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Myeloperoxidase and Neurological disorder:A cross talk Kanta Pravalika, Deepaneeta Sarmah, Harpreet Kaur, Madhuri Wanve, Jackson Saraf, Kiran Kalia, Anupom Borah, Dileep R Yavagal, Kunjan R. Dave, and Pallab Bhattacharya ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00462 • Publication Date (Web): 19 Jan 2018 Downloaded from http://pubs.acs.org on January 21, 2018

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ACS Chemical Neuroscience

Myeloperoxidase and Neurological disorder: A crosstalk

1 2 3 4 5 6 7 8 9 10 11 12

Kanta Pravalika1, Deepaneeta Sarmah1, Harpreet Kaur 1, Madhuri Wanve1, Jackson Saraf1,Kiran Kalia1,Anupom Borah2,Dileep R Yavagal, Kunjan R Dave3,Pallab Bhattacharya1* 1

Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India.2 Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University,Silchar,Assam,India.3Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA.

13 14 15 16

*Corresponding author:

17

Pallab Bhattacharya, Ph.D

18

Assistant Professor and I/C Dean,

19

National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad

20

Palaj, Gandhinagar-382355, Gujarat, India.

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Phone: +91-79 66745555

22

Fax: +91 79 66745560

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Email: [email protected]

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[email protected]

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Abstract:

2

Myeloperoxidase (MPO) is a protein present in azurophilic granules, macrophages,

3

and neutrophils that are released into extracellular fluid (ECF) during inflammation.

4

MPO releases hypochlorous acid (HOCL) and other chlorinated species. It is derived

5

from hydrogen peroxide (H2O2) showing response during inflammatory conditions

6

and plays a role in the immune defense against pathogens. MPO may show

7

unwanted effects by indirectly increasing the formation of reactive nitrogen species

8

(RNS), reactive oxygen species (ROS), and tumor necrosis factor alpha (TNF-α)

9

leading to inflammation and oxidative stress. As neuroinflammation is one of the

10

inevitable biological components among most of the neurological disorders, MPO

11

and its receptor may be explored as candidates for future clinical interventions. The

12

purpose of this review is to provide an overview of the pathophysiological

13

characteristics of MPO and further explore the possibilities to target it for clinical use.

14

Targeting MPO is promising and may open an avenue to act as a biomarker for

15

diagnosis with defined risk stratification on patients with various neurological

16

disorders.

17 18 19 20

Keywords: Myeloperoxidase, Neuroinflammation, Neuroprotection.

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ABBREVIATIONS: Myeloperoxidase (MPO) Extracellular fluid (ECF) Hypochlorous acid (HOCL) Hydrogen peroxide (H2O2) Reactive nitrogen species (RNS) Reactive oxygen species (ROS) Tumor necrosis factor alpha (TNF-α) Parkinson’s disease (PD) Huntington’s disease (HD) Multiple sclerosis (MS) Alzheimer’s disease (AD) Myocardial infarction (MI) C-reactive protein (CRP) Mitogen-activated protein kinase (MAPKs) Matrix metalloproteinase (MMP) Endoplasmic reticulum (ER) Adenosine triphosphate (ATP) Hydroxyl radical (OH•) Nicotinamide adenine dinucleotide (NAD) Central nervous system (CNS) Superoxide dismutase (SOD) Blood-brain barrier (BBB) Polymorphonuclear cells (PMNs) Multiple sclerosis (MS) Nitric oxide synthase (NOS) Nitric oxide (NO) Peroxynitrite (ONOO-) Nitrite (NO2-) Nitrate (NO3-) Inducible nitric oxide synthase (iNOS) Lipopolysaccharides (LPS) Cetyl-trimethyl ammonium bromide (CTAB) α-synuclein (α-syn). Malondialdehyde (MDA) Brain-derived neurotrophic factor-cAMP response element binding (BDNF-CREB) N-acetyl lysyltyrosylcysteine amide (KYC) Major depressive disorder (MDD) Recurrent depressive disorder (rDD) Multiple sclerosis (MS) 4-aminobenzoic acid hydrazide (4-ABAH) Non-steroidal anti-inflammatory drugs (NSAIDs) Angiotensin-converting enzyme (ACE) Magnetic resonance imaging (MRI) Myeloperoxidase Gadolinium (MPO-Gd) Thoracic Aortic Ischemia-Reperfusion Injury (TAR) Spinal cord injury (SCI) Neutrophils extracellular traps (NETs) Phorbol myristate acetate (PMA) N-chloro taurine (NCT) 3 ACS Paragon Plus Environment


1 2

Oncostatin M (OSM)


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1

1. INTRODUCTION

2

Myeloperoxidase (MPO) is a peroxidase enzyme that is coded by the MPO gene on

3

chromosome number17q23.1 which was first isolated and purified by Agner 1. MPO

4

can be traced in a green colored fluid collected from patients suffering from

5

tubercular empyema and contains haem that shows specificity towards myeloid cells.

