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Non steroidal anti inflammatory drugs inhibit prostaglandin biology essay

This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. NSAIDs are used for a variety of conditions including pain, rheumatoid arthritis, and musculoskeletal disorders. The beneficial effects of NSAIDs in reducing or relieving pain are well established, and other benefits such as reducing inflammation and anticancer effects are also documented.

The undesirable side effects of NSAIDs include ulcers, internal bleeding, kidney failure, and increased risk of heart attack and stroke. Some of these side effects may be due to the oxidative stress induced by NSAIDs in different tissues. NSAIDs have been shown to induce reactive oxygen species ROS in different cell types including cardiac and cardiovascular related cells. Increases in ROS result in increased levels of oxidized proteins which alters key intracellular signaling pathways.

One of these key pathways is apoptosis which causes cell death when significantly activated. Introduction Nonsteroidal anti-inflammatory drugs NSAIDs are the most widely used over-the-counter drugs as well as the most prescribed class of drugs for a variety of conditions including pains, rheumatoid arthritis, osteoarthritis, musculoskeletal disorders, and other comorbid conditions [ 1 ].

Besides reducing or relieving pain Non steroidal anti inflammatory drugs inhibit prostaglandin biology essay have been shown to be useful as anticancer agents in various kinds of cancers [ 2 — 4 ]. However, NSAIDs also have undesirable side effects including ulcers [ 5 ], bleeding [ 6 ], kidney failure [ 78 ], and increased risk of heart attack and stroke [ 89 ].

One of the mechanisms which has been associated with the adverse effects of NSAIDs is the generation of oxidative stress. Administration of nonselective NSAIDs has been associated with side effects like peptic ulcer disease and gastrointestinal bleeding [ 10 ].

However, irrespective of their mechanism of action, prolonged exposure to any class of NSAIDs has been shown to have potential adverse effects on cardiovascular events in patients with or without preexisting cardiovascular conditions, depending on the duration and dosage of these drugs [ 1415 ] Table 1. Patients with preexisting cardiovascular conditions such as coronary artery disease, hypertension, and history of stroke are at the greatest risk of cardiovascular events after taking NSAIDs [ 1415 ].

Patients who have recently had cardiovascular bypass surgery are advised not to take NSAIDs due to a high risk of heart attacks [ 1617 ]. Meta-analyses of several trials have shown that coxibs are associated with a high risk of atherothrombotic vascular events [ 20 ].

  1. Received 2012 Sep 20; Accepted 2013 Jan 21.
  2. Microglial NADPH oxidase has been involved as a primary source of ROS and oxidative damage found in both AD brains and mouse models of neurodegenerative diseases [ 58 ], suggesting that long term use of these compounds could worsen tissue damage. Peroxide tone and swamping explain lack of peripheral analgesic and anti-inflammatory effect by paracetamol in peripheral organs, as the recruited leukocytes generate high concentrations of cellular peroxides.
  3. Apart from the phagocytic NADPH oxidase, in the last decade NADPH oxidase-dependent ROS generation was also identified in nonphagocytic cells including the endothelial cells, vascular smooth muscle cells, and cardiomyocytes of the cardiovascular system [ 113 ].
  4. Non-steroidal anti-inflammatory drugs inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes -2 and prostaglandin e 2.
  5. The committee concluded that the increased risk of fatal cardiovascular thrombotic events, myocardial infarction, and stroke by NSAIDS should be lessened by using the lowest effective dose of NSAIDs for the shortest period of time possible.

This pathway is responsible for the conversion of arachidonic acid to prostaglandins and thromboxanes [ 21 ]. In genetics, the abbreviation PTGS is officially used for the cyclooxygenase family of genes and proteins to prevent ambiguity with the cytochrome c oxidase family of genes and proteins which are also abbreviated COX. Arachidonic acid is the main precursor to the formation of various eicosanoids in the cyclooxygenase pathway.

