Cyclooxygenase-1 mediates neuroinflammation and neurotoxicity in a mouse model of retinitis pigmentosa

Abstract Background Retinitis pigmentosa (RP) is a group of inherited eye disorders with progressive degeneration of photoreceptors in the retina, ultimately leading to partial or complete blindness. The mechanisms underlying photoreceptor degeneration are not yet completely understood. Neuroinflammation is reported to play a pathological role in RP. However, the mechanisms that trigger neuroinflammation remain largely unknown. To address this question, we investigated the role of cyclooxygenase-1 (COX-1), a key enzyme in the conversion of arachidonic acid to proinflammatory prostaglandins, in the rd10 mouse model of RP. Methods We backcrossed COX-1 knockout mice (COX-1−/−) onto the rd10 mouse model of RP and investigated the impact of COX-1 deletion on neuroinflammation in the resulting COX-1−/−/rd10 mouse line, using a combination of immunocytochemistry, flow cytometry, qPCR, ELISA, and a series of simple visual tests. Results We found that genetic ablation or pharmacological inhibition of COX-1 alleviated neuroinflammation and subsequently preserved retinal photoreceptor and function and visual performance in rd10 mice. Moreover, we observed that the pharmacological inhibition of the prostaglandin E2 (PGE2) EP2 receptors largely replicated the beneficial effects of COX-1 deletion, suggesting that EP2 receptor was a critical downstream effector of COX-1-mediated neurotoxicity in rd10 mice. Conclusion Our data suggest that the COX-1/PGE2/EP2 signaling pathway was partly responsible for significantly increased neuroinflammation and disease progression in rd10 mice, and that EP2 receptor could be targeted therapeutically to block the pathological activity of COX-1 without inducing any potential side effects in treating RP patients.

Download Full-text

Structural Basis of Enantioselective Inhibition of Cyclooxygenase-1 by S-α-Substituted Indomethacin Ethanolamides

Journal of Biological Chemistry ◽

10.1074/jbc.m701335200 ◽

2007 ◽

Vol 282 (38) ◽

pp. 28096-28105 ◽

Cited By ~ 55

Author(s):

Christine A. Harman ◽

Melissa V. Turman ◽

Kevin R. Kozak ◽

Lawrence J. Marnett ◽

William L. Smith ◽

...

Keyword(s):

Binding Pocket ◽

Drug Binding ◽

Structural Basis ◽

Cyclooxygenase 1 ◽

Cox 2 ◽

The Impact ◽

First Time ◽

Side Pocket ◽

Cox 1 ◽

Equal Efficacy

The modification of the nonselective nonsteroidal anti-inflammatory drug, indomethacin, by amidation presents a promising strategy for designing novel cyclooxygenase (COX)-2-selective inhibitors. A series of α-substituted indomethacin ethanolamides, which exist as R/S-enantiomeric pairs, provides a means to study the impact of stereochemistry on COX inhibition. Comparative studies revealed that the R- and S-enantiomers of the α-substituted analogs inhibit COX-2 with almost equal efficacy, whereas COX-1 is selectively inhibited by the S-enantiomers. Mutagenesis studies have not been able to identify residues that manifest the enantioselectivity in COX-1. In an effort to understand the structural impact of chirality on COX-1 selectivity, the crystal structures of ovine COX-1 in complexes with an enantiomeric pair of these indomethacin ethanolamides were determined at resolutions between 2.75 and 2.85Å. These structures reveal unique, enantiomer-selective interactions within the COX-1 side pocket region that stabilize drug binding and account for the chiral selectivity observed with the (S)-α-substituted indomethacin ethanolamides. Kinetic analysis of binding demonstrates that both inhibitors bind quickly utilizing a two-step mechanism. However, the second binding step is readily reversible for the R-enantiomer, whereas for the S-enantiomer, it is not. These studies establish for the first time the structural and kinetic basis of high affinity binding of a neutral inhibitor to COX-1 and demonstrate that the side pocket of COX-1, previously thought to be sterically inaccessible, can serve as a binding pocket for inhibitor association.

Download Full-text

Assessment of the impact of PTGS1, PTGS2 and CYP2C9 polymorphisms on pain, effectiveness and safety of NSAID therapies

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0014.5497 ◽

2020 ◽

Vol 74 ◽

pp. 504-516

Author(s):

Miriam Dawidowicz ◽

Agnieszka Kula ◽

Paweł Świętochowski ◽

Zofia Ostrowska

Keyword(s):