6

It belongs to the family of mammalian peroxidases and of the class hydrogen

7

peroxide oxidoreductases, released mainly by circulating neutrophils, azurophilic

8

granules, microglia kupffer cells, monocytes, and astrocytes

9

action and also plays a key role in reducing oxidative stress at inflammatory areas 5.

10

Studies have shown that there are links between neurological disorders and

11

neuroinflammation, mainly in the atypical assembling of proteins that causes cell

12

death 6. Oxidative stress is considered to be highly responsible. Reactive oxygen

13

species (ROS) mediate the oxidative stress and inflammatory injury. ROS are

14

generated in the brain and can be used for assessing the severity of

15

neurodegeneration 7. Sources of ROS include redox-active iron, mitochondria, and

16

NADPH oxidase 8. Hypochlorous acid-sphingomyelinase (HOCl-SM), produced by

17

MPO, acts as a source of ROS; hence, MPO is an indirect source of ROS 8.

18

MPO plays an important role in neurodegenerative diseases viz. Parkinson disease

19

(PD) 9, Amyotrophic lateral sclerosis (ALS)

20

sclerosis (MS)

21

the increase in the MPO levels in serum (as the MPO gene gets expressed in

22

patients) and a decline in cognitive functions

23

reported in the caudate, midbrain, and putamen of patients with neurological

24

disorders (PD), but in amyotrophic lateral sclerosis (ALS), this difference in the level

25

of MPO is insignificant

12

10

. It shows bactericidal

, Huntington’s disease (HD)

, and Alzheimer’s disease (AD)

10, 15, 16

2-5

13

11

, multiple

. There are correlations between

14

. Higher MPO levels have been

. MPO also participates in other pathological conditions



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1

like atherosclerosis, cardiac dysfunction, stroke, and respiratory tract diseases

2

therefore warrants attention as a therapeutic target in the future.

1

and

3 4

2. MPO

5

MPO has been reported to show clinical significance in host defense mechanism but

6

has a disadvantage of over activation that can lead to tissue damage

7

significant role in maintaining the immune system; its deficiency may be an outcome

8

of a hereditary condition 18. According to a past study by Brenner et al., MPO acts as

9

a predictor for the assessment of myocardial infarction (MI) in patients having chest 19

17

. It plays a

10

pain

. Heslop et al. reported that measuring C-reactive protein (CRP) along with

11

MPO serves as a benefit for predicting the risk of inflammation

12

leukemia and myeloid sarcoma can also be diagnosed by administration of immuno-

13

histochemically stained MPO, which shows that cells of leukemia have been derived

14

from a myeloid lineage

15

carbon nanotubes used in targeted drug delivery 22.

16

2.1 MPO STRUCTURE

17

MPO is a protein that undergoes glycosylation reaction, containing two light chains

18

(13.5-kDa) and two heavy chains (59-kDa) linked by a disulfide bond

19

Molecular weight of MPO ranges from 120 to 160-kDa

20

iron within its structure

21

44 kDa

22

1, MPO 2, and MPO 3 are possible

23

heavy, light, and intermediate peptides 27, 28.

24

2.2 FUNCTIONS OF MPO

25

21

24

20

. Acute myeloid

. MPO was also considered as the first enzyme that breaks

23

. The

22, 23

. It has two molecules of

. In a non-reducing condition, it has an extra peptide of 39-

. The heavy chain is asymmetric so that production of three species MPO 26

. MPO has three native forms which have


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1

MPO releases hypochlorous acid (HOCL) and other chlorinated species. It has been

2

derived from hydrogen peroxide (H2O2) showing response during inflammatory

3

conditions and displays immunity against pathogens

4

leukocytes get activated and produce reactive oxygen metabolites, a prominent

5

defense mechanism of the body against microbes

6

cytotoxicity, damage the DNA, and interfere with the formation of enzymes like

7

NADPH oxidase, nitric oxide synthase (NOS), xanthine oxidase, and lipoxygenase.

8

During microbial infections (diphtheria, tetanus) and tissue injury, there is an

9

increase in MPO levels, particularly at inflammatory sites. Infections lead to an

10

increase in toxins that can be detoxified by MPO. Thus, it plays a protective role in

11

infectious diseases 31.

12

The superoxide radical causes more damage than H2O2. It acts as a substrate for all

13

the reactions that are catalyzed by MPO

14

growth by acting as a mitogen-activated protein kinase (MAPK)

15

matrix metalloproteinase (MMP) and through protease activity, MPO also promotes

16

immune responses during pathological conditions29, 34.

17

Role of MPO in immunity:

18

Neutrophils are the first leukocytes which appear at infection sites. Through

19

phagocytosis and by releasing neutrophils extracellular traps (NETs), neutrophils

20

clear pathogens

21

processes like apoptosis and necrosis

22

(e.g., Pseudomonas aeruginosa) and fungicidal (e.g., Candida albicans) actions

23

In the presence or absence of MPO, RNS and proteases play a key role in the

24

microbicidal activity of neutrophils

25

compare normal neutrophils and MPO-deficient neutrophils which reveal that MPO

35

32

30

29

. During phagocytosis,

. Excessive free radicals lead to

. HOCl, mediated by MPO, regulates cell 33

. By modulating

. They release MPO via degranulation and also by cell death

38

36

. MPO/HOCL together have bactericidal 37

.

