position of membrane phospholipids [42]. Arachidonic acid can be metabolized by cyclooxygenases (COX) [43], lipoxygenases (LOX) [44], or cytochrome P450s (CYP450) [45].…”