L4 Bio

L4 BIO
Oxidative stress
Oxidative stress is the condition of oxidative damage resulting from unfavorable balance
between free radical generation and antioxidant defenses.
A free radical is:
a molecule that contains an unpaired electron in its outer orbital. It is generally represented
by a superscript dot, (R.). The presence of an unpaired electron results in that these radicals
are unstable and highly reactive. They can either donate or accept an electron from other
molecules, therefore behaving as oxidants or reductants.
Free radicals include:
1-reactive oxygen species (ROS):
 Superoxide anion radical (O2.-)
 Hydroxyl radical (OH.)
 Peroxide O2.-2
 Hydrogen peroxide (H2O2)
2--reactive nitrogen species (RNS):
 Nitric oxide radical,
 Peroxynitrite radical.
Characteristics of free radicals are:
1-extreme reactivity.
2-short life span.
3-generation of new ROS by chain reaction:
Oxidative stress is frequently referred to as a self-replicating process. When oxidative stress-
induced excessive ROS emission causes cellular damage, the damaged macromolecules may
act as and/or develop into ROS.
4- damage to various tissues.
Generation of Free Radicals in the human body:
Free radicals and other ROS are derived either from:
1- Normal essential metabolic processes:
Free radical formation occurs continuously in the cells as a consequence of:
-Enzymatic reactions: include those involved in:
 Respiratory chain
 Phagocytosis
 prostaglandin synthesis,
 cytochrome P-450 system.
-Nonenzymatic reactions
2- External sources:such as UV light, exposure to X-rays, ozone, cigarette smoking,
air pollutants, and industrial chemicals.
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L4 BIO
BENEFICIAL EFFECTS OF FREE RADICALS:

1- phagocytes (neutrophils, macrophages, monocytes) release free radicals to destroy invading
pathogenic microbes as part of the body's defense mechanism against disease.
2-ROS modulates cell proliferation and apoptotic pathways to ensure proper regulation of the
cell cycle and programmed cell death.
Biologically relevant molecules damaged by free radicals are:
1- DNA:
DNA and RNA are susceptible to oxidative damage. DNA especially mitochondrial DNA is
considered as a major target in aging and cancer.
2- proteins:
Proteins can be oxidatively modified in three ways:
 oxidative modification of specific amino acid
 free radical mediated peptide cleavage
 formation of protein cross-linkage
These proteins are recognized as non self by immune system that produces antibodies (also
cross-react with normal tissue proteins) causing autoimmune diseases.
3- lipids:
lipid peroxidation producing a number of compounds are formed e.g. malondialdehyde that is
used as a markers in lipid peroxidation assay.
Chemical modification of protein and lipid of LDL --->abnormal LDL that is not rcognozed by
LDL receptors and not cleared by the liver and is taken by macrophages and scavenger
receptors. Lipid engorged macrophages infiltrate under blood vessel endothelium--->
atherosclerotic plaques.
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L4 BIO
Free Radical Scavenger System:

Antioxidants
An antioxidant is a molecule stable enough to donate an electron to a free radical and
neutralize it, thus reducing its capacity to damage. These antioxidants delay or inhibit cellular
damage through their free radical scavenging property. They include:
A-Enzymatic antioxidants:
1. Superoxide dismutase (SOD)
 The mitochondrial SOD is manganese dependent.
 Cytoplasmic enzyme is copper-zinc dependent.
2. Peroxidases:
 It removes H2O2.
3. Catalase
 It is used to remove H2O2 when generated in large quantities.
4. Glutathione reductase (GR) & glutathione peroxidase (GPX)
 The oxidized glutathione is reduced by the glutathione reductase (GR), in presence
of NADPH That is generated with the help of glucose-6-phosphate dehydrogenase
(G6PD) in HMP shunt.
 Therefore, in G6PD deficiency, the RBCs are liable to lysis, when oxidizing agents
are administered (drug induce hemolytic anemia).
B-Non-enzymatic antioxidants:
such as, Vitamin E , Vitamin C, Uric acid, Glutathione, Coenzyme Q10, Caffiene, Cysteine,
Vitamin A ,Beta carotene.
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L4 BIO
Clinical Significance
Brain:  Vessel Atherosclerosis
 Aging  Myocardial infarction
 Parkinsonism  Aging
 Alzheimer′s disease  Joints Rheumatoid arthritis
 Dementia  Aging
 Lateral sclerosis  cancer
 Huntington’s disease
 epilepsy and drug-resistant epilepsy
Eye
 Degenerative retinal damage
 Cataract formation
Kidney
 Glomerulonephritis
WHAT ARE THE EFFECTS OF OXIDATIVE STRESS ON THE CENTRAL NERVOUS