. Researchers have carried out studies to



Page 8 of 35

1

plays a role in NET formation and its release in response to stimulation by microbes

2

or phorbol myristate acetate (PMA)

3

MPO activity, severe immunodeficiency is seen as compared to those having only

4

partial deficiency. However, most MPO deficient individuals are healthy that can be

5

attributed to the redundant mechanisms with which the immune system is equipped

6

with

7

activity and HOCl generated via the MPO/H2O2/chloride system is highly effective as

8

an microbicidal agent against wide range of microbes 40-42.

9

Under pathological conditions MPO and its metabolites show effect on T cells. Anti-

10

inflammatory cytokines activates a special type of T cells, the regulatory T-cells, like

11

IL-10 and TGF-β

12

and PMNs

13

towards T cells. Lymphocytes obtained from MPO knockout mice have shown

14

increased activity parameters at inflammatory site in comparison to cells obtained

15

from wild type mice

16

by MPO, the effect on Th1 cytokines is much greater

17

of MPO that show effects on the T cell functioning are still unknown, while at the in

18

vitro level the MPO product taurine chloramine inhibits T cells and antigen presenting

19

cells 48, 49.

20

2.3. BIOSYNTHESIS OF MPO

21

MPO synthesis takes place due to the differentiation of myeloid cells that occur in

22

promyelomonocytes and promyelocytes

23

place in the endoplasmic reticulum (ER) which results in the biosynthesis of prepro-

24

MPO (80 kDa) consisting of a small subunit (10-15 kDa, 108 AA) and a signal

25

peptide (41 AA). Enzymatically, inactive Apo-pro MPO (90 kDa) formation takes

39

39

. In individuals who are completely deficient in

. H2O2 likely acts via MPO and alone does not show an effective microbicidal

43, 44

. At inflammatory sites there is an interaction between T cells

45

. MPO products, as well as ROS produced by PMNs are inhibitory

46, 47

. Although both Th1 and Th2 cytokines are downregulated

50

47

. At the in vivo level products

. The translation process of MPO takes


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1

place

2

oligosaccharides. Due to the incorporation of haem, the inactive form gets converted

3

into an active form which is then exported to the Golgi apparatus where the removal

4

of propeptide (125 AA) from proMPO takes place. Symmetric homodimer (146 kDa)

5

formation occurs due to proteolytic processes that take place in azurophilic granules

6

50, 51

due

to

proteolytic

cleavage

and

incorporation

of

high

mannose

. A disulfide bond is linked to the homodimer, however, the processing

7

mechanism of promyeloperoxidase is not yet clear.

8

MPO is stored inside the primary granules of the myeloid cell lineage. MPO is a

9

haem protein which is extremely cationic, glycosylated, and arginine-rich with an

10

isoelectric point greater than 10. The optimum pH of MPO is 5.5, even though it

11

remains active over a wide range of pH 52.

12

3. MPO AND NEUROLOGICAL DISORDERS: THE CONNECTING LINK

13

Neurological disorders accompanying neurodegeneration occur either due to the

14

loss of neurons, programmed cell death, oxidative stress, or disorders of protein

15

degradation and protein aggregation

16

and adenosine triphosphate (ATP) depletion are the other major causes of

17

neurodegenerative diseases

18

stress has a significant role in cell loss leading to cognitive decline, which is a

19

characteristic feature of these diseases

20

neurodegenerative diseases leading to severe tissue damage

21

shown that there is an increased level of 3-chlorotyrosine (bio-marker of HOCl) in

22

damaged brain areas. HOCl causes cellular damage and tissue destruction that can

23

lead to cell death 55.

53

52

. Excitotoxicity, intracellular calcium increase,

. There is evidence that microglial-mediated oxidative

33

. MPO and HOCl are increased in

24 25


54

. Researchers have


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1 2

HOCl diffuses from the plasma membrane and interacts with glyceraldehyde-3-

3

phosphate dehydrogenase, hexokinase, lactate dehydrogenase, and creatine kinase

4

(intracellular enzymes) and inhibits them

5

and disturb the energy metabolism process

6

decreasing intracellular nicotinamide adenine dinucleotide (NAD), ATP, and

7

glutathione levels

8

HOCl from peripheral leukocytes and microglia which then diffuses into the brain

9

parenchyma

58,59

57

56

. High levels of HOCl interact with ATP 56

. It inhibits mitochondrial respiration by

. During pathological conditions, there is a continuous release of

. Even a small concentration of HOCl can cause a serious threat to 60

10

the anatomy of the brain by damaging cellular targets

11

oxidoreductase by donating a proton to H2O2. H2O2 in the presence of chloride ions

12

gets converted to HOCl. Hence, the oxidative conversion of H2O2 to HOCl plays a

13

key role in neurological diseases

14

place due to HOCl, implicating the neurodegenerative role of MPO 61.

