MPO FA and Its Role in Ischemic Brain Injury

Myeloperoxidase (MPO) is an antimicrobial enzyme that catalyzes the oxidation of various reducing substrates. It is known to contribute to the pathogenesis of a number of diseases, including inflammatory, cardiovascular and liver diseases.

MPO is activated by a variety of stimuli, such as granulocyte macrophage colony stimulating factor (GM-CSF), phorbol mysristate acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (fMLP). Inhibition of MPO leads to a reduction in the activity of these signaling proteins and reduces oxidative stress and inflammation.

Reduces Inflammation

Inflammation plays an important role in ischemic brain injury. It involves a complex array of cellular mediators and signaling pathways. Among them, MPO activity is one of the most significant ones. Inhibition of MPO activity by LY294002 and ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats) reduces the oxidative stress, neuroinflammation, and the development of brain dysfunctions in ischemic stroke mice. In addition, 4-ABAH, a novel anti-inflammation agent, promoted neurogenesis and protected neuronal stem cells in post-ischemic brains.

MPO can activate the PI3K/AKT pathway, which mediates inflammation. Inhibition of PI3K/AKT by LY294002 and ADAMTS13 also significantly reduced the MPO-induced inflammation and oxidative stress in ischemic brain injury mice. Additionally, a recombinant MPO-deficient protein, KYC, was found to inhibit pro-inflammatory M1 microglial cells and N1 neutrophils in post-ischemic rat brains and promote the development of neurons in the subventricular zone, striatum, and cortex.

Furthermore, MPO deficiency suppresses hepatic inflammation and liver fibrogenesis in NASH mice, which is mediated by neutrophil recruitment. This is a surprising finding, because it is generally assumed that the recruitment of macrophages is essential for inflammation-driven hepatic fibrogenesis and NASH progression.

Moreover, AZM198 induced a robust decrease in the MPO-induced expression of proinflammatory genes in liver tissues, including Il1b, Tnfa, and Ccl2, which were previously shown to be relevant to NASH-related liver injury. These results suggest that MPO plays a critical role in hepatic inflammation and fibrogenesis during NASH progression, thereby contributing to hepatoprotection by AZM198.

Another important role of MPO in inflammatory processes is its capacity to produce HOCl, which is a toxic oxidant that promotes tissue damage and can lead to infection and disease. In vivo, HOCl overproduction is associated with several respiratory pathologies, including cystic fibrosis and chronic obstructive pulmonary disorder. In addition, oxidative stress by MPO-mediated HOCl is an important pathological process in vascular diseases such as ischemic heart disease and stroke.

It is therefore possible that MPO inhibitors can be used in a range of inflammatory diseases, as they may provide an anti-inflammatory and anti-tumor effect without impairing innate immunity or pathogen killing. Nevertheless, further studies are needed to evaluate the therapeutic potential of MPO inhibition.

Anti-Inflammatory

MPO FA has been shown to reduce inflammation and improve neuronal function following ischemic brain injury. This enzyme is a member of the peroxidase family, which catalyzes the reaction of hydrogen peroxide (H2O2) with chloride ions to form hypochlorous acid (HOCl). HOCl promotes inflammatory responses and can also induce tissue damage. It can also initiate the development of autoimmune conditions and cancers, as well as contribute to heart disease by damaging vascular tissue.

The MPO enzyme is secreted by a subset of neutrophils (about 5% of the dry mass) to protect the body from infection by microorganisms and other pathogens. It is released during neutrophil activation by phagosome-lysosome fusion and by NADPH oxidase complex assembly on the phagolysosome internal membrane surface. It is present in a variety of cellular compartments, including endothelial cells, monocytes, macrophages, astrocytes and lymphocytes.

In the innate immune system, MPO is found mainly in lysosomal azurophilic granules of activated neutrophils and phagocytes. It is a highly active peroxidase that is capable of generating superoxide anions (O2*-), which dismutate to hydrogen peroxide (H2O2), and other reactive species. It is a key player in the inflammatory response and plays a critical role in various autoimmune diseases, such as lupus erythematosus, multiple sclerosis and rheumatoid arthritis.

However, MPO may also be involved in a wide range of other inflammatory processes such as atherosclerosis, bronchitis and inflammatory bowel disease. It is the key molecule MPO FA responsible for oxidative stress and inflammation, affecting several major inflammatory pathways. It is believed that MPO mediated cytotoxicity, oxidative damage and tissue dysfunction are important factors in the progression of chronic inflammatory diseases such as diabetes, obesity and hypertension.