Of all the metabolites formed in the arachidonic acid metabolism, thromboxane A2 in the platelets is the major product which along with prostacyclin prostaglandin I2 maintains vascular homeostasis [ 22 ] Figure 1.

Paracetamol:

Both these eicosanoids thromboxane A2 and prostaglandin I2 have opposing effects. While thromboxane is well known for its role in vasoconstriction and aggregation of platelets, prostacyclin is important for platelet aggregation inhibition and vasodilation. Coxibs as well as nonselective NSAIDs inhibit the formation of the metabolites of the cyclooxygenase pathway thereby disrupting the homeostasis maintained by these metabolites.

Coxibs cause an imbalance between the levels of thromboxane and prostacyclin being more favorable towards thromboxane and decreasing prostacyclin levels leading to the aggregation of platelets and causing thrombosis.

The COX enzyme is present as two isoforms, each with distinct functions: COX-1 is constitutively expressed in the stomach, kidneys, intestinal mucosa, and other tissues [ 23 ]. It protects the mucosal lining of the stomach and plays an important role in vasoconstriction and platelet aggregation [ 23 ]. On the other hand the inducible COX-2 is upregulated during times of inflammation where it causes vasodilation [ 24 ].

The critical difference between the isoenzymes, which permits the selective inhibition of each isoform, is the substitution of isoleucine 523 in COX-1 with valine in COX-2 [ 25 ]. The presence of valine, which is a smaller amino acid than isoleucine, allows drugs entrance to a hydrophobic side-pocket only accessible in COX-2.

Oxidative Medicine and Cellular Longevity

Expression of both isoforms, COX-1 and COX-2, may be upregulated and downregulated under various pathological conditions [ 26 ]. It is likely that the classification of the COX enzymes into two isoforms was an oversimplification [ 26 ] as COX-2 may be constitutively expressed in the brain [ 27 ], kidney [ 28 ], and testes [ 29 ]. In fact immunohistochemical studies have revealed the constitutive expression of COX-2 mRNA in the lung, thyroid gland, spleen, and adipose tissue, which was greater than COX-1 in these tissues, and in the liver both isoforms were expressed equally [ 29 ].

Therefore the idea that COX-2 can only be expressed under inducible conditions is unlikely since recent evidence suggests their occurrence in various human tissues under normal conditions. Coxibs disrupt the balance between the levels of thromboxane A2 and prostaglandin I2 leading to atherosclerosis, thrombosis, and other cardiovascular complications.

Coxibs, through their selective inhibition of COX-2, inhibit endothelial cell synthesis of prostacyclin [ 30 ]. Apoptosis programmed cell death induced by NSAIDs has been suggested to be due to oxidative stress caused by increased generation of reactive oxygen species ROS [ 37 ]. A series of mechanisms are involved wherein NSAIDs exert their cardiotoxic effects and cause various cardiac conditions. Various non-NSAID drugs like doxorubicin, azidothymidine, and cisplatin have been shown to induce oxidative stress as a consequence of elevated ROS levels [ 38 ].

Doxorubicin, for example, induced cardiotoxicity through DNA damage and apoptosis in cardiac cells as a result of oxidative stress which were reduced by the antioxidant effect of statin [ 37 ].

It is possible that the oxidative stress induced by NSAIDs, which is known to cause apoptosis and cell death, is significantly involved in causing cardiovascular dysfunction Figure 2. Few trials were carried out on patients with no history of CVD. An important finding is that not only nonselective NSAIDs lead to the development of hypertension in both normotensive and hypertensive individuals [ 39 ], but their use interferes with the antihypertensive medications except for the calcium channel blockers [ 40 ].