15

4. IMPORTANCE OF CHLORINATIVE STRESS AND NITRATIVE STRESS IN

16

NEURODEGENERATION: INVOLVEMENT OF MPO

17

When the central nervous system (CNS) is under stress it induces the release of

18

superoxide anion via the mitochondrial respiratory cycle by interacting with different

19

enzymes like NADPH oxidase, nitric oxide synthases (NOS), and xanthine oxidase

20

31

21

superoxide dismutase (SOD) which, in the presence of MPO, reacts with chloride to

22

produce HOCl causing chlorinative stress

23

microglia also release inducible nitric oxide synthase (iNOS) that produces NO,

24

which is converted to reactive oxidants like NO2Cl and ONOO- which can cause

25

neuronal injury 31. When microglia are activated, they release MPO which forms NO2-

61

. MPO acts as an H2O2

. Wagner et al. reported that apoptosis takes

. Activated microglia also produce superoxides which are converted to H2O2 by

61

. Along with superoxides, the activated


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62

1

in the presence of NO which cause nitrative stress

2

stress cause protein nitration and oxidation, lipid peroxidation, oxidative damage to

3

DNA, and activation of MMP 31.

4

NO combines with superoxide (O2-●) generating peroxynitrite (ONOO-) which is

5

responsible for neuronal damage

6

takes place due to auto-oxidation of NO, levels of which increase in the plasma

7

during inflammation but can decrease by reacting with MPO (which is released by

8

microglia, astrocytes, and neurons)

9

of endothelial cells are induced by MPO which is responsible for the formation of

10

63

. Nitrative and chlorinative

. Generation of nitrite (NO2-) and nitrate (NO3-)

64

. iNOS upregulation and abnormal functioning

peroxynitrite that causes nitrative stress.

11 12

5. MPO –ROLE IN NEURONAL NETWORK

13

The Human brain is frequently exposed to oxidative stress. Formation of free

14

radicals takes place if any damage occurs to the brain, blood-brain barrier (BBB) or

15

both, which leads to various physiological and pathological outcomes

16

brain is composed of glial cells

17

state” and secrete neurotropic factors which protect neurons and oligodendrocytes

18

67

19

PD. Also, monocytes and polymorphonuclear cells (PMNs) have shown to be

20

involved in producing oxidative stress in MS 68.

21

The remodeling of astrocytes, activation of microglia, and chronic inflammatory

22

conditions change the integrity of the brain parenchyma leading to pathology

23

Expression of MPO rarely occurs in the normal brain but in diseased brains, it gets

24

expressed because of the activated extensions of microglia linking to activated MPO

25

in diseased or damaged brain

66

65

. 90% of the

. 5-10% microglial cells usually exist in the “resting

. Astrocytes and microglia respond to the oxidative stress that occurs in AD and

16

69

.

. In controlled tissue, low levels of MPO release can



Page 12 of 35

1

be seen in hippocampal neurons, but in cultured neurons, MPO shows a

2

performance that is equivalent to NOS

3

oxide (NO) and MPO may synergistically regulate the activity of each other. The

4

availability of NO can be decreased by oxidizing NO by MPO. Thus, all the signaling

5

pathways that take place due to NO triggering redox signaling during inflammation

6

can be inhibited, suggestive of a relationship between NO and MPO. MPO has been

7

reported to show protection against the deleterious effects of NO 70.

8

A recent study revealed that MPO shows catalytic activity and also has features

9

similar to that of cytokines. Hence, it can regulate inflammatory signaling pathways 71

31

. Hence, the end products formed by nitric

10

directly

. Lipopolysaccharides (LPS) mediate the breakdown of the BBB directly by

11

taking part in many pathways which release HOCl, 2-chlorohexadecanal, cytotoxic

12

agents, and indirectly by increasing neutrophil levels due to the interaction between

13

MPO and brain endothelial cells

14

BBB by altering the expressions of cytokines and chemokines. Therefore, it is

15

suggestive that MPO may dysregulate brain homeostasis 73, 74.

16

6. MPO ROLE IN SPINAL CORD INJURY

17

A study by Albadawi et al. has revealed that there is an appearance of myeloid cells

18

in the injured spinal cord 24 hours after inducing Thoracic Aortic Ischemia-

19

Reperfusion Injury (TAR) in mice. Observed was an enhancement of MPO levels in

20

thoracic and lumbar spinal nerves after 24 hours of TAR, and they have concluded

21

that MPO acts as a biomarker for detecting spinal cord injury after TAR.

22

activity of MPO is considered as an indicator of accumulated polymorphonuclear

23

leukocytes in spinal cord injury (SCI) after 4 hours of SCI.

