Reactive Oxygen Species and Antioxidant Enzymes in the
Developing Brain
Olga
Galkina
Olga
Galkina, Department of
Biochemistry, Saint Petersburg State University, St.Petersburg, 199034, Russia
Correspondence to: Olga Galkina, Department of
Biochemistry, Saint Petersburg State University, St.Petersburg, 199034, Russia
Email: galkina@bio.spbu.ru
Telephone: +7-812-328-2182
Received: April 21,
2015
Revised: June 5, 2015
Accepted: June 9, 2015
Published online: September 1, 2015
ABSTRACT
Reactive
oxygen and nitrogen species can regulate cellular processes fundamental for
development such as proliferation, migration, differentiation and apoptosis.
Brain cells at various stage of development can exhibit discrete changes in
their parameters of oxidation and antioxidant defence. This review will focus
on the role of reactive oxygen and nitrogen species and antioxidants in brain
development. The following topics will be discussed: critical periods of the
brain development, control of physiological functions by free radicals,
especially the development process, participation of free radicals and
antioxidants in brain development. Emphasis will be on changing in the activity
and expression of antioxidant enzymes.
© 2015 ACT. All
rights reserved.
Key words: Free radicals; Antioxidant enzymes; Brain development
Galkina O. Reactive Oxygen
Species and Antioxidant Enzymes in the Developing Brain. International
Journal of Neurology Research 2015; 1(3): 123-128 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/1178
Introduction
The developing brain is very susceptible to oxidizing agents such as
free radicals. The vulnerability of the developing brain to oxidative stress is
due to high metabolic activity, sufficiently high concentration of iron ions
and relatively low antioxidant system. One of the main pathogenic factors of
the brain damage is perinatal hypoxia-ischemia leading to oxidative stress. On
the other hand, free radicals such as reactive oxygen or reactive nitrogen
species can regulate fundamental cellular processes during development. This
review will focus on the role of such oxygen derivatives and antioxidants in
the developmental processes.
Free
radicals and control of physiological functions
A free radical can be defined as a molecule with one or more unpaired
electrons in its outer orbital. This unpaired electron usually gives a
considerable degree of reactivity to the free radicals. Main radicals generated
in the mammalian organism are oxygen derivatives called reactive oxygen species
(ROS). The most common ROS are superoxide anion, hydrogen peroxide and their
derivatives, e.g. hydroxyl radical. There are also reactive nitrogen species
(RNS); the best known among them are nitric oxide (NO) and peroxynitrite.
However, there exist other special “reactive species” (abbreviation “RS”
introduced by Halliwell[1]) manifesting biological effects, e.g.
reactive chlorine species (hypochlorite) or reactive sulfur species[1-4].
RS are highly reactive oxidants and their uncontrolled production may destroy
cellular function. The harmful effect of free radicals causing potential
biological damage is termed “oxidative stress”[5]. In order to avoid
oxidative stress in the cells, special mechanisms have developed during
evolution. Compounds that prevent cellular damage may act in a number of ways –
from prevention of ROS and RNS formation, to reparation of oxidative molecules.
The antioxidant system involves various types of antioxidants, which are
usually found in cells and tissues. Antioxidants can be classified as enzymatic
(superoxide dismutase, catalase, glutathione-dependent enzymes, glutaredoxins,
peroxiredoxins, thioredoxin system) and non-enzymatic (vitamins C, E,
glutathione, carotenoids, flavonoids and so on)[6,7]. Under normal
conditions there is a balance between the intensity of free radical oxidation
and the activity of antioxidant defense. When there is a deficiency of
antioxidants on the one side and overproduction of free radicals on the other,
oxidative stress occurs in the cells[8,9].
The steady
state level of oxygen radicals and related “reactive species” plays an
important physiological roles. Due to their high reactivity, the location where
they are produced is essential for manifestation of their biological functions[3,10].
ROS play a key role in the defence of organisms against pathogens[2];
it is now well accepted that ROS are signaling molecules, which are involved in
the intracellular signaling cascade and the regulation of signal transduction[10,11,12].