Enzymatic Activity ◽

Inflammatory Diseases ◽

Aspirin Resistance ◽

Nucleotide Polymorphisms ◽

Cyclooxygenase 1 ◽

Genes Encoding ◽

Cox 2 ◽

Anti Inflammatory ◽

The Impact ◽

Cox 1

Cyclooxygenase 1 and 2 (COX-1, COX-2) are enzymes that catalyze the first reaction in the arachidonic acid pathway. COXs are the therapeutic target for non-steroidal anti-inflammatory drugs. Inhibition of COX enzymatic activity has an analgesic, anti-inflammatory and sometimes antiplatelet effect. Single-nucleotide polymorphisms (SNPs) within genes encoding COX-1 and COX-2 (PTGS1, PTGS2) influence the risk of pain and their intensity in some diseases. They also affect the effectiveness of NSAID therapy in rheumatoid diseases. Moreover, the relationship between certain polymorphisms of PTGS2 and a higher risk of migraine and the development of aspirin resistance in the prophylaxis of cardiovascular diseases was demonstrated. The isoform of cytochrome P450, CYP2C9 has a significant influence on the efficacy and safety of NSAID use. It is responsible for the metabolism and speed of removal of these drugs. The occurrence of some of its polymorphic forms is associated with a decrease in CYP2C9 enzymatic activity, leading to changes in the pharmacokinetics and pharmacodynamics of NSAIDs. The prolonged half-life and decrease in clearance of these drugs lead to serious side effects such as hepatotoxicity, nephrotoxicity, anaphylactic reactions, cardiovascular or gastrointestinal incidents. Studies on polymorphisms of cyclooxygenases and CYP2C9 may improve the safety and efficacy of NSAIDs therapy by adjusting the dose to individual polymorphic variants, as well as expanding knowledge about the pathomechanism of inflammatory diseases.

Download Full-text

Compensatory Prostaglandin E2 Biosynthesis in Cyclooxygenase 1 or 2 Null Cells

Journal of Experimental Medicine ◽

10.1084/jem.187.4.517 ◽

1998 ◽

Vol 187 (4) ◽

pp. 517-523 ◽

Cited By ~ 102

Author(s):

Kanyawim Kirtikara ◽

Scott G. Morham ◽

Rajendra Raghow ◽

Stanley J. F. Laulederkind ◽

Takuro Kanekura ◽

...

Keyword(s):

Prostaglandin E2 ◽

Wild Type ◽

Acidic Fibroblast Growth Factor ◽

Cox Inhibitors ◽

Cyclooxygenase 1 ◽

Enhanced Expression ◽

Key Enzyme ◽

Cox 2 ◽

Factor Α ◽

Cox 1

Prostaglandin E2 (PGE2) production in immortalized, nontransformed cells derived from wild-type, cyclooxygenase 1–deficient (COX-1−/−) or cyclooxygenase 2–deficient (COX-2−/−) mice was examined after treatment with interleukin (IL)-1β, tumor necrosis factor α, acidic fibroblast growth factor, and phorbol ester (phorbol myristate acetate). Compared with their wild-type counterparts, COX-1−/− or COX-2−/− cells exhibited substantially enhanced expression of the remaining functional COX gene. Furthermore, both basal and IL-1–induced expression of cytosolic phospholipase A2 (cPLA2), a key enzyme-regulating substrate mobilization for PGE2 biosynthesis, was also more pronounced in both COX-1−/− and COX-2−/− cells. Thus, COX-1−/− and COX-2−/− cells have the ability to coordinate the upregulation of the alternate COX isozyme as well as cPLA2 genes to overcome defects in prostaglandin biosynthetic machinery. The potential for cells to alter and thereby compensate for defects in the expression of specific genes such as COX has significant clinical implications given the central role of COX in a variety of disease processes and the widespread use of COX inhibitors as therapeutic agents.

Download Full-text

The impact of ST3GAL5 deficiency, the key enzyme in brain-specific ganglioside synthesis, on behaviour, metabolic regulation and neuroinflammation: a study in a new mouse model

10.26226/morressier.5b31ec712afeeb001345adf6 ◽

2018 ◽

Author(s):

Ekaterina Veniaminova ◽

Anna Gorlova

Keyword(s):

Mouse Model ◽

Metabolic Regulation ◽

Key Enzyme ◽

The Impact

Download Full-text

In vivo aspirin supplementation inhibits nitric oxide consumption by human platelets

Blood ◽

10.1182/blood-2005-02-0664 ◽

2005 ◽

Vol 106 (8) ◽

pp. 2737-2743 ◽

Cited By ~ 15

Author(s):

P. Claire Williams ◽

Marcus J. Coffey ◽

Barbara Coles ◽

Stephanie Sanchez ◽

Jason D. Morrow ◽

...