24

MPO activity can be defined as the amount of MPO enzyme required to degrade 1

25

µmol of peroxide at 37°C

76

72

. MPO can compromise the functionality of the

75

The

. N-chloro taurine (NCT) has been considered as a new


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1

therapeutic molecule for SCI. Taurine (sulfur-containing amino acid) exhibits its

2

protective action by scavenging inflammatory mediators like MPO and ROS and

3

converting HOCl to less toxic substances

4

reduced by giving Oncostatin M (OSM) before inducing ischemia and reperfusion

5

injury to the spinal cord 78.

77

. The activity of MPO after SCI can be

6 7

7. ROLE OF MPO IN DIFFERENT NEUROLOGICAL DISORDERS

8

7.1 ALZHEIMER’S DISEASE (AD)

9

Studies have shown that polymorphisms at the promoter region of MPO increase its 79

10

expression resulting in an increase in the occurrence of AD

11

concentrated in amyloid plaques and in neurons of the neocortex and hippocampus

12

region, which can be detected by brain cetyl-trimethyl ammonium bromide (CTAB)

13

extracts and lectin affinity chromatography. Researchers have confirmed that MPO is

14

present at higher levels in the AD brain when the frontal cortex samples of AD

15

patients were compared with the frontal cortex samples without the disorder.

16

Immunoreactivity of MPO was reported to be increased by 2-fold in AD pathology.

17

Similarly, a 2.1-fold increase was observed in the temporal cortex 16. Oxidative stress

18

is involved in AD, but the pathway of production of reactive intermediates is not

19

clear. MPO provides free iron which takes part in cellular oxidative stress 80.

20

Cytotoxic oxidants are generally produced by MPO, 3-chlorotyrosine, and o, o’-

21

dityrosine. Advanced glycoxidation end products (AGEs), 3-nitrotyrosine, lipid

22

oxidation products, and oxidized DNA are the oxidation products of MPO enzyme

23

These oxidants are increased three-fold in the hippocampus of AD patients. It

24

implies that MPO levels are increased in AD. These cytotoxic oxidants assist lipid

25

peroxidation and protein nitration in AD 82.


. MPO is mainly

81

.


Page 14 of 35

1

Studies suggest that there is a relation between MPO and ApoE. The ApoE4 allele is

2

correlated with the occurrence of AD and deposition of amyloid. Patients with two or

3

more ApoE4 alleles also have high levels of MPO accumulated at plaques

4

patients with senile plaques (where Apo-E is found) are highly sensitive to oxidation

5

by MPO. Microglia-derived free radicals affect the brain tissue providing evidence

6

that oxidative stress is increased in AD but via indirect demonstration 84.

7

7.2 PARKINSON’S DISEASE (PD)

8

A number of studies have been conducted to understand the molecular mechanism

9

of PD. However, the exact steps and mechanisms are inconclusive. By the addition

10

of inorganic radicals to MPO, MPO plays a key role in the progress of PD. This can

11

be proven by the following: (1) the substantia nigra pars compacta has several

12

haem-containing enzymes which have peroxidase activity, (2) oxidation of lipids and

13

proteins can be catalyzed by peroxidases, (3) cells are destroyed by these

14

haemeperoxidases (in vivo), (4) haemeperoxidases have the characteristics of

15

specificity and stability, hence, only specific molecules and cells undergo damage,

16

(5) some reactions in PD are mediated by the activation of haemperoxidases

17

enzymes, and (6) haemperoxidases do not show a compatibility with the oxy-radical

18

theory 9.

19

In vitro studies indicate that microglia activation and the release of MPO takes place

20

by α-synuclein (α-syn). The released MPO reacts with ROS and releases HOCl

21

which contributes to oxidative stress that leads to neuronal damage. In this manner,

22

microglia activation is linked to neuronal degeneration

23

choreographer for the destructive processes undertaken by TNF-α and ROS which

24

cause neuronal damage (Figure 1) 85.


85

83

. The

. MPO also acts as a

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1

Inflammatory oxidants have an important role in PD. MPO shows response when

2

there is a production of oxidants. MPO gets upregulated in the midbrain of PD

3

patients during inflammation

4

and 3-chlorotyrosine, levels of which are increased in the brains of PD patients

5

These biomarkers and MPO are also observed in the activated astrocytes and

6

microglial cells of the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

7

treated animals and PD patients 51.

8

7.3 STROKE

9

A number of studies have shown that MPO plays a key role in the pathology of 86

63

. Bio-markers which are specific for MPO are HOCl 68

.

10

stroke

. There is an increase in the infarct volume along with a decrease in the

11

functionality within the ischemic region of brain

12

the plasma and serum of stroke patients

13

is an increase in the levels of ROS like O2-●, ONOO-, H2O2, and RNS which cause

14

damage to the brain (Figure 2). Levels of these reactive species increase after

15

reperfusion

16

generation of protein carbonyls, lipid peroxidase, and plasma malondialdehyde

17

(MDA) 89.

18

MPO has been considered to be an inflammatory biomarker associated with stroke

19

90

20

be decreased significantly by depletion of leukocytes that results in the reduction of

21

infarct size

22

stages of stroke

23

including differentiation, cell proliferation, migration, and survival of newborn cells.

24

This indicates that there may be a link between MPO and neurogenesis in stroke 92.