SYSTEM?
Certain factors make CNS prone to ROS invasion:
A-Very high production rate of ROS
1-Oxygen demand of the brain is very high, accounting for 20% of the oxygen consumption of
the human. High rate of oxidative metabolism.
2- Microglia are specialised immune cells therefore generate O2.- during phaogcytosis.
3 -Amine based neurotransmitter (e.g. dopamine) metabolism generates mitochondrial H2O2
via monoamine oxidase enzymes.
4-The brains reliance on Ca2+ signaling can cause oxidative stress:
-Ca2+ transients stimulate neuronal nitric oxide synthase (nNOS) mediated nitric oxide (NO.)
synthesis
-local Ca2+/H2O2 signalling
5-Excessive glutamate uptake by (NMDARs)) causes excitotoxicity. Glutamate excitotoxicity
leads to Ca2+ overload linked mitochondrial [O2.-/H2O2] release associated cell death,
typically via apoptosis and necrosis. Ca2+ influx can activate nNOS.
6-Neurotransmitters can auto-oxidise:: dopamine reacts with O2 to generate a dopamine
semiquinone radical, which can then react with another O2 to generate O2.- and a dopamine
quinone.
7-The brain uses NOS and NOX isoform for signalling to achieve essential functions.
First, nNOS uses O2, NADPH and L-arginine to catalytically synthesise NO.
Second, NOX isoforms use prosthetic redox groups to oxidise NADPH to reduce O2 to
O2.-
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L4 BIO
B-Modest endogenous antioxidant defence:

1-Comparatively low endogenous antioxidant defence relative to many tissues (e.g. liver).
Neurons possess 50 times lower catalase content compared to hepatocytes.
2-Relatively low due to relatively low levels of glutathione (GSH) in the brain.
3- Blood-brain barrier selectivity for antioxidants.
4-High concentration of polyunsaturated fatty acids, which restricts the distribution of several
antioxidants, such as vitamin E.
α-tocopherol has two functions in the brain:

1-It maintains the integrity of cell membranes through inhibiting oxidation of PUFAs
particularly arachidonic acid (AA) and docosahexaenoic acid (DHA), the two major PUFAs found
in the brain.
2-It possesses non-antioxidant functions, including the regulation of gene expression (down-
regulate the expression of pro-inflammatory genes).
This explains the inverse association between α-tocopherol and cognitive
impairment/dementia in humans.
C-Brain lipids:
1-Brain’s phospholipids are particularly susceptible to ROS-mediated peroxidation.
2-Unsaturated lipid enrichment: The brain is the major sink for polyunsaturated. Given their
ATP demands, neurons oxidise lipids to generate ATP, particularly since the ATP yield is greater:
106 ATP per mol palmitic acid vs 32 ATP per mol glucose.
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L4 BIO

BENEFICIAL EFFECTS OF FREE RADICALS:

Free Radical Scavenger System:

WHAT ARE THE EFFECTS OF OXIDATIVE STRESS ON THE CENTRAL NERVOUS

B-Modest endogenous antioxidant defence:

α-tocopherol has two functions in the brain:

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