Disease Modification in Parkinsons

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What are disease modifying strategies?
Things that interrupt the course of the disease but do not always do so by tackling the pathogenesis
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Two forms disease modifying strategies can take
Neuroprotective and neurorepair
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Define neuroprotective
intervention that affects the pathogenesis of the disease to preserve neurones or slow down / halt ongoing degeneration.
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Define neurorepair
provide cell replacement, regeneration or repair
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Whyr do we need disease modifying strategies in PD
There is progressive cell loss, current drugs only provide symptomatic relief and prolonged use of current drugs have serious side effects.
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Benefits of disease modifying strategies in PD
Symptom stabilisation, no need to change drug dose over time, less side effects, and improved quality of life.
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Design reasons why clinical trials have failed
Small nos, washout period insufficient. lack of dose-dependancy casts doubt, lack of placebo, level of dopamine depletion variable between patients at the start. Readouts not robust.
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How can we monitor DMS in clinical trials?
Neuroimaging, eg, PET scans or SPECT. Benamer, 2000 showed this
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Why should we look for preclinical markers?
Clinical signs only appear when >60% of degeneration has taken place.
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One important preclinical symptom
Olfactory Dysfucntion. 80-90% of patients experience this. Braak stage 1 is in the olf bulb.
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Another way of preclinical diagnosis
Biomarkers - there is a release of neuromelanin on cell death. this triggers an immune response. ELISA can be made to identify this
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Problems w animal models
Not based on all apsects of disease together. Models are rapid with no progression and LB. Degeneration is restricted to SnPC.
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How can we monitor motor behaviour and NS tract
tyrosine hydroxylase immunoreactivity
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Key details of the -0HDA
Kills dopaminergic neurons by inhibiting complex 1, which leads to the formaiton of ROS. the lesion develops over 2 weeks.
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Measures to assess 6-OHDA lesioned rats?
Tests of forelimb akinesia - opposite paw is lame. Or, readout of dopamine neurone integrity.
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How does MPTP work?
Crossess the BBB and is taken up into astrocytes. this is where it is converted to MPP+ by MAO-B.
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Good things about MPTP models.
Chronic LDOPA induces realistic LIDs.
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Elements of underlying PD pathogenesis
Activated microglia, prion like transmission, neurotrophic factors, glu and calcium increase. Mitochondrial dysfunction
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What is the result of activated microglia?
Release of inflammatory mediators that leads to neuronal cell death
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How can we target this?
Antiinflammatory NSAIDs, but these have had mixed evidence.
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How can excitotoxicity occur in the SNpc
increased calcium load, resulting from opening calcium channels, glu transmission
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How is Glu transmission increased
Elevated firing between the STN and SNpc, leading to NMDA-R activation and Ca2+ influx
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Why are Snc neurons are vulnerable to elevated Ca2+
they have low calbindin levels, whuch usually binds 95% of ca2+
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Another route for increasing ca2 influx in SNpc
They have Cav1.3 pacemaker calcium channels.
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Strategies targetting excitotoxicity
Deep brain stimulation to silence STN which improves symptoms. Temel 2006 - reduction of cell loss following DBS
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Drug trials to combat glutamate overexcitotoxicity in the SNpc
Riluzole - increase glu uptake into Glia. No effect trials.
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What is MTEP and how does it work
mGlu5 antagonist. This a post synaptic receptor. Activation leads to excitation of the striatum.
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Evidence for it working
Reduced loss of TH stain in the striatum, and reduced severity of PD in animal models. Gunasingh, 2011.
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What part of the mitochondrial complex is impaired in THE SNC IN PD
complex 1, this uncouples electron transport chain and results in electron leakage.
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The result of electron leakage?
Decreased ATP production, and O2 joining with H20. then H202 undergoes a fenton reaction to form OH-, 0H. AND fe3+
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the result of the fenton reaction
increased free radical production, decreased ATP production, cell death.
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What happens following free radical production?
antioxidant defences such as glutathione, superoxide dismutase.
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how can oxygen free radicals cause damage
increase lipid peroxidation, protien carbonyl formation, and DNA bases are damaged.
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Antioxidant enzymes in SNpc in PD
Reduced levels of gltuathione - 30-40%.
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How to free radicals lead to apoptosis
1- swelling of mitochondria, opening of permeability transition pore, collapse of mt membrane potential. - this leads to release of cytochrome x, and activation of caspase cascafe.
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How can we tell that cell death in SNc in PD is apoptotic
Nirit 2003 - nigrall cells show elevated pro-apoptotic BAX. elevaged caspase 3 immunoreactivity.
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How can we target mitochondrial dysfunction?
Combat oxidative stress by giving antioxidants, such as iron chelators.
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Dopamine agonists that have shown some promise in disease progression
Ropinirole, or pramipexole byt they also show no improvement in some clinical signs.
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What do bcl-2 and bcl-xl do?
Inhibit releasse of apoptosis initating factors, and caspasse cascade.
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How can we elevate these pharma
MAOB inhibitors in propargylamine class, eg, rasagiline, can elevate them.
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Who showed tat rasailine works
Blandini 2004 - protects against 6-OHDA induced tract lesions in rats.
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Another evidence for rasagiline
induces anti-apoptotic factors in SH-SY5Y neuroblastoma cells. Akao, 2002
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What is tropic support like in PD
Reduced levels of GDNF and BDNF in PD brain, which increase neuronal vulnerabilit
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How can we target depleted growth factor
viral vector delivery of GFs or related enzymes. Intraputamen injection, was successful (blinded trials foor efficacy)
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Drug based growth factor elevation
Rasagiline induces GDNF in SH-SY5Y cells.
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What is rasagiline?
A monoamine oxidase B inhibiter.
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Key pathway for degrading abnormal protiens
Ubiquitin proteasome system. ubiquitination of prots leads to degredation
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Evidence for protien dysreg in parkinsons?
Many of the PARK genes lead to misfolding and are related to ub system.
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What could be the next big thing?
Cell replacement strategies. fetal nigral transplants, or DAergic neurons derived from stem cells.
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Problems with cell replacement therapies
they need to be driven into DA phenotype consistently. and survival of cells post implantation into the hosst brain is poor.
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Another promising neurorepair strategy
Release of NSC from the subventricular zone which is close to the striatum, allowing effective reinnervation.
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Two forms disease modifying strategies can take

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Neuroprotective and neurorepair

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Define neuroprotective

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Define neurorepair

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Whyr do we need disease modifying strategies in PD

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