88

87

87

. Increased MPO levels are seen in

. Studies have shown that in stroke, there

. Studies have also shown that in animal stroke models there is a

. Matsuo et al. have reported that MPO acts as a bystander because its activity can

91

. MPO levels may decrease by giving inhibitors even at sub-acute 86

. Deficiency in MPO stimulates many aspects of neurogenesis



Page 16 of 35

1

Kim et al. have stated that inhibition of MPO increases brain-derived neurotrophic

2

factor-cAMP response element binding (BDNF-CREB) signaling pathway, indicating

3

that the activity of MPO inversely affects signaling pathways of neurogenesis

4

There are no drugs available in the market till date that specifically inhibit MPO

5

following stroke. Some drugs are in preclinical stages and there is only one molecule

6

that has completed a phase IIa trial

7

lysyltyrosylcysteine amide (KYC) effectively, specifically, and competitively inhibits

8

MPO, decreasing MPO activity and improving neurological function of the brain in

9

stroke 95.

94

93

.

. Guoliang et al. have reported that N-acetyl

10

Breckwoldt et al. have reported that in a stroke-induced mouse model, there is an

11

increase in MPO levels which persists for 21 days following stroke

12

of

13

outcome and could reduce MPO activity after stroke as seen in the mice stroke

14

model 96. There is a correlation between the increase in MPO levels and activity after

15

ischemia with that of neutrophil infiltration and post-ischemic brain injury. Their

16

results have shown that when there is depletion in neutrophils, it inhibits the activity

17

of MPO. This may indicate that MPO acts as a marker for the estimation of

18

neutrophil infiltration and brain injury after reperfusion 91.

19

7.4 DEPRESSION

20

Disturbances in the functionality of neuroendocrine and a relation between immunity

21

and depression have recently been reported

22

MPO in depressive brains which helps in the release of inflammatory mediators such

23

as HOCl

24

MPO is therefore considered as an important biomarker for major depressive

25

disorder (MDD). Smith et al. also reported that the genes involved in inflammation

59

. Administration

AM-36, an antioxidant and a sodium channel blocker, improved functional

97

31

. There is an increase in the levels of

. Smith et al. reported that depression is associated with inflammation


98

.

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1

mostly take part in the pathophysiology of MDD. Several studies have stated that

2

there is a link between MPO and MDD, inflammatory, and immune biomarkers 99.

3

Galecki et al. have investigated the role of the MPO gene (G-463A polymorphism) in

4

recurrent depressive disorder (rDD). They have reported that the risk of occurrence

5

of depression increases 1.5-fold in a protein having the 463G allele

6

a marker but does not take any part in the occurrence of depression, because there

7

is no significant difference in MPO levels between patients with rDD and patients

8

with the initial occurrence of depression

9

correlated with MPO, but both inflammation and depression have a common

101

100

. MPO acts as

. The symptoms of depression were not

10

pathophysiology related to immune dysfunction 102.

11

Anand et al. have reported that MPO is considered as a specific biomarker; hence, it

12

is more relevant for depression and other brain-related disorders. Their research

13

work suggests that twins with depression had 32% higher levels of MPO when

14

compared with twins without depression. Other inflammatory biomarkers, except for

15

TNF-α, are also elevated but not as significantly as that of MPO. It suggests that

16

MPO plays a significant role in depression 103.

17

7.5 MULTIPLE SCLEROSIS

18

Studies have reported that MPO has a role in multiple sclerosis (MS) and at the

19

lesion site, it gets activated by macrophages/microglia in human MS plaques

20

Nagra et al. have reported that MPO exists in two alleles, Sp and N. When these two

21

alleles are observed, there is a difference at position 463(G-A) 58.

22

Furthermore, there is an increase in levels of MPO and its activity also gets

23

increased due to demyelination, which ultimately causes neuronal death and

24

neurodegeneration

25

macrophages/microglia, contributing to the release of cytotoxic HOCl which

104

12

.

. MPO gets activated and released by the activation of



Page 18 of 35

1

damages the myelin sheath 105. Some studies have shown that by inhibiting MPO by

2

using 4-aminobenzoic acid hydrazide (4-ABAH), one could decrease the complexity

3

of the disease 8.

4

Several studies have reported that there is a generation of free radicals that causes

5

tissue damage through biochemical methods, oxidized nucleotides, lipids, and

6

proteins which have been identified through immune cytochemical studies 105. In MS,

7

due to the activation of NOS 1-3, there is a production of RNS while ROS are

8

produced by the activation of macrophages/microglia

9

mitochondria is also responsible for the production of ROS and oxidative stress 107.

106

. Furthermore, injury to the

10

MPO is activated by white matter demyelination and cortical lesions. NOX2 and

11

NADPH oxidase are mostly responsible for oxidative stress in MS. There is evidence

12

that NOX activation and formation of ROS are the main pathomechanisms for

13

microglial, oligodendrocyte, and macrophage-mediated neuronal injury in MS 108.