Nitric oxide is involved in vascular tone, innate immunity, and neuronal signal
transduction. Moreover, RS can play a role in development[10,13]. At
least the ability of ROS to regulate cellular processes fundamental for
development such as proliferation, migration, differentiation and apoptosis was
shown[14,15]. Cells and tissues at various stages of differentiation
can exhibit discrete changes in their parameters of oxidation and antioxidant
defence[13]. Control of cell proliferation and differentiation
involves changes in gene expression and is characterized by the appearance of
tissue-specific enzymes and other proteins. The mechanisms by which RS can
regulate these processes generally involve changes in the redox status (the
ratio of oxidizing and reducing equivalents – Rox/red) of cells. It
includes Rox/red for the thiol groups of peptides and proteins
involved in almost all signaling pathways known to date[2,16,17].
These oxidative modifications result in changes in the structure and/or
function of the proteins including protein conformation, enzyme activity,
transporters and receptors modification, protein–protein interactions,
protein–DNA interactions and so on[18].
Critical
periods of the brain development
Nervous system development is marked by several periods, each of them
defined by major events in brain growth and structural maturation[19,20,21,22].
In general, these processes are remarkably parallel for rodents and humans, but
the temporal windows are significantly different[22]. In the rat
central nervous system (CNS) there is a considerable period of postnatal
development. Neurogenesis (process that includes proliferation, migration and
differentiation of neurons) starts in embryogenesis (in Embryonic Day (ED)
12-15), but the maximal rate of proliferation occurs in Postnatal days (PD)
10-15, including an increase of cell size, growth of axons and dendrites[19].
It should be noted that timing of neurogenesis varies in different brain
regions.
The most
important period in postnatal ontogenesis of the brain is the process of
myelination. Formation of myelin begins in different animals in different ways:
some neurons in humans begin to be covered by myelin quite early in the
prenatal period and at the age of 3-5 years the brain is almost completely
myelinated; in rats and other nest-building animals myelination occurs mainly
in the postnatal period: beginning in about 10-12 days and reaching the maximal
rate of myelin accumulation in about 20-21 days[19,22,23].
The period of
maximal myelination and gliogenesis coincides with other important changes in
the CNS. Myelination dramatically alters the lipid composition of the brain[24].
Brain weight increases more than four times and reaches 90-95% of adult weight.
It is known as “brain growth spurt”. The critical period of synaptogenesis in
rats occurs during the first three postnatal weeks with the changes in many
neurotransmitter systems[25]. These processes need energy. The rate
of glucose metabolism and energy utilization as well as in oxygen uptake
significantly increases (from 3 to 7 times according to various estimates)
between PD7-10 and PD21 days[20]. Within the cells the number of
mitochondria increases. Acceleration in mitochondrial respiration occurs
immediately after birth and then the number of mitochondria per cell quadruples
from PD1 to PD21; changes also occur in the density, structure and functional
activity[26].
Another
important event in the developing brain is the programmed cell death
(apoptosis). The excess of neuronal cells, forming during the brain
development, is eliminated by apoptosis that is triggered by internal signal
(e.g. from ROS). In certain brain regions more than half of neurons die due to
apoptosis during normal brain development[27]. This process occurs
during pre- and postnatal development. The earlier apoptosis occurs in
proliferative zones and the later one – in neuronal and glial post mitotic
cells[19].
ROS/RNS,
antioxidants and brain development
Several metabolic features of the adult brain suggest that it is
sensitive to oxidative damage. These features include enhanced oxygen metabolic
rate (brain uses 20% of O2 body consumption), leading to excessive
levels of ROS; high content of polyunsaturated fatty acids and the presence of
redox-active metals (Cu2+ and Fe2+) in some brain
regions; an inadequate defense system against oxidative stress[28].
At the same time, the brain can use the increased production of ROS to perform
specific neuronal functions.
Oxygen derivatives generated
metabolically may be a cause of the initiation of certain developmental events
in the brain[29]. It has been shown that ROS can influence multiple
aspects of neurogenesis, including the proliferation of neural precursors, their
differentiation into specific neuronal cell types. For example, high levels of
ROS are present in newborn neurons[30,31]. In cell cultures from
embryonic rat cortex (isolated from ED 14-15) ROS were generated as soon as
neurons differentiated from multipotent progenitor cells and are not associated
with cell death. Worth noting that a high level of ROS persists in the adult
brain only in neurogenic regions such as the hippocampus and olfactory bulb.
These neurons differentiate in the clonal culture into two types of cells:
large pyramidal-like neurons and smaller neurons that express nuclear
calretinin. Treatment with antioxidants, lowering ROS level, does not alter
number of neuron but dramatically changes the ratio of formation of these two
types shifting differentiation towards an increase in the number of smaller
neurons[31]. These data indicate that the level of ROS in the cells
can influence neuronal differentiation.
