Credit seminar on

Credit seminar
on
Pharmacology
Of Oxidative
Stress

Kamini Bisht
I.D.33184
4/21/2012

Overview

Free radicals
Sources of ROS
Oxidative stress
Oxidative damage in biological systems
Role of ROS
Oxidative stress and disease
Detection methods for ROS & oxidative stress
Antioxidative defense

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BIOLOGICAL ROLE OF OXYGEN

Carbohydrate metabolism for ATP Production (Mitochondria)

Degradation
of metabolic by-products by (Peroxisomes) 3
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CELLULAR RESPIRATION

Production of Reactive Oxygen Species

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Oxidative Stress

Antioxidants

Prooxidants
An imbalance favoring prooxidants and/or disfavoring
antioxidants, potentially leading to damage - H. Sies
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All matter in universe is composed of

basic unit element
Elements consist of atoms of one kind
e.g. oxygen ,nitrogen
H2,N2,O2,Carbon account for 96% of
bd.wt and 99% of atoms of body

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Atom-proton,electron,neutron
Atom-central-nucleus(proton+neutron)
Electorn-revolve around nucleus

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10

No of electron= no . of proton =atomic no.

eg.atomic no of oxygen is 8
protons and electrons =8
Electrons are arranged in shells

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11

Atoms are most stable in the

ground state.
"ground" -every electron in
the outermost shell has a
complimentary electron
spins in the opposite direction.

Electron valance theory

Inner orbital fills first and

hold maximum 2 electrons
Outer orbital contains octet.
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12

2 electron in inner shell

6 electron in outer shell
1s2

2s2

2px2

2py1

Sharing of electron-octate

2pz1

Breakage of covalent bond

atom with one
unpaired
electron in outer orbital
radical
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13

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14

Radical
Chemical species or atom that have
unpaired electron in outer orbital
Independent existence
Unstable and highly reactive
Autocatalytic reactions
R3C. Carbon-centered
R3N. Nitrogen-centered
R-O. Oxygen-centered
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15

Non radicals
Species that have strong oxidizing
potential
Species that favour the formation of
radical(e.g.transition metals)
H2O2 Hydrogen peroxide
HOCl- Hypochlorous acid
O3 Ozone
1
O2 Singlet oxygen
ONOO- Peroxynitrite
Men+ Transition metals
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16

Reactive Oxygen Species (ROS)

Radicals:
O2. OH.

Superoxide
Hydroxyl

RO2. Peroxyl
RO.

Alkoxyl

HO2. Hydroperoxy
perhydroxyl

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Non-Radicals:
H2O2 Hydrogen
peroxide
HOCl- Hypochlorous
acid
O3
1

O2

Ozone
Singlet oxygen

ONOO- Peroxynitrite

17

Reactive Nitrogen Species (RNS)

Radicals:
NO. Nitric Oxide
NO2. Nitrogen
dioxide

Non-Radicals:

ONOO- Peroxynitrite
ROONO Alkyl
peroxynitrites
N2O3 Dinitrogen
trioxide
N2O4 Dinitrogen
tetroxide
HNO2 Nitrous acid
NO2+ Nitronium anion
NO+ Nitrosyl cation

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18

Superoxide /Hyperoxide
Oxygen -13 electron in outer orbital
Extra unpaired electron
Negative radical-oxide
Extremely reactive-super
FORMATION
Transfer of single electron to O 2
Cytoplasmic enzyme- CytP450, xanthine oxidase
Neutrophil enzyme-NADPH
oxidase(respiratory burst oxidase)
NADPH oxidase
O2 + eO2.4/21/2012

19

Hydroxyl radicals
short-lived, most damaging radicals within
the body.
7 e- in outer orbital
Troposphere-act as detergent(eliminates
greenhouse gas-methane)

Fenton
HaberWeiss
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O2.- + Fe3+

O2 + Fe2+ (ferrous)

H2O2 + Fe2+

OH- + .OH. + Fe3+

O2.- + H2O2

OH- + O2 + .OH.

Iron and superoxide synergistic

20

Hydrogen peroxide

Dismutation of superoxide
free radical by superoxide dismutase

2 O2 + 2 H+
H2O2 + O2
Oxidases in peroxisomes

Converted to the highly damaging

hydroxyl radical or be catalyzed and
excreted harmlessly as water.
H2O2 + 2GSH
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GSH(oxidized) + 2H2O +2OH.

