Prof. ATEF DONIA Professor of Pediatrics

Al Azhar University

Future Applications of

Antioxidants in Premature Infants

Purpose of ReviewThis review will examine:

•The role of reactive oxygen species (ROS)

in pathogenesis of common disorders of the

preterm infant.

• The unique susceptibility of premature infants

to oxidative stress.

• Potential for therapeutic interventions using

enzymatic and/or non-enzymatic antioxidants

A paradox in metabolism is that, while the

vast majority of complex life on Earth requires

oxygen for its existence, oxygen is a highly

reactive molecule that damages living

organisms by producing reactive oxygen

species (ROS).

This 'dark side' of oxygen relates directly to

the fact that each oxygen atom has one

unpaired electron in its outer valence shell (

free radical ),

while molecular oxygen has two electrons (

stable ).

Stable atomic configuration

(paired electrons in the outer

shell )

Free radicals are a class of compounds

where the valence electrons contain an

odd number of electrons, at least one, in

the valence shell.

So they

They are always searching for an extra electron they

can "steal" to become stable.

these radicals can start

chain reactions

with widespread damage

When the chain reaction occurs in a cell,

it can cause damage or death to this cell.

Cell

Death

Antioxidants terminate these chain reactions by supplying

the deficient energy.

المتطوع المتبرع

glutathione, vitamin C, vitamin A, and vitamin E,

thiols, and polyphenols, as well as enzymes such

as catalase, superoxide dismutase and various

peroxidases are famous examples.

consequently

They do this by being oxidized

themselves, so antioxidants are reducing

agents

plants and animals maintain

multiple systems of antioxidants that work together to

prevent oxidative damage to cellular components,

such as cell membrane proteins and lipids as well as DNA.

Oxidative

stress

Combinati

on with

GSH

Depletion of cellular

GSH

Depletion of cellular levels of GSH is the

common pathway for cell injury

cell

Reactive O

species

Direct

damage

These antioxidants may be

synthesized in the body or obtained

from the diet.

• Under normal conditions, a delicate balanceexists between the production of ROS and theantioxidant defenses that protect cells in vivo.

• The balance may be disturbed by increasedROS production or inadequate antioxidantdefenses.

• There is increasing evidence that :

early exposure to oxidative stress = lifelongconsequences

• Increased generation of ROS can occur as a

result of many conditions affecting newborn

infants, including:

- Hyperoxia.

- Reperfusion.

- Inflammation.

- Exposure to radiation.

•The premature infants are especially

susceptible to ROS-induced damage

because of:

- Inadequate antioxidant stores at birth.

- Impaired upregulation in response to

oxidative stress.

• So that the premature infant is at increased

risk for development of ROS-induced

diseases of newborn, such as BPD, ROP,

NEC, and PVL.

As a Result

Disruptions in Oxidant/Antioxidant

Balance Can Cause Significant Cell

Injury

Preterm Birth and Oxidative Stress

• the gestation & delivery of the newborn constitutes a significant oxidative stress and This will affect the overall burden.

• The premature delivery often occurs before the normal upregulation of antioxidant systems and other reactive oxygen species scavengers, such as glutathione and ceruloplasmin.

• This is in addition to the relatively deficient

trans-placental transfer of nutrients important

to antioxidant defenses and this places the

newborn at particular risk of ROS-induced

injury.

Therapeutic Interventions with

Antioxidants• Supplementation with enzymatic and/or non-

enzymatic antioxidants might have beneficial

effects in decreasing the injury from excess

production of ROS, particularly in disorders

such as:

- Bronchopulmonary dysplasia

- Retinopathy of prematurity

- Periventricular leukomalacia

- Necrotizing enterocolitis.

Bronchopulmonary Dysplasia:

• Although the pathogenesis of BPD is complex,

studies do support a role for ROS-mediated

damage.

• Vitamins A, C, and E are important factors in

the normal physiology as well as antioxidant

defense.

• In infants with BPD, plasma β-carotene and

vitamin A concentrations are lower, likely

reducing antioxidant protection.

• exogenous antioxidants such as vitamin A,

vitamin E and recombinant human SOD

(rhSOD) have been administered in attempts

to prevent BPD.

• Copper, zinc, iron, and selenium are also

antioxidant and if they are supplemented,

could prevent BPD.

Retinopathy of Prematurity:

• The developing retina in premature infants is particularly susceptible to damage mediated by ROS.

• Repeated oxygen fluctuations also increased the retinal vascular endothelial growth factor (VEGF) and ROS.

So,

• The use of epicatechin (a green tea extract) as

well as NAC could also be considered a new

therapeutic target for the ischemic proliferative

diseases of the retina.

Periventricular Leukomalacia (PVL):

• Preterm infants are vulnerable to PVL due to

oxidative stress.

• ROS have also been implicated in causing

of neuronal cell death.

• Melatonin is studied as a neuroprotective agent in PVL. The effects of melatonin were only observed when given within the first two hours following insult .

• However, Agomelatine was still neuroprotectivewhen administered eight hours after the insult.

• While the etiology of NEC is multifactorial,

inflammation and ROS production appear to

play a key role.

• An increased incidence of NEC has recently

been noted in infants who are born to mothers

with chorioamnionitis.

Necrotizing Enterocolitis(NEC)

So,

• Enteral glutamine and arginine may be useful

for preventing NEC in premature neonates.

Antioxidant Therapies in Premature Neonates:

• all of the following play a role in maintaining a

delicate balance between ROS production

and oxidant damage to tissues and organs:

A) - Non-enzymatic Antioxidants:

- Transferrin - Ferritin - Ceruloplasmin

B) - Enzymes:

- Superoxide dismutases - Catalase

- Glutathione peroxidase

C) - Oxidizable molecules:

- Glutathione - Vitamins E, A, C

- Carotenoids - Flavonoids

D) - Trace elements:

- Copper - Zinc - Selenium

Enzymatic antioxidants:

• Enzymatic antioxidants are gestationally

regulated, with premature newborns having

decreased expression relative to full term

neonates.

• Melatonin reduces ROS production and

increased antioxidant levels in the hyperoxia

induced lung damage, indicating a potential

protective effect in BPD.

• Naturally derived commercial surfactants

contain both SOD and CAT activity in

significant concentrations.

• Intratracheal administeration of recombinant

human SOD (rhSOD) to premature infants

resulted in significant decrease in the number

of ROS induced injueries.

- Ceruloplasm, transferrin, and ferroxidase

all aid in the metabolism of iron, which can

act as a potent oxidizing agent.

New Antioxidants Under Investigation

• There are multiple potential therapeutic

antioxidants currently under I nvestigation

that could benefit premature infants.

1. One protein under investigation, Pon3, was

shown in the laboratory studies to have

antioxidant properties

2. Supplementation of preterm infants with

lactoferrin and cysteine.

3. Early administration of human erythropoietin in

very preterm infants.

4. NAC administration to women with intra-

amniotic infection and/or flammation.

5. Early enteral administration of vitamin

E to extremely premature infants.

6. Multiple trials involving inhaled nitric oxide.

The results from these trials may change the way we treat many common neonatal conditions.