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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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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DOI: https://doi.org/10.1007/s12035-017-0435-4