21

Nitric oxide
NO free radical gas.
First gas known to act as a biological messenger
Used by the body as a signaling molecule.
In 1980-Furchgott & Zawadeki show that vasorelaxation
evoked by Ach was endothelium dependent (EDRF).
In 1987-Furchgott, Ignarro and Palmer- EDRF was NO.
Lipid soluble /non polar gas, Short lived
Molecule of the year-1992.
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22

Synthesis

NOS I
NOS II
NOS III
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Central and peripheral neuronal cells

Ca+2 dependent, used for neuronal
communication
Most nucleated cells, particularly macrophages
Independent of intracellular Ca+2
Inducible in presence of inflammatory cytokines
Vascular endothelial cells
Ca+2 dependent
Vascular regulation

23

SINGLET OXYGEN ( O2)

1

Violates Hund's rule of

electron filling.
When oxygen is energetically
excited one of the electrons
can jump to empty orbital
creating unpaired electrons.
Singlet oxygen can then
transfer the energy to a new
molecule
Act as a catalyst for free
radical formation.
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1s2

2s2 2px2 2py1 2pz1

24

Reactive Species

Half-life

Hydrogen peroxide
Organic hydroperoxide
Hypohalous acids

~ minutes

Peroxyl radicals

~ seconds

Nitric oxide
Peroxynitrite

~milliseconds

Superoxide anion
Singlet oxygen

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Hydroxyl radical

~microsecond

~nanosecond

25

Radical-mediated reactions

Addition

R.

Hydrogen abstraction

R.

Electron abstraction

R.

Termination

R.

Dismutation

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H2C=CH2

LH

RH

ArNH2

CH CH

R-CH2-CH2.

R-

Y.

+ CH CH

+ L.

+ ArNH2.+

R-Y

CH CH + CH =CH

26

Sources of ROS/RNS

Endogenous

Microsomal Oxidation,
Flavoproteins,
CYP enzymes

Xanthine Oxidase,
NOS isoforms

Oxidases,
Flavoproteins

Endoplasmic Reticulum
Cytoplasm

Myeloperoxidase
(phagocytes)

Peroxisomes

Lipoxygenases,
Prostaglandin synthase
NADPH oxidase
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Lysosomes

Fe
Cu

Transit
ion
metals

Mitochondria

Plasma Membrane

Electron
transport
27

Mitochondria as a source

Mitochondrial electron chain

Quinone cycle

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28

Peroxisomes as a source

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29

NADPH oxidase as a source

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Neutrophill ,Eosinophill ,Endothelial cell ,fibroblast

30

Lysosome as a source of ROS and RNS

Cl- + H2O2
Tyrosine

MPO
MPO

HOCl + H2O
tyrosine radical

Myeloperoidase-azuriophillic granules
Eosinophil-cytoplasmic peroxidases-HOCL production
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31

Cytoplasmic sources

xanthine oxidase

xanthine oxidase

Nitric Oxide
Synthases (NOS):
neuronal

nNOS (I)

NO

endothelial eNOS (III)

inducible
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iNOS (II)

32

Endoplasmic reticulum as a source

of ROS
Cytochrome P450 (O2 to O2.-)

Cyclooxygenase(plasma membrane
as a source
Aracidonic
acid

cyclooxygenase

Prostaglandins,
leukotrines
ROS

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33

Exogenous sources of free radicals

Radiation
UV light, x-rays, gamma rays
Chemicals that react to form peroxides
Ozone and singlet oxygen
Chemicals that promote superoxide
formation
Quinones, nitroaromatics,
bipyrimidinium herbicides
Chemicals that are metabolized to
radicals
polyhalogenated alkanes, phenols,
aminophenols
Chemicals that release iron
ferritin
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34

UV radiation
H2O2

OH + OH
UV

UVA = 315-400 nm
UVB = 280-315 nm
UVC = 100-280 nm

Primarily a concern in skin and eye

Can also cause DNA damage
Can form singlet oxygen

Ionizing radiation
2H2O
H2O*
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Y-rays

H2O + e- + H2O*

H + .OH
35

Chemical that promote ROS

Premarin

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Nucl.36
Acids
Res.(210)38(12):e133

