Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System

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, PGF2α, 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, PGF2α, 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 Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange via EP1, resulting in the excess Ca(2+) accumulation. Neither PGE2, PGF2α, 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-Δ(12,14)-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.

The Role of mPGES-1 in Inflammatory Brain Diseases

“…On the contrary, the neuroprotective effects of PGE 2 have also been reported, thus, the effects of COX-2 inhibitors on the symptoms of epilepsy are still controversial. 5,39) The induction of mPGES-1 by KA has been recently reported in venous endothelial cells, and its deficiency significantly decreased not only hippocampal PGE 2 production, but also hippocampal neuronal damage.…”

“…31) PGE 2 , one of the most likely candidates for propagation of the inflammation, is known to accumulate in the SN of postmortem PD patients and animal models of PD induced by the neurotoxins 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA). 5) COX-2 has been demonstrated to be up-regulated in dopaminergic neurons and microglia of PD specimens and neurotoxin-induced animal models of PD. The genetic disruption and chemical inhibition of COX-2 have been shown to ameliorate dopaminergic neuronal death in neurotoxin-induced animal models of PD, suggesting that the PGE 2 accumulated through COX-2 induction mediates the toxic effects in the brain.…”

“…Under pathological conditions, excess PGE 2 is known to be produced in lesion sites in the brain and contributes to the progression of symptoms, while in some cases, it rather ameliorates the progression. 5,6) PGE 2 is derived from membrane phospholipids through three sequential enzymatic processes; phospholipase A 2 (PLA 2 ) which releases arachidonic acid (AA) from membrane phospholipids, cyclooxygenase (COX) which converts AA to PGH 2 , and prostaglandin E synthase (PGES) which isomerize PGH 2 to PGE 2 ( Fig. 1).…”

“…9) A large number of studies have demonstrated a neurotoxic role for COX-2 in a broad spectrum of inflammatory brain disease models, such as cerebral ischemia, neurodegenerative diseases, and traumatic brain injury. 5) In these brain disease models, since the genetic disruption and chemical inhibition of COX-2 resulted in the reduction of PGE 2 and amelioration of symptoms, it had been thought that PGE 2 produced by COX-2 may be involved in the progression of injuries. However, COX-2 produces not only PGE 2 , but also PGI 2 , PGD 2 , PGF 2α and thromboxane (TX) A 2 ( Fig.…”

Cyclooxygenase-1 as a Potential Therapeutic Target for Seizure Suppression: Evidences from Zebrafish Pentylenetetrazole-Seizure Model

“…Prostaglandin endoperoxide synthases (PTGS) or COX-1 and COX-2 are isoenzymes that catalyze the conversion of arachidonic acid into PGs (20). COX-1 and COX-2 have been traditionally classified into constitutive and inducible expression, respectively (20).…”