It contains sources of free radicals generations and its impact on Neurons.

1. ROLES OF FREE RADICALS
IN NEURODEGENRATIVE
DISEASES
PRESENTED BY
E.POOVARASAN
M.PHARM FIRST YEAR
DEPARTMENT OF PHARMACOLOGY
COIMBATORE
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2. CONTENTS
• NEURODEGENERATIVE DISEASES
• EFFECTS OF FREE RADICAL IN NEURODEGENERATIVE
DISEASES
• PARKINSON’S DISEASE
• OXIDATIVE DAMAGE IN PARKINSON’S DISEASE
• HUNTINGTON’S DISEASE
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3. NEURODEGENRATIVE DISEASES
• Neurodegenerative diseases are specifically characterized by apoptosis/necrosis and
dysfunction of neuronal cells, leading to a malign effect on the neural system.
• Being the extensively active part of body, the brain is more vulnerable to oxidative
stress.
• The brain has a higher demand for oxygen and thus consumes 20% more oxygen than
other parts of body
• The brain is also enriched in redox-active metals (copper and iron) that actively
participate in ROS generation. As the brain cell membranes are rich in PUFA, they are
more prone to lipid peroxidation.
• Although, when present in the optimum concentration, the antioxidant glutathione
(GSH) plays a major role in detoxification of ROS species in brain cells
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4. • A decreased level of GSH in brain is linked with the elevated level of ROS leading
to neurodegenerative diseases such as
• Alzheimer’s disease
• Parkinson’s disease
• Huntington’s disease,
• Machado–Joseph disease
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Image source: molecules articles

6. FREE RADICALS IN
NEURODEGENERATIVE DISEASES:
• ROS significantly contribute to the deterioration of neuronal cells via modulating
the function of biomolecules
• These species target different biomolecules (DNA, RNA, lipids, and proteins) and
processes (nucleic acid oxidation, lipid peroxidation) in the cell.
• The ROS involved in neurodegeneration include
• hydrogen peroxide (H2O2),
• superoxide anion (O2-), and
• highly reactive hydroxyl radical (HO)
• The reactive nitrogen species (RNS) such as nitric oxide (NO) are also found to
have a deleterious effect on neurons.
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7. Image source: molecules articles

8. Image source: molecules articles

9. PARKINSON’S DISEASE (PD)
• PD is the second most common neurodegenerative disorder after AD in elderly
people characterized by selective neuronal impairment of dopaminergic (DA)
neurons in the substantia nigra pas compacta (SNc), along with the reduction of
DA levels in the nigrostriatal DA pathway in the brain.
• This disease is exhibited by the emergence of insoluble inclusions in neurons
known as Lewy bodies, consisting mainly of synuclein.
• As neurons regulate and control the voluntary movements of the body, their
deterioration leads to impaired motor function , bradykinesia, postural
instability, rigidity, and tremor at rest.
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10. • Various exogenous sources such as overuse of herbicides, pesticides, exposure to
organic chemicals, carbon monoxide, carbon disulphide, plant derived toxins,
and bacterial as well as viral infections are supposed to play a substantial role in
the manifestation of PD
• It is also believed that ageing plays a pivotal role in PD, as with ageing, normal
cellular processes are more prone to ceasing, which leads to degeneration of
DAergic neurons.
• The familial forms of PD exhibited various mutations in a number of genes.
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11. OXIDATIVE STRESS IN PD
• Oxidative stress is implicated as a major factor for nigral neuronal cell death.
• Oxidative stress promotes aggregation and accumulation of α-synuclein in
sporadic PD.
• There are several potential sources of the increased free radical production in
Parkinson’s disease including
• Increased dopamine metabolism and formation of neuromelanin,
• Increased free iron levels, and low ferritin concentration.
• Mitochondrial dysfunction,
• Other exogenous sources such as overuse of herbicides, pesticides, exposure to
organic chemicals, carbon monoxide, carbon disulphide, plant derived toxins,
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12. Increased oxidation of dopamine and Formation of
neuromelanin
• Catecholamines and particularly dopamine (DA) are an important source of free
radicals in the brain.
• when it is in excess in cytosol, it is oxidized either enzymatically by monoamine
oxidase (MAO) or autoxidized to generate hydrogen peroxide.
• Autoxidation of dopamine or L-dopa via quinone formation generates free radicals
such as superoxide radical and hydrogen peroxide.
• DA reduces the oxidation state of the transition metals such as Cu 2+ and Fe 3+
and subsequently stimulates production of H 2 O 2
• By Fenton reaction, hydrogen peroxide and reduced metal ions(Fe2+)
• produce hydroxyl radicals
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13. • Dopamine and L-dopa quinone are easily oxidized to aminochromes and finally
polymerize to form neuromelanin.
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Image source: frontiers..com