Chemicals that promote O2.- formation

NAD(P)H

NAD(P)+

Flavoprotein

H3C

N+

N+

Paraquat
N,N-dimethyl-4,4bipyridinium dichloride

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O2

.-

CH3

H3C

N+

CH3

Paraquat
radical
cation

O2

37

Chemicals : metabolized to radicals

Polyhalogenated alkanes

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Phenols, aminophenols

38

Chemicals that release iron

Ferretin + e-

Fe2+

Fenton Chemistry

Requires reductant
Promotes .OH formation
Promotes lipid peroxidation in vitro

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39

OXIDATIVE DAMAGE TO PROTEINS

Amino acid side chain

modifications
Disulphide bond breakage
Disulphide stress
peptide bond cleavage
protein protein cross
linked derivatives
Increased susceptibility
to proteolysis
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Amino acid
Arginine
Cysteine
Glutamyl
Histidine
Tyrosine

oxidative product
Glutamic semialdehyde
Disulfides, cysteic acid
Oxalic acid, pyruvicacid
2-Oxohistidineaspargine
Tyr-Tyr cross-linkages
40

Oxidative damage to lipids

Lipid peroxidation

Termination
4/21/2012

2 LOO

non-radical products
41

Structural changes in membranes

alter fluidity and channels
alter membrane-bound signaling proteins
increases ion permeability
Lipid peroxidation products form DNA adducts
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Oxidative damage to nucleotide

DNA adducts
Strand breaks
mutations
initiation of
cancer

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Free radicals- role in body

Signaling
Neurotransmitter
Vasodilatation
Peristalsis
Penile erection
Memory
Angiogenesis
Gene expression
Apoptosis
Killing of pathogen
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Nitric oxide signaling

guanylyl cyclase
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46

Penile erection

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Iron-sulfur proteins and free radical

signaling
Fe
Active protein

ROS

Fe
Inactive protein

Sulfide, cysteine thiolate groups in non-heme iron proteins

Mammalian (4Fe-4S) aconitase (citric acid

cycle, citrate isocitrate)
Contains non-heme iron complex Fe-S-Cys
ROS and RNS disrupt Fe-S clusters and inhibit
aconitase activity
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ROS in transcription

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Nitric oxide as neurotransmitter

Non adrenergic non cholinergic transmitter
Similarities with neurotransmitter
Present in presynaptic terminal
Natural removal from synaptic junction
Dissimilarities
Synthesized on demand ,not stored.
NO diffuses out of the cell ,no exocytosis
NO does not bind to surface receptors, enters
the target cell
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Neurotransmitter

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NO in memory

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52

 Science news articles about oxygen free

radicals :
BRAIN PLAYS AN IMP KEY ROLE IN
APPETITE BY REGULATING O.F.R.
Researchers at Yale School of Medicine have found
the brain's appetite centre uses fat for fuel by
involving oxygen free radicals - molecules associated
with ageing and neurodegeneration.
The findings, reported in the Journal Nature,
Suggest that antioxidants could play a role in
weight control..
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53

ROS in apoptosis

Apopto
sis
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54

ROS in Immune system

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55

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56

Oxidative stress and disease

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Atherosclerosis

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Ischemia/reperfusion injury

lactate

4/21/2012

protease
s
XD
XO

59

Cancer and ROS

Oxidative Stress

DNA damage
Gene mutation
Alteration of
DNA structure

Inheritable mutation

Initiation

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Persistent oxidative
stress

Abnormal
gene
expression

Cell proliferation

Promotion

Abnormal
enzyme
activity

Resistance
to
chemotherapy

Metastasis and invasion

Progression

60

ROS and aging

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Ros in neurodegenration
ROS
poly-ADP-synthetase
Ca2+
phospholipases/enonucleases
DNA damage

ROS

LDL oxidation
injury

interfere blood flow to brain

Fe rich area(substantia nigra)

injury
Ischemia-reperfusion
stroke
4/21/2012

ROS

obstruction in blood supply

62

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63

 Parkinsons

Alzheimer

H2O2,OH.

amyloid
precursor
protein(neuron
growth,survival,p
ost injury repair)

Degenration
of substensia
nigeri
.Damage to
dopaminergic
neurons

ROS
Fragmentation
Beta amyloid
Neuron death

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64

Detection of oxidative stress

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65

Direct detection of Free Radicals: EPR

Detection of unpaired
electron in applied
magnetic field
Electron
is
placed
in magnetic field it
spins in two direction

