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Molecular Neurobiology

, Volume 53, Issue 7, pp 4754–4771 | Cite as

Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System

  • Tatsurou YagamiEmail author
  • Hiromi Koma
  • Yasuhiro Yamamoto
Article

Abstract

Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippocampal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates cAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD2, PGE2, and PGI2 exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD2, PGE2, PGF, and TXA2 are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE2, PGF, and TXA2 can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE2 disrupts Ca2+ homeostasis by impairing Na+-Ca2+ exchange via EP1, resulting in the excess Ca2+ accumulation. Neither PGE2, PGF, nor TXA2 causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE2 is non-enzymatically dehydrated to a cyclopentenone PGA2, which induces neuronal cell death. Although PGD2 induces neuronal apoptosis after a lag time, neither DP1 nor DP2 is involved in the neurotoxicity. As well as PGE2, PGD2 is non-enzymatically dehydrated to a cyclopentenone 15-deoxy-Δ12,14-PGJ2, which induces neuronal apoptosis without a lag time. However, neurotoxicities of these cyclopentenones are independent of their receptors. The COX-2 inhibitor inhibits both the anchorage-dependent and anchorage-independent growth of glioma cell lines regardless of COX-2 expression, suggesting that some COX-2-independent mechanisms underlie the antineoplastic effect of the inhibitor. PGE2 attenuates this antineoplastic effect, suggesting that the predominant mechanism is COX-dependent. COX-2 or EP1 inhibitors show anti-neoplastic effects. Thus, our review presents evidences for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system.

Keywords

Cyclooxygenase Prostaglandin Thromboxane Cyclopentenone Long-term potentiation Stroke Alzheimer’s disease 

Abbreviations

AA

Arachidonic acid

Amyloid β protein

AC

Adenylate cyclase

AD

Alzheimer’s disease

AIDS

Acquired immunodeficiency syndrome

ALS

Amyotrophic lateral sclerosis

AMPA

Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BD

Bipolar disorder

CaMK II

Calcium/calmodulin-dependent protein kinase II

CJD

Creutzfeldt-Jakob disease

CNS

Central nervous system

COX

Cyclooxygenase

CRTH2

Chemoattractant receptor homologous molecule expressed on Th2 cells

CSF

Cerebrospinal fluid

cPGES

Cytosolic PGE synthase

cPLA2

Cytosolic phospholipase A2

15d-PGJ2

15-deoxy-Δ12,14-PGJ2

DP

Receptors for PGD2

EP

Receptors for PGE2

ER

Endoplasmic reticulum

FP

Receptors for PGF

H-PGDS

Hematopoietic PGD synthase

6-OHDA

6-Hydroxydopamine

IP

Receptors for PGI2

L-VDCC

L-type voltage-dependent calcium channel

L-PGDS

Lipocalin-type PGD synthase

LTP

Long-term potentiation

L-VDCC

L-type voltage-dependent Ca2+ channel

MAPK

Mitogen-activated protein kinase

MCA

Middle cerebral artery

mPGES

Membrane-associated perinuclear PGE synthase

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS

Multiple sclerosis

NMDA

N-methyl-d-aspartate

NSAIDs

Nonsteroidal anti-inflammatory drugs

MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS

Multiple sclerosis

PD

Parkinson’s disease

PG

Prostaglandin

PPARγ

Peroxysome proliferators-activated receptor γ

PLA2

Phospholipase A2

PLC

Phospholipase C

PKC

Calcium-dependent protein kinase

PKA

cAMP-dependent protein kinase

sPLA2

Secreted phospholipase A2

SNpc

Substantia nigra pars compacta

TP

Receptors for TXA2

TXA2

Thromboxane A2

WT

Wild type

Notes

Conflict of Interest

The authors have declared that no competing interests exist.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Tatsurou Yagami
    • 1
    Email author
  • Hiromi Koma
    • 1
  • Yasuhiro Yamamoto
    • 1
  1. 1.Division of Physiology, Faculty of Pharmaceutical SciencesHimeji Dokkyo UniversityHimejiJapan

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