By Prof. ATEF DONIA Professor of Pediatrics Al Azhar University 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

1. Future Applications of
Antioxidants in Premature Infants
Prof. ATEF DONIA
Professor of Pediatrics
Al Azhar University

2. Purpose of Review
This 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

4. 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).

5. 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 ).

6. Stable atomic configuration
(paired electrons in the outer
shell )

7. 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.

9. these radicals can start
chain reactions
with widespread damage

10. When the chain reaction occurs in a cell,
it can cause damage or death to this cell.
Cell
Death

11. Antioxidants terminate these chain reactions by supplying
the deficient energy.
المتطوع المتبرع

12. consequently
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.
They do this by being oxidized
themselves, so antioxidants are reducing
agents
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.

13. cell
Oxidative
stress
Reactive O
species
Combinati
on with
GSH
Direct
damage
Depletion of cellular
GSH
Depletion of cellular levels of GSH is the
common pathway for cell injury

14. These antioxidants may be
synthesized in the body or obtained
from the diet.

15. • Under normal conditions, a delicate balance
exists between the production of ROS and the
antioxidant defenses that protect cells in vivo.
• The balance may be disturbed by increased
ROS production or inadequate antioxidant
defenses.
• There is increasing evidence that :
early exposure to oxidative stress = lifelong
consequences

16. • Increased generation of ROS can occur as a
result of many conditions affecting newborn
infants, including:
- Hyperoxia.
- Reperfusion.
- Inflammation.
- Exposure to radiation.

17. •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.

18. As a Result
Disruptions in Oxidant/Antioxidant
Balance Can Cause Significant Cell
Injury

19. 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.

20. • 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.

21. 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.

22. 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.

23. • 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.

24. 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.

25. 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.

26. Periventricular Leukomalacia (PVL):
• Preterm infants are vulnerable to PVL due to
oxidative stress.
• ROS have also been implicated in causing
of neuronal cell death.

27. • 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 neuroprotective
when administered eight hours after the insult.

28. Necrotizing Enterocolitis(NEC)
• 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.

29. So,
• Enteral glutamine and arginine may be useful
for preventing NEC in premature neonates.

30. 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

31. B) - Enzymes:
- Superoxide dismutases - Catalase
- Glutathione peroxidase
C) - Oxidizable molecules:
- Glutathione - Vitamins E, A, C
- Carotenoids - Flavonoids
D) - Trace elements:
- Copper - Zinc - Selenium

32. Enzymatic antioxidants:
• Enzymatic antioxidants are gestationally
regulated, with premature newborns having
decreased expression relative to full term
neonates.

33. • 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.

34. • Intratracheal administeration of recombinant
human SOD (rhSOD) to premature infants
resulted in significant decrease in the number
of ROS induced injueries.

35. - Ceruloplasm, transferrin, and ferroxidase
all aid in the metabolism of iron, which can
act as a potent oxidizing agent.

36. New Antioxidants Under Investigation
• There are multiple potential therapeutic
antioxidants currently under I nvestigation
that could benefit premature infants.

37. 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.

38. 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.