Parallel or antiparallel

two alignments have

different energy

Energy difference is
measured
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Detection of Free Radical Immuno-spin trapping

T1/2msec

5,5Dimethyl
pyrolineNoxide
T1/2sec
s

Protein-DMPO
adducts-green

T1/2-hrs

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67

Detection of Free Radicals: Fluorescent

Probes
ROS/RNS
Chemical compound Fluorescent chemical compound
Live
bovine
pulmonary
artery endothelial cells
(BPAEC) are incubated
with
blue-fluorescent
dihydroethidium and the
green-fluorescent
mitochondrial stain.
Upon oxidation, by ROS
red-fluorescent ethidium
is accumulated in the
nucleus.
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68

Detection of Free Radicals: Modified Lipids

Thiobarbituric Acid-Reactive Substances
(TBARS)/MDA:
detect lipid peroxidation
measures MDA a breakdown product of lipid
peroxidation
Method: sample is heated with TBA at low pH
TBA-MDA adduct is formed
absorbance is quantified at 532 nm or
fluorescence at 553 nm
Advantages: easy, equipment readily available
Disadvantages: not specific
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69

Are you ready to fight the

attack of prooxidants?

Prooxidant Jail

Antioxida
nt

O-2, 1O2, .OH, H2O2,

Cu, Fe.

R, RO, ROO

R, RO,
ROO,
O2, O-2,

-OH, H2O2,
Cu, Fe

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Antioxidants

any substance that when present at low

concentrations compared to that of an
oxidizable substrate would significantly delay
or prevent oxidation of that substrate

or

Antioxidants are substances that protect

cells from the damage caused by unstable
molecules known as free radicals.
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Neutralize free radicals by donating

one electron, ending the
electron-"stealing" reaction

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Ideal antioxidant
Effective in low concentration.
Non-toxic and non-irritant
Odorless, tasteless,should not impart color
Decomposition product should be non- toxic
Stable and effective over wide range of
pH.
Should not react chemically with other
constituent present
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Classification
Endogenous
enzymatic
Superoxide
dismutase
Catalase
Glutathione
Peroxidase
Paraoxonase
Aldehyde DH

4/21/2012

Natural

Dietary

Non enzymatic
Thiolsbiochemica
Glutahione,Lipoic
acid
N-acetyl
ls cystine
Uric acid,Melatonin
Pterins
Metal binding proteins
Albumin
Ceruloplasmin
Transferrin
Cofactors
coenzymeQ10

Minerals
Se,Cu,Fe
Vitamins
VitaminC
Vitamin E
Carotenoid
Phytochemicals
polyphenols
flavonoids
74

Synthetic

Butylated hydroxyl anisole (BHA).

Butylated hydroxyrotoluene (BHT).
Propyl gallate (PG)
metal chelating agent (EDTA).
Tertiary butyl hydroquinone (TBHQ).
Nordihydro guaretic acid (NDGA).
Ethoxyquin (6-Ethoxy-1,2-dihydro2,2,4-trimethylquinoline)

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75

On the basis of mechanism

Primary or
Chain breaking antioxidant

Natural
Flavonoids
Phenolic acids
Tocopherols
Quercitin
anthocyanin
Synthetic
Butylated hydroxyanisole (BHA)
Butylated hydroxytoluene (BHT)
Ethoxyquin
Propyl gallate (PG)
Tertiary-butylhydroquinone
(TBHQ)
4/21/2012

secondary or
Preventive antioxidant
Metal chelation
Cirtic, Malic, Succinic and Tartaric
acids
Ethylenediaminetetraacetic acid,
Phosphates
Oxygen scavenging and reducing agents
Ascorbic acid, Ascorbyl palmitate,
Erythorbic acid,
Singlet oxygen quenching Carotenoids
( B-Carotene, Lycopene and Lutein)
Endogenous enzyme
SOD,catalase,glutathione peroxidase
76

Primary or type 1 or chainbreaking antioxidants

Free radical acceptors/scavengers
Delay or inhibit the initiation step
Interrupt the propagation step of
autoxidation.
ROO. + AH
ROOH + A.
R. +
AH
RH + A.
ROO. + A.
ROOA
A. +
A.
AA

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77

Vitamin E :
most abundant fat-soluble antioxidant
most efficient chain-breaking antioxidants within
cell membrane
protect membrane fatty acids lipid peroxidation.