14

7.6 EPILEPSY

15

Seizures cause hyper-excitability of neurons and contribute towards free radical

16

generation that causes injury to the neurons

17

studies have shown that generation of MPO takes place via the activation of

18

macrophages/microglia and by inflammatory cell infiltration, stimulating chlorinative

19

stress leading to epileptogenesis. Therefore, it is clear that inhibition of MPO can be

20

a potential treatment for epilepsy and neurodegenerative diseases

21

displays vulnerability towards inflammation and oxidative stress during epilepsy.

22

There is a need to know the role of MPO and its oxidants that cause damage in the

23

epileptic condition 110.

24

In murine models with epilepsy, the temporal lobe showed increased levels of MPO

25

and its products, particularly in the hippocampal regions. Its level also increases in

109

. Recent human refractory epilepsy


109

. The brain

Page 19 of 35 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


111

1

refractory epilepsy

. By inhibiting MPO, the recurrence of seizures in animal

2

models of temporal lobe epilepsy was seen to be reduced 111.

3

7.7

4

Epidemiological studies have shown that an increase in the levels of MPO would

5

increase the risk of cardiovascular diseases

6

coronary artery disease patients

7

atherosclerosis

8

cause lung injury. Infusion of glucose to rats, which were suffering from severe lung

9

injury, served as a source for H2O2 and MPO (Figure 3) 115.

MPO: ROLE IN OTHER DISEASES

114

112

. MPO levels are also increased in

113

. MPO acts as a biomarker for the detection of

. In lung diseases, experiments have revealed that MPO can

10

In kidney diseases, MPO acts as an important factor in tubule-interstitial and

11

glomerular diseases. Several studies have reported that MPO has a role in renal

12

disorders. When neutrophils get attached to the glomeruli, the generation of oxidants

13

takes place through reactions catalyzed by MPO. The oxidants cause damage to the

14

basement membrane of the glomerulus. When renal perfusion experiments were

15

conducted with MPO along with its substrates such as H2O2 and chloride ions, some

16

morphological changes were observed in the glomerulus

17

therapy and chemotherapeutic factors show antitumor activity by producing ROS,

18

H2O2, OH, and O2-, which cause oxidative stress that results in cancer cell death 117.

116

. In cancer, radiation

19 20

8. MYELOPEROXIDASE- A PROBABLE FUTURE THERAPEUTIC TARGET FOR

21

NEUROLOGICAL DISORDERS.

22

Inflammatory processes are regulated by MPO in many neurological disorders

23

Under pathological conditions, the brain releases MPO and therefore, inhibition of

24

MPO may be a novel therapeutic target for neurodegenerative disorders

25

et al. have reported that quercetin, a flavonoid, acts as a potent MPO inhibitor. It is 19 ACS Paragon Plus Environment

111

111

.

. Momic


Page 20 of 35

1

thought to inhibit both MPO and also its chlorinative activity, acting as a mixed and

2

reversible MPO inhibitor

3

anti-inflammatory drugs (NSAIDs) play a key role in MPO activity but have less

4

antioxidant property towards H2O2. Flufenamic acid specifically inhibits HOCl and has

5

the best inhibitory property than other NSAIDS 119.

6

Apolipoprotein B-100 is considered as a primary protein for chylomicrons whose

7

activity is modulated by MPO and inhibited by angiotensin converting enzyme (ACE)

8

inhibitors such as lisinopril, captopril, enalapril, ramipril, and sodium fosinopril.

9

Captopril is most effective when compared to all other ACE-inhibitors as it has a thiol

10

functional group while others have an amino group function that does not react with

11

HOCl. Captopril also reacts chemically with HOCl 119.

12

MPO-derived oxidants can be inhibited by nitroxides, but they are reduced rapidly in

13

plasma. In animals, hydroxylamine (inactive), glutathione, ascorbic acid, and other

14

reductants have limited reductive activity

15

indazolones molecules were synthesized by using Davis-Beirut reaction which has

16

demonstrated potent MPO inhibition activity. Molecules which have N1-substitution

17

have not shown effective inhibitory activity, but compounds containing a N2-C3 fused

18

ring system showed a potent inhibitory activity 121.

19

Magnetic resonance imaging (MRI) has shown fruitful results in imaging MPO at

20

active sites of inflammatory loci causing tissue damage

21

imaging with some contrast agents such as Gd-bis-5-HT-DTPA (MPO-Gd) may

22

provide novel translational aspects for non-invasive temporal monitoring along with

23

accurate detection 31.

118

. In addition, some studies have stated that non-steroidal

120

. Series of 1H-indazolones and 2H-

24 25 20 ACS Paragon Plus Environment

122

. Therefore MPO-MR

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1

9. CONCLUSION

2

Evidence suggests that MPO contributes towards the propagation of inflammatory

3

diseases, leading to tissue damage. It plays a key role in neurodegenerative

4

disorders, inflammatory diseases, kidney diseases, and immune-mediated diseases

5

like AD, PD, MS, and stroke. Suppressing MPO can be a new treatment approach

6

for several diseases. The relation between MPO and neurodegeneration is of

7

promising importance. MPO, by causing oxidative stress, inflammatory sequelae

8

propagation, and apoptosis induces neuropathology. Clinical and experimental

9

studies have revealed the detrimental role of MPO. Hence, targeting MPO may be a

10

strategy of choice for future interventions of neurological disorders.

