Iron Chelators in Brain Disorders
Presented by:
Jennifer Carter, He (Joanna)Li,
Vincent Chan, Naomi Lo
PHM142 Fall 2014
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Generation of ROS
1. Free Fe2+ present
in the brain can
react with peroxide
to produce hydroxy
radicals
1. Free Fe2+ present in the brain can
react with peroxide to produce
hydroxy radicals
2. .OH causes peroxidation of
polyunsaturated fatty acids (LH)
3. This leads to the formation of
reactive aldehydes
4. Reactive aldehydes and other
reactive species can create carbonyl
groups on proteins
5. Damaged and misfolded proteins
aggregate
Hydroxyl Radical
Reaction with Fatty Acids
1. Free Fe2+ present in the brain can react
with peroxide to produce hydroxy radicals
.
2. OH causes peroxidation of
polyunsaturated fatty acids (LH)
3. This leads to the formation of reactive
aldehydes
4. Reactive aldehydes and other reactive
species can create carbonyl groups on
proteins
5. Damaged and misfolded proteins
aggregate
Reactions with Proteins
1. Free Fe2+ present in the brain can react
with peroxide to produce hydroxy radicals
2. .OH causes peroxidation of
polyunsaturated fatty acids (LH)
3. This leads to the formation of reactive
aldehydes
4. Reactive aldehydes and other reactive
species can create carbonyl groups on
proteins
5. Damaged and misfolded proteins
aggregate
Chelators
● Used to treat Fe overload
● Multidentate ligands; form
more than one bond with
a metal
● Bind free Fe to prevent
harmful reactions
● Ex. Desferrioxamine
forms a hexadentate
complex which is
unreactive
The Blood-Brain Barrier (BBB)
● composed of capillary endothelial cells, thick basal lamina, pericytes and
astrocytes endfeet, microglia
● BBB effectively inhibits free iron transport
● BBB epithelia express a variety of receptors at the luminal membrane
Iron Transport Mechanism:
Transferrin Receptors
● transferrin (Tf) : an iron transport protein that binds two atoms of Fe3+
(ferric state iron) to form diferric transferrin in systemic circulation
● transferrin-to-cell cycle: sequence of events for for iron uptake that only
occurs for cells with Tf receptors → regulates iron uptake
1) diferric transferrin binds to transferrin receptors to form diferric transferrinreceptor complexes, which then facilitates receptor-mediated endocytosis
2) endosome carrying the complexes transported towards the abluminal
membrane of endothelial cells
3) ubiquitous presence of transient receptor potential mucolipin 1 reveals that
it may be a significant helper in the release of iron from the endosome
Iron Transport Mechanism:
Transferrin Receptors (Cont’d)
4) unknown mechanism and local microenvironment
allows the release of iron at the abluminal
membrane into the brain’s interstitial fluid from
endothelial cells
5) local acidic pH promotes the high affinity of the Tfreceptor for apo-Tf
6) apo-Tf and bound receptor returns to luminal
membrane for release of Tf back into circulation
7) iron complexes bound to citrate or ATP circulates in
brain extracellular fluid (ECF) waiting for cellular
uptake or Tf-binding
8) Tf bind most of iron that passes through BBB
Neuronal Uptake of Iron
1) iron-Tf transported into astrocytic
endfeet by binding to Tf-receptors at
cell surface
2) enveloping of complex into
endosomes
3) ferric reductase within endosomes
reduce the ferric ions to ferrous ions in
order for DMT1 to take action
4) presence of DMT1 facilitates iron
transport into the cytosol
5) iron also enter alternatively when
bound to citrate or ATP
Iron Accumulation
-iron dysregulation: iron levels are not kept in check due to
hindered ferritin expression or synthesis of hepcidin
-compromised BBB allows greater access→ more iron natural aging significantly increases iron content in brain
-phagocytic monocytes travel across the BBB and
becomes macrophages that phagocytose damaged
neurons while microglia will also migrate to dying neurons
-however, these iron-rich macrophages and any microglia
will inevitably die and release high levels of iron into brain
interstitial fluid (monocyte extravasation)
-neurons may engulf the released iron, thus contributing
to iron deposition and neuronal damage in brain
Alzheimer’s Disease
● Progressive
neurodegenerative disorder
● Most common form of
dementia (60-80%)
● Neuronal death
Alzheimer’s and Beta Amyloid (Aβ)
● Alternative cleavage of APP
(Amyloid Precursor Protein)
● Amyloid plaques lead multiple
neuronal damages
Alzheimer’s and Iron
● Cause damage to DNA,cell
membrane and protein
● Required for amyloid toxicity
o Fe (III) can attach Aβ to
cell membrane
● APP is production is
upregulated by iron overload,
leading to more Aβ production
Alzheimer’s and Iron
● APP is a transmembrane protein
assisting in Fe (II) efflux.