As previously
mentioned the mechanisms by which ROS affect these processes involve changes in
redox state. Redox state has been shown to be essential for NGF (nerve growth
factor)-induced differentiation of pheochromocytoma PC12 cells[32,33].
It may influence differentiation of mesencephalic precursors[34] and
neural crest stem cells[35]. In addition, redox state modulates
differentiation of glial precursor cell (oligodendrocyte/type-2 astrocyte
progenitors)[36].
RNS can be
involved in the development and maturation of the nervous tissue too. It has
been hypothesized that messenger NO may affect axonal growth, differentiation
and migration process during embryonic development of the rat brain and play an
important role in neuronal maturation and cortical plasticity in early
postnatal development[37,38]. It is suggested also that NO can
mediate the switch from proliferation to differentiation during neurogenesis[39].
Transcription of all three NO-synthase isoforms (neuronal - nNOS, endothelial-
eNOS, and inducible - iNOS) take place in brain cells from early embryonic
period. Expression of nNOS in rats was first observed on ED14 in the marginal
zone of the cortical mantle –in cells responsible for migration of neuronal
precursors to their appropriate positions in the cortical plate[40].
This activity decreased from ED20. At the same time expression of iNOS during
embryonic development is significantly lower than that of nNOS. During early
postnatal development cortex of rats exhibits a high expression of nNOS and
iNOS. The expression of iNOS increases from PD1 to PD10 and then declines to a
very low level during the adult period, while nNOS maintains comparatively high
expression throughout adult life[41,42].
Expression and
activity of the antioxidant enzymes also change during the maturation of the
brain. Despite limited and contradictory data on this issue, the most
considerable changes in enzyme activity in mammals are observed immediately
after birth (in response to changes in oxygen tension), whereas the expression
of antioxidant enzymes takes place in embryogenesis.
One of the
main antioxidant enzymes is superoxide dismutase (SOD). It catalyzes the
dismutation of superoxide anion to hydrogen peroxide. In mammals there are
three SOD isoforms: the Cu/ZnSOD – abundant cytosolic enzyme coded by the Sod1
gene, the MnSOD – mitochondrial enzyme coded by the Sod2 gene and minor
extracellular Cu/ZnSOD coded by the Sod3 gene[43]. The
activity and expression of Cu/Zn SOD in the rodent brain were shown at ED15-18[44,45].
An increase in Cu/Zn SOD expression was demonstrated around the time of birth
in rats[45]. Activity of SOD in guinea pigs remained constant
throughout the ED30–60 period[46].
In the
postnatal period Cu/Zn SOD levels are reported either to reach a peak around
the second week of life and then declines to adult level[44,47] or
increases up to adult level with some variations[48,49,50,51]. On
the other hand the enzyme activity remained relatively constant whereas Cu/Zn
SOD protein level increased from PD1 to PD21 that may be related to copper
availability[52].
In the immature rat brain
widespread expression of Cu/Zn SOD is observed primarily in neurons: in
cortical layers II, III and V, in the sub-plate, in the pyriform cortex, in the
hippocampus, and in the hypothalamus[53], with the lack of
expression in glial cells. Very little is known about the presence of this
enzyme in progenitor cells in the immature brain. It is suggested that Cu/Zn
SOD is expressed in certain populations of these cells at certain stages of
maturation[54].
The activity
of mitochondrial superoxide dismutase (MnSOD) gradually increased during the
first month of life[44,50]. It is suggested that MnSOD plays a
critical role in protection of neuronal cells against oxidative stress and is
essential for animal survival[55]. Complete knockout of MnSOD (Sod2–/–)
in mice results in early neonatal death[56,57]. Over expression of
Cu/ZnSOD does not prevent oxidative unbalance and neonatal lethality in mice
that lack MnSOD[58], but over expression of MnSOD decreases death of
differentiated neuroblastoma cells with mutation in Sod1[59].
More over in the immature brain over expression of Cu/ZnSOD induced tissue
damage after perinatal hypoxia-ischemia[60].
The two main
enzymes involved in H2O2 detoxification are catalase and
glutathione peroxidase. In the adult brain the major systems responsible for
this process are peroxidase systems, including glutathione/glutathione
peroxidase and thioredoxin/peroxiredoxins[61]. Activity of catalase
and glutathione peroxidase in guinea pig brain has been demonstrated to remain
constant from ED30 to 45 and to increase from ED45 to ED60[46].