11

10. Authors Contributions

12

P.K, D.S, H.K and M.W conceived and designed the study. M.W, K.K , A.P,K.D,P.B

13

outlined the performed rigorous literature search. D.S K.D, A.P,K.K, PB conceived

14

and designed the figures and images. D.Y and J.S rigorously worked on revision and

15

addition of revised contents. K.P, P.B, K.D ,J.S and D.Y wrote the manuscript.

16

11. Ethical Approval

17

The article does not contain any studies with animal or human subjects.

18

12. Acknowledgement:

19

Authors acknowledges Department of Science and Technology (DST),Govt.of India

20

for their financial support through grant (SB/YS/LS-196/2014), International Society

21

for Neurochemistry (ISN) Return Home grant, Department of Pharmaceuticals,

22

Ministry of Chemical and Fertilizers, Govt of India and National Institute of

23

Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, India.

24

Authors also want to express their thanks to Boston Children’s Hospital, Harvard



1

Medical School, Boston, MA, USA and the Director, NIPER Ahmedabad, for

2

providing necessary support.

3

13. Conflict of Interest:

4

The authors have no conflict of interest to declare.

5

Figure Legends:

6

Figure 1. MPO in Parkinson’s disease. α-synuclein (α-syn) aggregates to form

7

lewy body (LB). Upon activation of the antigen presenting cell (APC) by α-syn, B-

8

cells, monocytes, and macrophages are expressed. Activated microglia can release

9

inflammatory mediators like myeloperoxidase (MPO), reactive oxygen species

10

(ROS), reactive nitrogen species (RNS) etc. MPO acts as a mediator for the

11

destruction caused by ROS and tumor necrosis factor-alpha (TNF-α) that lead to

12

neuronal damage. IL-1β- interleukine 1 beta; CKs- cytokines; TGF-1β- Transforming

13

growth factor beta 1; IFN-ˠ-Interferon gamma; IL-Interleukine; Th- T helper cells;

14

iTreg- induced T-regulatory cells; nTreg- natural T-regulatory cells; BBB- Blood brain

15

barrier.

16

Figure 2. MPO in stroke. Following inflammation, there is an activation of microglia,

17

cytokines and leukocytes which stimulate the release of MPO which reacts with H2O2

18

and releases hypochlorous acid (HOCl) (a cytotoxic agent) responsible for

19

neurodegeneration leading to stroke.

20

Figure 3. MPO in other diseases. Flow diagram depicting the various diseases

21

arising as a result of increased levels of reactive oxygen species (ROS), reactive

22

nitrogen species (RNS) and myeloperoxidase (MPO).

23


Page 22 of 35

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2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

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Myeloperoxidase and Neurological disorder: A crosstalk Kanta Pravalika1, Deepaneeta Sarmah1, Harpreet Kaur 1, Madhuri Wanve1, Jackson Saraf 1, Kiran Kalia1, Anupom Borah2, Dileep R Yavagal3, Kunjan R Dave3, Pallab Bhattacharya1*

INJURY

MYELOPEROXIDASE (MPO)

Multiple Sclerosis

Alzheimer’s Disease

Parkinson’s Disease

MPO inhibitors

Epilepsy Stroke

Depression

ACS Paragon Plus Environment

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Neuron 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

LB

LB

Dying neuron Microglia M1

α- Syn

Microglia

BBB LB Th17

TGF-β IL-12 IL-23

Th1

IFN-ˠ IL-23

Th2

IL-4

B-cell

TGF-β

APC ACS Paragon Plus Environment

Th0

iTreg

nTreg

ACS Chemical Neuroscience 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

MPO(+) TNF-α(+) iNOS(+)

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O2-.

O2

SOD

Mitochondria H2O2 MPO

Fe 2+ Fe 3+ Cytokine release, Microglia and Leukocyte activation

HOCl H2O2 H2O

Neuro-Inflammation

O2, HOCL

Oxidative stress

Stroke ACS Paragon Plus Environment

Neurodegeneration 13

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Neurological disorders -Alzheimer's Disease -Parkinson's Disease -Schizophrenia

Cardiovascular -Atherosclerosis -Ischemia/reperfusion injury -Hypertension

Fibrotic disease -Diabetic nephropathy -Liver fibrosis -Pulmonary fibrosis

Increased MPO, ROS, RNS Tumor/cancer -Lung -Breast -Renal

Inflammatory disorders -Lupus -Rheumatoid arthritis -Ulcerative colitis -Inflammatory bowel ACS Paragon Plus Environment disease

Metabolic disorders -Diabetes -Insulin resistance -Obesity

Myeloperoxidase and Neurological Disorder: A Crosstalk - American

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