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

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Abstract

Prostaglandins (PGs) are divided into conventional PGs, e.g., PGD2, and cyclopentenone-type PGs, e.g., 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2). PGD2 is non-enzymatically metabolized to PGJ2, Δ12-PGJ2, and 15d-PGJ2. In the central nervous system, 15d-PGJ2 differentiates embryonic midbrain cells into dopaminergic neuronal cells via its nuclear peroxysome proliferator-activated receptor-γ (PPARγ). 15d-PGJ2 exerts conflict actions: proinflammatory and anti-inflammatory activities. In the brain, 15d-PGJ2 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-PGJ2 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-PGJ2. 15d-PGJ2 induces neuronal apoptosis via inactivating ubiquitin proteasome pathway and activating caspase cascade. Alternatively, 15d-PGJ2 downregulates phosphoinositide 3-kinase (PI3K)-Akt pathway and suppresses neurite outgrowth. 15d-PGJ2 possesses α,β-unsaturated ketone moiety in its cyclopentenone ring and acts an endogenous electrophile. By the Michael addition reaction, 15d-PGJ2 is covalently bound to cellular nucleophiles, such as free cysteine residues of proteins that regulate intracellular signaling pathways. There are specific binding sites of [3H]15d-PGJ2 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-PGJ2. In the present review, we provide evidences for pathophysiological roles of 15d-PGJ2 in the central nervous system and neurological diseases.

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Abbreviations

AA:

Arachidonic acid

Aβ:

Amyloid β protein

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

CNS:

Central nervous system

COX:

Cyclooxygenase

cPLA2 :

Cytosolic phospholipase A2

CRTH2:

Chemoattractant receptor-homologous molecule expressed on Th2 cells

CSF:

Cerebrospinal fluid

CTX:

Cerebral cortex

15d-PGJ2 :

15-Deoxy-△12,14-PGJ2

DP:

Receptor for PGD2

ERK:

Extracellular regulated MAP kinase

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GSK3β:

Glycogen synthase 3β

HPC:

Hippocampus

H-PGDS:

Hematopoietic PGD synthase

HSA:

Human serum albumin

IP3 :

Phosphatidylinositol-3,4,5-trisphosphate

JNK:

c-Jun N-terminal kinase

L-PGDS:

Lipocalin-type PGD synthase

LTP:

Long-term potentiation

L-VDCC:

L-type voltage-dependent Ca2+ channels

MAPK:

Mitogen-activated protein kinases

MCA:

Middle cerebral artery

NFT:

Neurofibrillary tangles

NMDA:

N-methyl-d-aspartate

NPCs:

Neural precursor cells

PC12:

Pheochromocytoma 12

PD:

Parkinson’s diseases

PG:

Prostaglandin

PI3K:

Phosphoinositide 3-kinase

PK:

Pyruvate kinase

PLA2 :

Phospholipase A2

PMO:

trans-Plasma-membrane oxidoreductase

PPARγ:

Peroxysome proliferators-activated receptor-γ

SBJ:

Specific binding sites of 15d-PGJ2

sPLA2 :

Secreted phospholipase A2

SNpc:

Substantia nigra pars compacta

STAT3:

Signal transducer and activator of transcription 3

TRP:

Transient receptor potential

Ub:

Ubiquitinated

UCH-L1:

Ubiquitin C-terminal hydrolase L1

UPP:

Ubiquitin proteasome pathway

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Acknowledgements

This study was supported by a Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant no. 16K18892).

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Yagami, T., Yamamoto, Y. & Koma, H. Physiological and Pathological Roles of 15-Deoxy-Δ12,14-Prostaglandin J2 in the Central Nervous System and Neurological Diseases. Mol Neurobiol 55, 2227–2248 (2018). https://doi.org/10.1007/s12035-017-0435-4

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