The risk of atrial fibrillation, heart failure, myocardial infarction, and other cardiovascular conditions also increased in patients with a history of these pathological conditions Table 2. Additionally, this paper reported that the use of NSAIDs with other antiplatelet drugs except aspirin increased the rate of cardiovascular events like cardiovascular death, myocardial infarction, and stroke [ 41 ]. Although a few studies suggest that COX selectivity does not seem to be a determining factor for myocardial infarction [ 1342 ], several studies suggest that non steroidal anti inflammatory drugs inhibit prostaglandin biology essay elevate the rate of incidences of CVD compared to nonselective NSAIDs [ 18 — 20 ].

Several clinical trials have been completed and are still ongoing, but some inconsistencies in the results exist regarding the effect of different types of NSAIDs on cardiovascular outcomes Table 2.

Targeted inhibition of COX-2, even for a short term, was found to increase the risk of atherothrombosis [ 46 ]. The main increased risk of cardiovascular events associated with COX-2 inhibitors was an increased risk of myocardial infarction [ 46 ].

Increased thromboembolic events have been associated with rofecoxib compared to naproxen [ 49 ]. In another trial rofecoxib was found to be associated with cardiac arrhythmias and renal conditions [ 50 ]. However similar adverse effects were not encountered in patients treated with other COX-2 inhibitors [ 50 ].

This effect of diclofenac has been attributed to its greater selectivity for COX-2 inhibition. It has also been reported that ibuprofen is associated with CVD comparable to the effect of COX-2 selective inhibitor, celecoxib [ 20 ]. It has been suggested that the difference between the effect exhibited by rofecoxib and other NSAIDs of the same class on cardiovascular incidences is due to the distinct chemical properties and prooxidant activity of rofecoxib [ 52 ].

The toxic effect of rofecoxib was reportedly due to its ability to reduce the low density lipoprotein LDL antioxidant capacity as a result of increased lipid peroxidation [ 52 ].

Merck voluntarily withdrew rofecoxib Vioxx in 2004. Pfizer was asked by the US Food and Drug Administration FDA to withdraw valdecoxib Bextra from the market in 2005 because of a higher than expected number of reports of serious and potentially life-threatening skin reactions and deaths. Naproxen seems to show less cardiovascular events than other commonly used NSAIDs, possibly because it mimics the activity of acetylsalicylic acid aspirin by suppressing cyclooxygenase platelet thromboxane B2 [ 53 ].

However, the role of naproxen in the non steroidal anti inflammatory drugs inhibit prostaglandin biology essay of CVD has been controversial. Several studies have reported the cardioprotective effect of the compound [ 54 — 56 ], and on the other hand increased cardiovascular risk has been associated with the use of this NSAID [ 57 — 59 ].

Aspirin is the only known NSAID which has antithrombotic activity through the inhibition of platelet aggregation in the artery of the heart thereby exhibiting cardioprotective effects [ 60 ].

It does so by acetylating the platelet COX-1 and irreversibly suppressing thromboxane A2 production, which is required for platelet aggregation and thrombus formation [ 60 ].

  • The role of aspirin in cardioprotection by the inhibition of platelet aggregation due to the inhibition of platelet thromboxane A2 is well established [ 154 , 155 ];
  • COX-1 activity ratio will hold a powerful anti-inflammatory activity with fewer side-effects than drugs with a less favorable COX-2;
  • Doxorubicin, for example, induced cardiotoxicity through DNA damage and apoptosis in cardiac cells as a result of oxidative stress which were reduced by the antioxidant effect of statin [ 37 ];
  • Coxibs, through their selective inhibition of COX-2, inhibit endothelial cell synthesis of prostacyclin [ 30 ].

Naproxen on the other hand causes reversible inhibition of cyclooxygenase by binding to the enzyme [ 61 ]. In the heart the main producer of ROS is the mitochondria [ 62 ]. Under normal physiological conditions, mitochondria generate ROS as a consequence of aerobic respiration [ 63 ]. The mitochondria-dependent overproduction of ROS has been reported under numerous pathological conditions including myocardial heart failure, inflammatory diseases, cancer, hypertension, and diabetes [ 64 — 67 ].

