Neurodegeneration 3 Flashcards
Main issue with current ND treatment?
Most ND have on cure, treatment only alleviates/delays symptoms
Main target of ND treatment?
Aggregates
Time course for an ND patient?
Usually over 50 with no evidence–> develop minor psychological/behaviour/motor issues–> develop memory loss, or issues with navigation–> begin differential diagnosis–> begin QOL treatments–>delay symptoms treatment–> alleviate symptoms–> palliative care–> death from another casue
Do ND kill people?
No, usually smthn like pneumonia
What is special about Wilsons Disease?
It can be treated
How does someone get Wilsons Disease?
Inherited–> genetic mutation
Main cause of Wilsons Disease?
Copper metabolism disease
Which protein is mutated in Wilsons disease?
Copper ion transporting P type ATPase (ATP7B)
Role of Copper ion transporting P type ATPase (ATP7B)?
Movement of copper ions across the membrane
Symptoms of Wilsons disease?
Abdominal pain, dark urine, jaundice, mood changes, rings around edge of cornea, tremor and stiff muscles
How is wilsons disease treated?
A copper chelator–> helps remove copper from the body
What are two copper chelators used to treat wilsons disease?
Penicillamine and trientine
What are the two ways that aggregates are targeted in ND?
Preventing their formation or causing their breakdown
What are causes other than aggregates that can cause ND?
Oxidative stress (toxic radicals–> e.g. superoxide)
Mitochondrial damage–> could produce cytochrome C
How is aggregate formation prevented?
Target parent protein, stimulate breakdown enzymes, prevent misfolding
How are aggregate parent proteins targeted?
Antisense RNA, genetic knockout (CRISPR-Cas9)
How is breakdown of aggregates increased?
Increases the action of the proteasome on that specific protein, use antibody treatments
Which disease could be treated with antisense RNA?
Huntingtons
Which protein is targeted by antisense RNA in huntingtons?
Huntingtin (HTT)
Which (failed) treatment of Alzheimers involved gamma secretase inhibitors?
Brought in a gamma secretase inhibitor to reduce the amount of beta amyloid being produced
How effective have antibodies against ABeta been in alzheimers?
Reduced cognitive decline by 20-40%
How are the antibodies for Azheimers treatment delivered?
Cannula infusion
How are alzheimers antibodies believed to work?
Recruitment of microglia
Main cause of PD?
Loss of dopaminergic neurons in substantia nigra in pathway to striatum
What are parkinsons treatments aimed at?
Restoring dopamine for the normal function of the striatum
What are the two kinds of receptor in the striatum?
D1 and D2
What are the two pathways running between the striatum and the motor cortex?
Facilitatory, direct pathway, and the inhibitory, indirect pathway
Effect of dopamine on the facilitatory pathway between the striatum and the motor cortex?
It enhances it
Effect of dopamine on inhibitory pathway between the striatum and the motor cortex?
It inhibits it
Which dopamine receptor is targeted by dopamine for the facilitatory pathway?
D1
Which dopamine receptor is targeted by dopamine for the inhibitory pathway?
D2
Effect of dopamine loss in PD?
Reduced motor cortex activity
How can dopamine be increased?
Provide more dopamine or more dopamine precursor, decrease its reuptake, inhibit its breakdown, provide a dopamine agonist
Most common parkinsons treatment?
Provide L-Dopa
Why is L-Dopa provided instead of dopamine?
L-Dopa can cross the blood brain barrier
Main issues with L-Dopa?
It can be converted to dopamine (which cant cross BBB) in the blood
Which drug is given alongside L-Dopa to prevent dopamine formation in the blood?
Cabidopa (dopa decarbodylase inhibitor)
Side effect of L-Dopa?
Dyskinesia–> severe involuntary movement
How is the dyskinesia of L-Dopa treatment managed?
Patients have an “off” time where they dont take any L-Dopa in order to reduce the prevalence of side effects
Second treatment aim at PD after L-Dopa?
Inhibit breakdown of dopamine
How is dopamine breakdown inhibited?
Monoamime oxidase B (MAOB) inhibitors
What is the main MAOB inhibitor?
Selegeline
PD treatment after L-Dopa and MAOB inhibitor?
Catechol O-Methyl Transferase (COMT) inhibitor
Side effects of L-Dopa?
Nausea and dizziness
Side effects of COMT?
Toxicity to liver cells, diarrhoea and sleep disturbances
Main COMT used for PD?
Tolcapone
How do dopamine agonists work?
Acts directly on dopamine receptors
Side effects of dopamine agonists?
Nausea, dizziness, hallucinations, sleep attacks, hypotension
Examples of dopamine agonists?
Pramipexole, Ropinirole, Bromocriptine
What is deep brain stimulation?
Implanting an electrode into the striatum–> can stimulate it directly and thus stimulate the activity
Benefits of deep brain stimulation?
Doesnt have the same side effects of L-Dopa
Complications of deep brain stimulation?
Brain hemorrhage, seizures, death
Issues with stem cell treatment for ND?
Cost and time