MPO is known to be a target for anti-inflammatory therapies, such as t-PA treatment, and its plasma levels are increased in ischemic stroke patients (Dominguez et al., 2010). It is thought that MPO activity plays a role in the development of ischemia-reperfusion injury to the BBB and can also play a role in inflammatory mediators-mediated hemorrhagic transformation.

In a recent mouse model of heart failure, treatment with the MPO inhibitor AZM198 significantly reduced plasma MPO levels. Moreover, MPO-/- mice showed less adipose inflammation and fat accumulation, suggesting that MPO deficiency could preserve cardiac function in heart failure models.

Anti-Cancer

Activated leukocytes release myeloperoxidase (MPO), an oxidase enzyme that produces HOCl and other strong oxidants, which play a critical role in innate immune responses to bacterial or viral infection. However, excessive production of HOCl can lead to tissue damage and the development of disease (202).

In the peritoneal cavity, MPO-released HOCl has been shown to promote inflammatory conditions, including atherosclerosis, chronic kidney disease, arthritis, and cancer. These pathologies are associated with poor prognoses and significant morbidity and mortality worldwide.

As a result, there is an increasing need to find effective ways to inhibit MPO and limit the production of HOCl. One such approach involves modulating MPO activity via a thioxanthine derivative called 2-thioxanthine (253). Another strategy is to use an antioxidant, such as rosmarinic acid, which blocks MPO-mediated HOCl formation by scavenging superoxide radicals.

There is also evidence that MPO-mediated inflammation can contribute to tumor growth in the peritoneal cavity. Infiltrating tumor-associated neutrophils (TANs) express MPO and can interact with TANs to promote tumor growth by interfering with the ability of natural killer cells (NK cells) to clear cancer from the circulation and therefore promoting metastasis. TANs also secrete chemokines that promote the formation of blood-borne tumor-supporting cells, such as macrophages and dendritic cells.

The cytotoxic properties of MPO are largely dependent on the availability of hydrogen peroxide (H2O2). As MPO is catalytically active in vivo, H2O2 must be available to form the oxidants, and limiting this process can be achieved by supplementation with other anions, such as NO2- or SCN-, which can react with MPO to yield less potent, slow-reacting oxidants that are potentially safer for the body.

A key intermediate in the MPO reaction is Compound II, which is formed by a one-electron reduction of the heme group to give the ferric state. This can be reacted with O2 to produce O2*-, or it can react directly with the heme groups of Compound I and give the iron protoporphyrin IX (Fe3+) complex. This can then be recycled to generate the oxidant Compound III, which can also act as a catalyst for other MPO reactions.

Anti-Aging

Myeloperoxidase is an enzyme released from the polymorphonuclear neutrophils and other white blood cells during different inflammatory processes and at the site of infection. It is a biomarker of inflammation in various diseases such as tuberculosis, asthma, rheumatoid arthritis, chronic sinusitis, and peptic ulcers.

In normal conditions, MPO produces different reactive oxygen and nitrogen species (ROS and RNS), which are essential for oxidation and chemical modifications of various lipoproteins and lipids. It also mediates protein nitrosylation, tyrosyl radical formation, dityrosine crosslinking, and 3-chlorotyrosine formation. These oxidative activities of MPO have an antibacterial effect against bacteria and other pathogens.

Besides, MPO plays an important role in the production of hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanate (SCN-) that are used by neutrophils to kill bacterial invaders. These HOCl- and MPO-derived oxidants are potent oxidants that are toxic for bacteria in the presence of antioxidants such as superoxide dismutase and nitric oxide.

However, excessive production of MPO is a risk factor for several diseases such as cardiovascular disease, cancer, and liver diseases. The overproduction of MPO-derived oxidants can cause mutagenesis and cell damage. In some cases, this oxidant can even lead to cancerous tumors.

MPO has a high affinity for proteins and DNA. It can bind to cytosine and thymidine residues in the promoter region of the MPO gene, which can be responsible for abnormal transcription and expression of this peroxidase. Moreover, genetic defects in the MPO gene can increase the risk of certain types of cancers.

Therefore, there is a need for further research on the biochemical and pathological effects of MPO. This research may help in the development of new MPO FA drugs for treating inflammatory and oxidative stress-related diseases.

The anti-inflammatory properties of MPO can be attributed to the ability of this enzyme to inhibit the production of ROS by activated neutrophils and other cells. In addition, MPO inhibits the activation of different NF-kB and TLR2 signaling pathways. This explains its neuroprotective activity against the progression of brain injury in animal models.

Some naturally occurring compounds such as resveratrol, caffeic acid, indomethacin, flufenamic acid, and gallic acid have inhibitory activities against MPO. In addition, diclofenac and ferulic acid can also be effective in suppressing the activity of this enzyme.