In myocardial heart failure, cardiomyocytes have been shown to be targeted by excessive ROS generation [ 64 ]. ROS levels and the redox state of a cell are considered to be important in the dysfunction of various biological signaling pathways. The formation of ROS via the reduction of molecular oxygen or by the oxidation of water leads to the formation of free radicals such as superoxide anionhydroxyl radicaland hydrogen peroxide H2O2. Oxidative stress arises when the oxidant production sum of all the ROS surpasses the antioxidant capacity in the cells.

Under normal physiological conditions low amounts of in the cardiomyocytes are converted to the less toxic H2O2 by the enzyme superoxide dismutase SOD.

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The reaction further proceeds by the formation of water by the action of the enzyme catalase or glutathione peroxidase GPx system [ 68 ]. However, when a homeostatic imbalance between the cellular antioxidant capacity and ROS levels occurs, elevated ROS levels can damage cellular macromolecules including lipids, proteins, and nucleic acids.

High levels of ROS also accelerate cell death due to apoptosis as well as necrosis by the activation of poly adenosine diphosphate ribose polymerase [ 69 ] and thus significantly contribute to the development of various pathological conditions [ 70 ].

Non Steroidal Anti Inflammatory Drugs Inhibit Prostaglandin Biology Essay

The generation of ATP in the mitochondria utilizes the electrons from reduced substrates that are transferred to an acceptor molecule of the electron transport chain ETC. Leakage of electrons from the mitochondria ETC results in formation [ 71 ]. The generation of ROS increases in intact mitochondria as well as in submitochondrial particles due to the oxidation of complex I substrates as a result of inhibiting complex III by antimycin A [ 72 ]. On the other hand, rotenone, an inhibitor of complex I, prevented the antimycin A induced ROS generation in mitochondria but not in the submitochondrial particles [ 72 ].

The ROS status in the cellular system regulates many biological processes. While increased levels of ROS have been shown to be involved in various pathological conditions, under basal conditions, the generation of free radicals in the heart is needed for cellular responses including regulating myocyte growth and maintaining vascular smooth muscle tone [ 73 ].

Basal levels of ROS play an important role in the increase of cell cycle progression and intracellular signaling associated with phosphorylation of several signaling proteins like mitogen-activated protein kinases MAPKs and protein kinase B [ 74 ].

  1. Prostaglandins in the tummy lead to a lessening in stomachic secernments ; hence, suppressing the synthesis of prostaglandins leads to an addition in subdivisions which may take to ulcers. Paracetamol has few inauspicious side effects as it is tolerated by the tummy because suppression of prostaglandin in the fringe is weak ; allergic reactions and clamber roseola sometimes occur.
  2. Non-steroidal anti-inflammatory drugs inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes -2 and prostaglandin e 2.
  3. Meta-analyses of several trials have shown that coxibs are associated with a high risk of atherothrombotic vascular events [ 20 ]. It is possible that the oxidative stress induced by NSAIDs, which is known to cause apoptosis and cell death, is significantly involved in causing cardiovascular dysfunction Figure 2.
  4. This state is referred to as the uncoupled state of eNOS and is mainly attributed to the deficiency or lack of BH4 leading to the generation of free radicals [ 144 ]. It has two interconvertible forms.
  5. Among the synthetic agonists are the anti-diabetic thiazolidinediones and few NSAIDs, such as indomethacin, ibuprofen and diclofenac.

Under normal physiological conditions, ROS upregulates the Akt signaling pathway and promotes cell survival [ 75 ]. ROS also behaves as second messengers in signaling pathways wherein it has been demonstrated that, in the presence of basal ROS levels, tyrosine phosphatase activity is higher relative to its kinases [ 76 ].