Keyword(s):

Nitric Oxide ◽

Human Platelets ◽

Controlled Study ◽

Double Blind ◽

Beneficial Effects ◽

Cyclooxygenase 1 ◽

No Consumption ◽

Cox 1

AbstractAntiplatelet therapies improve endothelial function in atherosclerosis, suggesting that platelets regulate vascular nitric oxide (NO) bioactivity in vivo. Herein, washed platelets consumed NO on activation in an aspirin-sensitive manner, and aspirin enhanced platelet NO responses in vitro. To examine whether in vivo aspirin can inhibit platelet NO consumption, a double-blind placebo-controlled study was conducted. After a 2-week nonsteroidal anti-inflammatory drug (NSAID)–free period, healthy men were randomly assigned and administered aspirin (75 mg/d orally) or identical placebo for 14 days, then crossed over to the opposite arm. Following in vivo aspirin, NO consumption by platelets was inhibited 91%. Rate of onset and recovery following aspirin withdrawal was consistent with cyclooxygenase 1 (COX-1) inhibition. In a small substudy, NO consumption by platelets from postmenopausal women was faster in hypercholesterolemics and less sensitive to aspirin (ie, 39% versus 76% inhibition for hypercholesterolemics or normocholesterolemics, respectively). However, 150 mg aspirin/day increased inhibition of NO consumption by platelets of hypercholesterolemics to 80%. Comparisons of platelet COX-1 or -2 expression and urinary 11-dehydro-thromboxane B2 excretion suggested that aspirin was less able to block platelet activation in vivo in hypercholesterolemia. In conclusion, aspirin inhibits NO consumption by platelets from healthy subjects, but its beneficial effects on NO bioactivity may be compromised in some hypercholesterolemic patients.

Download Full-text

Beneficial effects of black bean (Rhynchosia volubilis) on ocular surface damage induced by benzalkonium chloride in mouse model of dry eye

10.1055/s-0037-1608307 ◽

2017 ◽

Author(s):

A Kim Kyung ◽

W Kang Suk ◽

H Lee Chung ◽

J Yang Sung ◽

K Kang Tae ◽

...

Keyword(s):

Mouse Model ◽

Dry Eye ◽

Ocular Surface ◽

Benzalkonium Chloride ◽

Surface Damage ◽

Black Bean ◽

Beneficial Effects

Download Full-text

1875-P: The Impact of Carbohydrate/Fat Intake Balance on Beta-Cell Dedifferentiation and Fatty Liver in Obese Mouse Model

Diabetes ◽

10.2337/db20-1875-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1875-P ◽

Cited By ~ 2

Author(s):

EMI ISHIDA ◽

XIAO LEI ◽

EIJIRO YAMADA ◽

SHUICHI OKADA ◽

MASANOBU YAMADA

Keyword(s):

Mouse Model ◽

Beta Cell ◽

Fatty Liver ◽

Obese Mouse ◽

Fat Intake ◽

Cell Dedifferentiation ◽

The Impact

Download Full-text

HBOT Application at Cases of Gingival Inflammation

Journal of Dentistry and Oral Sciences ◽

10.37191/mapsci-2582-3736-1(3)-017 ◽

2019 ◽

Author(s):

Ilma Robo

Keyword(s):

Root Resorption ◽

Periodontal Diseases ◽

Therapeutic Effects ◽

Clinical Effects ◽

Gingival Inflammation ◽

Beneficial Effects ◽

New Therapeutic Approaches ◽

Short Period ◽

Mechanical Therapy ◽

The Impact

The treatment of periodontal diseases, mainly of their origin, with the most common clinical manifestation in form of gingival inflammation, is manifold and powerful, including: mechanical therapy, antibiotic, antiseptic and various approaches to treatment, which are recommended to be used within a short period of time. New therapeutic approaches have been proven as alternative treatment to conventional therapy, or in combination with conventional therapies, to reduce the number of periodontopathic pathogens in gingival sulcus. HBOT has a detrimental effect on periodontal microorganisms, as well as beneficial effects on the healing of periodontal tissue, increasing oxygen pressure in gingival pockets. Our study is aimed at reviewing the current published literature on hyperbaric oxygen therapy and focuses on role of HBOT as a therapeutic measure for the individual with periodontal disease in general and for the impact on the recovery of gingival inflammation. HBOT and periodontal treatment together, reduce up to 99% of the gram-negative anaerobic load of subgingival flora. HBOT, significantly reduces subgingival anaerobic flora. Clinical effects in 2-year follow-up of treated patients are sensitive. Reduction of gingival hemorrhage indexes, depth of peritoneum, plaque index, occurs in cases of combination of HBOT and detraction. Reduced load persists up to 2 months after therapy. The significant increase in connective tissue removal starts at the end of 2nd week, to achieve the maximum in week 3-6 of application. HBOT used for re-implantation, stimulates the healing of periodontal membrane, pulp, prevents root resorption, healing of periodontal lining tissues. HBOT, significantly reduces the hemorrhage index with 1.2 value difference, 0.7mm probe depth, reduces gingival fluid by 2. HGH exposure is increased by gingival blood flow, with a difference of 2 in measured value. The therapeutic effects of HBOT in the value of the evaluation index can be saved up to 1-year post treatment.

Download Full-text