Catalase activity in the developing rat brain is apparently higher than in the
adult one[49,62]. It should be noted that the specific activity of
catalase is significantly lower in the adult brain than in other tissues[28].
According to various estimates the maximum enzyme activity in different brain
regions of rats is observed from birth to PD5 - PD10, thereafter decreasing to
the adult level around day 30[44,49]. Our data (not published)
suggest that the activity of catalase in the cytosolic fraction of rat brain
cortex is two times higher in PD5 than in PD10. On the other hand catalase
expression and activity were relatively constant during the maturation of
oligodendrocytes[63]. However, the complete absence of enzyme is not
critical for survival. Catalase knockout mice develop normally, but their brain
mitochondria are more susceptible to trauma-induced oxidative stress[64].
Glutathione
peroxidases (GPxs) are several-times more abundant than catalase in the adult
brain[28]. The GPx family includes eight different isoforms (GPx1 –
8), which are encoded by different genes and have different substrate
specificities. In addition to other enzymes, such as thioredoxin reductases and
deiodinases of thyroid hormones, GPxs (except for GPx5, rodent GPx6, and GPx7)
are members of a large group of selenium-containing proteins[65,66,67].
Main GPxs of the brain are classical GPxs (cGPx or GPx1), this enzyme has also
been called cytosolic or cellular GPx, and phospholipid hydroperoxide
glutathione peroxidase (PHGPx or GPx4)[28].
The total GPx
activity was very similar in different brain regions, it decreased after birth,
but then increased again after 10 days reaching the maximum activity by 11th
week[49]. Data of other authors demonstrated continued elevation in
GPx activity up to the P45[44]. Our data showed that the activity of
cytosolic GPxin the rat brain cortex did not substantially change during the
first 20 days of life, but it was significantly higher at the PD90[68].
Among others
glutathione peroxidases – GPx4 is a unique member playing a key role in brain
development and function, presumably due its impact on proliferation[69,70].
Gpx4 knockout mice show abnormalities in brain development. Complete absence of
the enzyme leads to the death of the embryo[70]. GPx4 exists as
cytosolic, mitochondrial, and nuclear isoforms[71]. Comparative
expression analysis showed that the onset of expression Gpx4 in rats had been
observed during gastrulation[72]. At ED6 all three isoforms are
expressed in extra-embryonic and embryonic structures, including the ecto-,
meso- and endoderm. During the somite stage of development, mitochondrial and
cytosolic isoforms of GPx4 mRNA were expressed in the forebrain, midbrain and
hindbrain and in the developing eye. Despite the fact that the expression of
nuclear isoforms was found during embryogenesis, it is very poorly expressed in
the neuroepithelium and expression disappears at ED16-17 until birth. During
postnatal development, GPx4 is mainly found in the cortex, hippocampus and
cerebellum. Expression of the enzyme reaches peak values in the PD15 and
gradually decreases thereafter[69,73].
Little is
known about the expression and function of glutaredoxins (Grxs), peroxiredoxins
(Prxs), thioredoxins (Trxs) during normal brain development. Glutaredoxin and
thioredoxin are present in many tissues of mouse embryo at organogenesis stage
(ED11-13) and increase later in development[74]. These
oxidoreductases may control the cellular redox state[66] which, as
mentioned above, is very important for brain embryonic development. Most
vertebrates contain four Grxs: Grx1, Grx2 (dithiol) and Grx3, Grx5 (monothiol)[75].
The developing zebrafish brain depends on the enzymatic activity of Grx2, loss
of Grx activity during development is associated with apoptotic neuronal death[76].
All these data
indicate that the steady state level of ROS/RNS plays an important role in the
development of mammalian brain. Besides that there seems to be a general trend
towards increasing antioxidant capacity in the brain during maturation.
Accordingly, a decrease in antioxidants (in some pathological states) can have
negative consequences for developmental processes. However, addition of
antioxidants can disturb the natural redox homeostasis in the brain and have
unpredictable deleterious consequences. It should be concluded that
experimental data about antioxidant system of the brain during embryonic and
early postnatal periods are still insufficient and contradictory.
Acknowledgments
I am grateful to Vasily
Stefanov for language polishing.
CONFLICT OF INTERESTS
The author has no conflicts of interest to declare.
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Peer reviewer: Mustafa
Aydin, Department Of Pediatrics/Neonatology, Firat University Hospital, 23119,
Elazig, Turkey
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