Flavanoids in green tea (Camellia sinensis )

Extracts of immature leaves
-flavan-3-ols and their gallic
acid derivative catechin,
epicatechin, gallocatechin,
epicatechin gallate
Primary
antioxidant-H+ donar
4/21/2012

Flavones-luteolin
Flavanones-naringenin
Flavonols-quercetin
Isoflavones-genisetin
Flavan-3-olsepicatechin
78

Phenolic compound
Polyphenolic compound-radical scavanger
Phenolic acid
Benozic acid,cinnamic acid and derivatives
Benzoic acid derivative
p-Hydroxybenzoic
Gallic
Procatechuic
Syringic
Vanillic
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Cinnamic acid derivative

Caffeic
Cinnamic
p-Coumaric
Ferulic
Sinapic
79

Lipoic acid
thiol antioxidant
catalyzes oxidative decarboxylation of
alpha-keto acid ( Krebs cycle.)
chelator
sparing effect
Lipoic acid and dihydrolipoic acid
(DHLA)- quench free radicals ( lipid and
aqueous domains)
universal antioxidant.
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80

Ethoxyquin
6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline
Fish product,apple-prevent pigment oxidation
animal feeds - protect carotenoid oxidation.
free radical terminater.

Butylated Hydroxyanisole (BHA)

3-tertiary-butyl-4-hydroxyanisole (90%) and
2-tertiary-butyl-4-hydroxyanisole (10%).
Delays lipid oxidation
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81

Butylated Hydroxytoluene (BHT)

BHA and BHT act synergistically
BHA + peroxy radicals BHA phenoxy
radical.
BHA phenoxy radical abstract hydrogen
from hydroxyl group of BHT.
BHA is regenerated
BHT radicals react with a
peroxy radical,act as a chain terminator
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Gallates
Esters of gallic acid
Synergistic activity with both primary
and some of the secondary antioxidants

Tertiary-Butylhydroquinone(TBHQ)
Diphenolic antioxidant
Possible mutagenic effect
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Secondary antioxidants
Not convert free radicals into stable molecules.
Chelators for prooxidant metal ions,
Deactivate singlet oxygen,
Absorb ultraviolet radiation, or act as oxygen
scavengers.
Enhance antioxidant activity of primary
4/21/2012
antioxidants..

84

4/21/2012

85

Chelators
Heavy metals ( Co, Cu, Fe, Mn,)shorten the
induction period, increase lipid oxidation
Occupy metal cordination site
Form insoluble complexes
Water soluble ,citrate is lipid soluble
Lactoferrin ,transferritin chelates Fe
Carnosine(peptide in muscle food) plants of
the Labiatae family ( rosemary) - chelator
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86

Oxygen Scavengers and Reducing

Agents
Vitamin C :
Reducing agent and oxygen scavenger.
Most abundant water-soluble antioxidant in ECF
Neutralize ROS in the aqueous phase before lipid
peroxidation is initiated.
Erythorbic acid
D-isomer of naturally present L-ascorbic acid
Ascorbyl palmitate and Ascorbyl stearate
Synthetic derivatives of ascorbicacid.
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87

Carotenoid
Primary and Secondary
Singlet oxygen inactivation(secondary)
1

O2 + 1-CAROTENE
3

-CAROTENE

O2 + 3-CAROTENE

CAROTENE

In absence of singlet oxygen carotenoids may

trap free radicals and act as a chain-breaking
antioxidant
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88

Glutathione

Tripeptide ( glycine, glutamate (glutamic

acid) and cysteine).
Cysteine is the "rate-limiting"
Thiol group donate electrons to free
radical
5-in one glutathione preperation-vit.C100mg,collagen-200mg,glutation100mg,lipoic acid-25mg,Zn-6.5mg
N-acetyl-cystiene-glutathione precursor

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89

Nitric oxide synthtase inhibitors

NG-monomethyl arginine (L-NMMA)
NG-Nitro-L-arginine Methyl Ester (L-NAME)

Melatonin
N-acetyl5methoxytrptamine
Scavanger of NO,
superoxide

coenzymeQ/ubiquinone
Prevent lipid peroxidation

Uric acid
Act
synergistically with vitaminE/C
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90

Endogenous enzyme
Superoxide dismutase

2O2-

2H+

H2O2

Catalase

O2

H2O

Catalase- peroxisome
MnSOD mitochondria Glutathione Peroxidase
Cu-ZnSOD-cytosol
EC-SOD
GSSG + 2H2O
Ni-SOD
2GSH
Glutathione oxidsed
NADP+

NADPH + H+
NADP+ Reductase

4/21/2012

GPX1
GPX2
PHGPX

91

Herbal antioxidants
Plant Sps

Family

Active
constituent

Terminalia chebula/ Myrobalanus

chebula or Harde.