Non-steroid anti-inflammatory drugs, prostaglandins, and cancer

Ligand stimulation as in the case of neutrophils, through the binding of cytosolic proteins to a membrane bound oxidase leads to increased ROS levels and deactivation of tyrosine phosphatases with a consequent increase in the kinase activity [ 76 ].

This condition is transient and is reversed by reductions in ROS levels. Current experimental data suggest that the main mechanism through which NSAIDs exert their anticancer activity is through the generation of ROS leading to oxidative stress and finally apoptosis in cancer cells [ 79 — 82 ].

ROS is accompanied by the activation and inhibition of several signaling pathways associated with cell death and cell survival although controversies exist regarding the role of ROS in the downregulation and upregulation of these pathways [ 8384 ].

The Akt pathway is one of the most important pathways for promoting cell survival and growth, and it has been shown that high ROS levels are lethal and can inactivate the Akt signaling pathway [ 85 ]. Its downregulation was demonstrated by exposure of HLEC human lymphatic endothelial cells cells to sustained oxidative stress [ 86 ]. Similarly, diclofenac-induced apoptosis of various kinds of cancer cells has been reported [ 87 ]. This apoptosis is mainly mediated by an increase in the intracellular levels of the ROS [ 87 ].

  • More specifically the yeast deletion strains lacking the genes encoding subunits of the mitochondrial complexes III and IV were significantly resistant to diclofenac as well as indomethacin and ketoprofen [ 95 ];
  • In this review, we appraise the biological activities of prostanoids and their cognate receptors in the context of cancer biology;
  • Two families with opposing effects belong to this category of fatty acids;
  • Under normal physiological conditions, ROS upregulates the Akt signaling pathway and promotes cell survival [ 75 ];
  • It is hence attractive to propose that the anti-inflammatory actions of NSAIDs are due to suppression of COX-2, whereas the unwanted side-effects, such as annoyance of the tummy liner, are due to suppression of COX-1;
  • The generation of ATP in the mitochondria utilizes the electrons from reduced substrates that are transferred to an acceptor molecule of the electron transport chain ETC.

In the cardiovascular system the major sources of ROS generation include the mitochondria, NADPH oxidases, xanthine oxidoreductases, lipoxygenase, cyclooxygenases, nitric oxide synthases, and cytochrome P450 based enzymes Figure 2. Continuous exposure of cardiovascular cells to oxidative stress associated with elevated ROS levels would result in altered cellular homeostasis which could be an important contributing factor for various cardiovascular conditions.

Endothelial cells play a critical role in maintaining vascular homeostasis which is important for the control of many cardiovascular diseases including atherosclerosis and thrombosis [ 88 ].

  • Therefore the idea that COX-2 can only be expressed under inducible conditions is unlikely since recent evidence suggests their occurrence in various human tissues under normal conditions;
  • It is a really good anti-inflammatory effects it helps in status for illustration the intervention of musculoskeletal upsets, such as arthritic arthritis, degenerative arthritis and ancylosing spondylitis;
  • Although direct comparisons between the different clinical studies shown in Table 2 are not possible, these studies suggest that CVD in NSAID users are influenced by the study populations used such as with versus without preexisting acute myocardial infarction;
  • Differential inhibition of prostaglandin endoperoxide synthase cyclooxygenase isozymes by aspirin and other non-steroidal anti-inflammatory drugs;
  • As smoking or use of non steroidal anti-inflammatory drugs prostaglandin biology in inflammatory anti-inflammatory drugs and inflammatory.

Both sulindac and indomethacin significantly increased cleaved poly ADP-ribose polymerase PARP levels as well as increasing the level of the apoptotic activating factor caspase-3 [ 89 ]. Mitochondria Are the Main Target Organelles of the NSAIDs It has been shown that the heart is more susceptible to ROS generation induced by drugs like doxorubicin compared to other tissues of the body although the drugs are evenly distributed throughout the body [ 90 ].

This is possibly due to high levels of mitochondria in the heart which are the major producers of ROS in the cardiovascular system.