14. Increased Iron Concentration and Low Concentration of
Ferritin
• Iron is important for developing the activity of tyrosine hydroxylase and
monoamine oxidase enzymes
• The tyrosine hydroxylase catalyzes the conversion of L-tyrosine to L-
dihydroxyphenylalanine, and the monoamine oxidase catalyzes the oxidative
degradation of dopamine.
• In the cells most of the iron binds to ferritin, others formed chelate compounds
with phosphate groups of membrane components and some included in iron
micronutrient enzymes.
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15. • Ferritin serves to store iron (Fe 3+ ) in a nontoxic form, to deposit it in a safe form
and to transport it to areas where it is required.
• Increased iron stimulates the formation of free radicals, and changes in the ratio of
Fe 2+ /Fe 3+ confirmed the presence of oxidative stress
• Iron mediates oxidative damage to cellular components through the one-electron
transfer called the Fenton reaction, which leads to production of the unstable
hydroxyl radical (OH•) that oxidizes lipid, protein, nucleic acid, and
carbohydrate.
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www.google images. com

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source:www.mpdi.com

17. OXIDATIVE DAMAGE IN PD:
• Mitochondrial dysfunction,
• Dopamine auto-oxidation,
• α-synuclein aggregation,
• Glial cell activation,
• Alterations in calcium signaling,
• Excess free iron.
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18. Mitochondrial Dysfunction:
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Mitochondrial Dysfunction:
Reduce ATP Production and
increase oxidative stress
Altered mitochondrial morphology, impaired calcium
buffering, damage to mitochondrial DNA (mtDNA),
Alterations in mitochondrial fission and
fusion,
leading to cell death
Increased production of
ROS

19. MITROCHONDRIAL DNA MUTATION
IN PD
Mutations in mitochondrial DNA
decreased activity of enzymes involved in the respiratory
chain and in the production of ATP,
increased apoptosis, accelerated aging, and reduced lifespan

20. MUTATION EFFECTS Mt DNA ON PROTEINS
Mutations in parkin and PINK1 account for early-onset
familial PD
Mutations in PARK7, which encodes DJ-1, are oxidatively
damaged and increase significantly in brains of patients with
sporadic PD
Loss of function of DJ-1, parkin, and PINK1 leads to
decreased mitochondrial protection against oxidative stress,
causing enhanced mitochondrial dysfunction

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Image source: horizon
dicovery

22. Role of alpha synuclein:
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23. Role of Glial Cells
Microglia:
• Activated microglia are the most abundant source of free radicals in the brain by
releasing free radicals such as O2− and NO
• over-activated microglia contribute to neurodegenerative processes by producing
various neurotoxic factors including free radicals and proinflammatory cytokines ,
or via free radicals generated by activated NAD(P)H oxidases
• Microglia maintain microenvironmental homeostasis during brain injury by
• migrating to the lesion site,
• clearing cellular debris, and
• producing pro-inflammatory cytokines such as t (TNFα), interleukins 1 beta (IL-
1β) and 6 (IL-6), and anti-inflammatory cytokines such as interleukin 10 (IL-10)
and transforming growth factor beta 1 (TGFβ1)
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24. MICROGLIAACTIVATION
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25. Astrocytes
• Astrocytes play a significant role in brain injury, as they respond to injury in
conjunction with microglia through a process called reactive gliosis or astrogliosis
• Glial fibrillary acidic protein (GFAP) is the most commonly used marker of
mature astrocytes in the CNS and has been the most common change observed
during aging
• Thus, astrocytes are thought to be the major contributor of GSH and help in
removal of ROS. The GSH content in the SN of patients with PD is significantly
reduced (~40%), making them more vulnerable to the deleterious effect of free
radicals
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27. Regulation of Calcium
• SN neurons rely upon L-type Ca2+ channels to govern pacemaking
• Mitochondria and the endoplasmic reticulum are the principal organelles involved
in sequestering Ca2+ in neurons , and dysfunction in these organelles that occurs
during aging and PD could result in the generation of oxidative stress.
• oxidants cause a rapid increase in Ca2+ concentrations in the cytoplasm of diverse
cell types
• Oxidants such as H2O2 cause a sustained elevation in cytosolic Ca2+
• severe oxidative stress causes Ca2+ uptake by cells from the extracellular space
• An increase after hyperpolarization during aging is partially related to Ca2+ influx
through L-type Ca2+ channels as well as changes in Ca2+ buffering
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28. HUNTINGTON’S DISEASE:
• Huntington’s disease (HD) is progressive neurodegenerative disorder resulting in
neuronal degeneration in the striatum followed by deterioration of the cerebral
cortex and thalamus.
• HD is caused by a mutation in the huntingtin (HTT) gene. It is characterized by
an abnormal extension in the cytosine–adenine–guanine (CAG) repeat in this
gene, which in turn translates into an abnormally long repeat of polyglutathione
in the mutant huntingtin protein
• Huntington disease is mainly characterized by impaired motor and cognitive traits,
personality change, and psychiatric illness
• Protein misfolding, abnormal proteolysis, protein aggregation, transcriptional
dysfunction, excitotoxic and oxidative stress, and glial activation has also been
associated with neuronal death in HD
• protein carbonylation were found to be more pronounced in HD
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29. OXIDATIVE STRESS IN HUNTINGTON’S
DISEASE
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30. REFERENECES
• Oxidative Stress: A Key Modulator inNeurodegenerative Diseases by Anju Singh 1,2 , Ritushree Kukreti 3,4,
Luciano Saso 5 and Shr
• Free Radicals in Human Health and Disease by Darshika Nigam.
• www. Google .com
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