Combretaceae

Gallic acid

Eucalyptus globules: - Karpura

maram.

Myrtaceae

Phenolic compounds

Acacia arabica bark:-

Mimosae.

Quercitin

Zingiber officinale
ginger.

Zingiberaceae

zingerone,

Emblica officinalis(Amla)
Annona squamosa / Custard apple
/ Sitaphal
4/21/2012

Euphorbiaceae
Annonaceae

Vitamin C
Flavanoids
92

Plant Sps
Acacia catechu(Khadira)

Family
Leguminosae

Active constituent
Cathechin,quercitin

Aerva percisca

Amaranthceae

Flavanoids

Carlina acanthifolia

Asteraceae

Essential oils

Morus alba

Moraceae

B-carotene

Piecea albies

Pinaceae

Tocopherol

Rhododendron

Ericaceae

Flavanoids

Rosmarinus officinalis:-

Labiatae

Ursolic acid,borneol

Mentha arvensis

Labiatae

Menthe oil

Glycyrrhiza glabra
4/21/2012
yastimadhu.

Leguminosae.

flavones
93

zinge
r

Acacia
catechu

Hard
e

Eucalyptu
s

Amla

Mentha

Rosemary

lemon
sitaphal
4/21/2012

Glycyrrh
iza
94

Evaluation of antioxidant activity

AA = (tAH tCONTROL)/([AH])tCONTROL

where
tAH is time taken by the substrate to reach a predetermined level
of oxidation
tCONTROL is the time for untreated substrate or control to reach
the same level of oxidation
[AH] is the concentration of antioxidant in appropriate units
tCONTROL= tAH; no antioxidant activity is exerted
tCONTROL < tAH; antioxidant activity is exhibited
tCONTROL > tAH; prooxidant activity is observed and AA has a
negative value.

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95

Oxygen radical absorbance capacity

(ORAC)
Quantify
degree of
protection
to
florescent
molecule

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96

INVESTIGATIONAL THERAPY
Free radical scavenger in stroke :
Strategies aimed at restoring blood flow to the
ischemic brain have been most promising.
ANCORD a defibrogenating agent has been
shown to improve outcome when initiated within
3 hrs of onset of symptoms.
Pro urokinase, when administered intra
arterially to patients with large strokes within 6
hrs of symptoms onset, also has been shown to
improve stroke outcome
Lazaroids (U-74500A and U-78517F )
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97

Division of Pharmacology, SmithKline Beecham Pharmaceuticals,King of

Prussia Pennsylvania.

Carvedilol, a new vasodilator and beta adrenoceptor

antagonist, is an antioxidant and free radical scavenger :
The antioxidant effect of carvedilol, a new vasodilating,
beta adrenoceptor blocker was studied and compared
with five other beta blockers.
Carvedilol
rapidly
inhibited
Fe(++)-initiated
lipid
peroxidation, measured as thiobarbituric acid reactive
substance (TBARS), in rat brain homogenate with an
IC50 of 8.1 uM.
Under the same conditions, the IC50 values of atenolol,
pindolol propranolol, celiprolol and labetalol were over 1.0
mM.
TL Yue, HY Cheng, PG Lysko, PJ McKenna, R Feuerstein, JL Gu, KA Lysko, LL
Davis
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Conclusion
Monitoring and rapid detection of free radical is necessary to
combat various diseases, moreover this would serve as a concise
knowledge about free radicals for the study of students as well as
researchers.
Difficulty in producing free radical scavengers in dosage form
illustrates the need for more research about the chemical nature
and behaviour of free radicals.
So if we can intensify our knowledge regarding free radicals & go
deep into it we can easily prove the proverb PREVENTION IS
BETTER THAN CURE but at the same time we should remember,
AN APPLE A DAY KEEPS A DOCTOR AWAY.
Detailed knowledge regarding the benefits and hazard of free
radicals must be known so that in a busy life where everyone is
involved in a rat race one can easily combat against the deadly
effect of free radicals and can live a healthy life.
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