● IRP-1 binds IRE at 5’end of APP
mRNA under normal condition.
Alzheimer’s and Iron
● APP is a transmembrane protein
assisting in Fe (II) efflux.
● IRP-1 binds IRE at 5’end of APP
mRNA under normal condition.
● Iron binds to IRP-1 when
excessive iron is present.
Fe2+
Alzheimer’s and Iron
● APP is a transmembrane protein
assisting in Fe (II) efflux.
● IRP-1 binds IRE at 5’end of APP
mRNA under normal condition.
● Iron binds to IRP-1 when
excessive iron is present.
● IRP-1 undergoes conformational
change and dissociate from IRE.
Fe2+
Alzheimer’s and Iron
● APP is a transmembrane protein
assisting in Fe (II) efflux
● IRP-1 binds IRE at 5’end of APP
mRNA under normal condition.
● Iron binds to IRP-1 when
excessive iron is present.
● IRP-1 undergoes conformational
change and dissociate from IRE.
● APP is translated to assist
ferroportin transport excessive iron
out of the cell.
Fe2+
Desferoxamine (DFO)
● Treatment with
o iron overload disease
o assist iron excretion
● Slows clinical dementia in AD
● Reverses iron induced memory deficits, and
amyloidogenic APP processing in mice.
● The hydrophilic nature of DFO and large
molecular size
o Neurotoxicity and systemic metal iron
depletion
o poor gastrointestinal absorption
o difficulty crossing the blood-brain barrier.
Novel Iron-chelator M-30
● incorporates neuroprotective
propargylamin moiety into brainpermeable iron chelator.
● induces the outgrowth of neurites,
triggered cell cycle arrest in G0/G1
phase and enhanced the expression of
growth-associated protein-43.
● reduces the levels of cellular APP the
levels of the amyloidogenic Aβ peptide
Parkinson’s disease (PD)
Epidemiology
•Less common than Alzheimer’s disease
•Mean age of onset: 60 y/o
4 Cardinal Signs
•Resting Tremor
•Bradykinesia (Slowed movement)
•Rigidity
•Postural Instability
Causes
•Idiopathic
•Genetic + Environmental
Pathogenesis of PD
α-synuclein accumulation @substantia nigra pars compacta (SNpc)
⇒Formation of Lewy bodies
⇒Neuronal death
⇒Decreased dopamine release from SNpc
Pathogenesis of PD
α-synuclein accumulation @substantia nigra pars compacta (SNpc)
⇒Formation of Lewy bodies
⇒Neuronal death
⇒Decreased dopamine release from SNpc
Pathogenesis of PD
α-synuclein accumulation @substantia nigra pars compacta (SNpc)
⇒Formation of Lewy bodies
⇒Neuronal death
⇒Decreased dopamine release from SNpc
Pathogenesis of PD
α-synuclein accumulation @substantia nigra pars compacta (SNpc)
⇒Formation of Lewy bodies
⇒Neuronal death
⇒Decreased dopamine release from SNpc
⇒Increased inhibition of higher motor centres
Role of Iron in PD
Role of Iron in PD
Role of Iron in PD
Iron chelators and PD
(Deferoxamine)
Progress
Deferiprone
Apomorphine
VK-28
M30
etc.
Phase II clinical trials
Animal models
The End
Summary Slide
Fe toxicity:
1. Free Fe2+ present in the brain can react with peroxide to produce hydroxy radicals
2. .OH causes peroxidation of polyunsaturated fatty acids (LH)
3. This leads to the formation of reactive aldehydes
4. Reactive aldehydes and other reactive species can create carbonyl groups on proteins
5. Damaged and misfolded proteins aggregate
-Chelators can be used as a treatment to bind free metal
-Transferrin binds and carries two ferric iron atoms to become diferric transferrin, which is transported in circulation.
-Only certain cells with transferrin receptors have the ability to take in iron, hence regulating iron uptake.
-The blood-brain barrier expresses transferrin receptors that facilitate the uptake of diferric transferrins.
-Natural human aging, iron dysregulation due to low levels of ferritin or high levels of hepcidin, blood-brain barrier disruption,
extravasation or death of microglial and macrophage cells all contribute to the detrimental accumulation of iron.
Alzheimer’s Disease:
-iron assists Aβ aggregation, attaches Aβ to membrane and increases APP production (through IRE)
-desferroxamine and M-30
Parkinson’s Disease:
-Accumulation of iron causes oxidative stress and neuronal death at SNpc. The reduced dopamine release from SNpc directly and
indirectly results in an overall inhibition of higher motor centres, leading to motor-related symptoms
-Removing unbound iron at SNpc is the main pharmacological goal for iron chelators aimed to treat PD
-Most iron chelators are in animal models stage; Deferiprone at Phase II of clinical trials
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