Animal Models of Parkinson's Disease Flashcards
Explain the pathophysiology of PD
The basal ganglia degeneration - Less dopamine comes from the substantial nigra which results in less stimulation of the striatum. Striatum activity decreases which allow globus pallidus to increase. The role of the medial Globus pallidus is to inhibit the VA nucleus which stimulates the motor cortex. As this inhibits the VA nucleus, this reduces the activity of the motor cortex so less activity of the muscles (bradykinesia).
What would be included in the ideal PD model
Pathological and clinical features
Dopaminergic and nondopaminergic systems
Central and peripheral nervous system
Motor and non-motor symptoms
Age-dependent onset and progressive nature
Why is it difficult to develop a PD model
Animals dont get PD so needs to be induced artificially
What is in silico models and what are they useful for
Computer simulation - good for assessing drug candidates but require indepth knowledge of cellular processes for it to be realistic.
Why are in vitro candidates good for PD
Can look at drug candidate reactions on an organ level
Good for looking at cellular disease mechanism
Inexpensive
How are non-mammalian models in vivo models good for PD
Genetically easily manipulated
Less ethical issues
Drug discovery
Largely similar to humans
Why are mammalian models needed for PD
Only way to get validation of efforts - e.g. new drugs etc
Complex organisms and easy to study behaviour and compare to humans
What is the MPTP model
The gold standard of mice for parkinsons research
Has PD phenotype
Injected systemically
Key for development of dopamine therapies
What is the 6-OHDA model
Inject into substantia nigra or striatum which results in - oxidative stress, neurodegeneration, neuroinflammation, neuronal death by apoptosis
Good for therapy not disease reversal
Works in hours to weeks
Give some techniques to study the behaviour of mice
Catwalk - gait
Rotarod - balance
Open field - helps determine anxiousness
Y maze - cognition (exploring)
Agora - social behaviour
What is the overall message
There is no expert model for PD - have to pick either transgenic, neurotoxic or seeding model. Based on research question
How was MPTP discovered
EXTRA READING -Konnova 2018
through cases of chemically induced parkinsonism after failed synthesis of the opioid drug 1-methyl-4-phenyl-4-propionpiperidine (MPPP)
Why is the MPTP model good
EXTRA READING -Konnova 2018
Easily given for acute or chronic presentation and crosses the BBB in minutes as it is lipophilic in nature
How does MPTP work
EXTRA READING -Konnova 2018
Turns into MPP+ by MAO-B and MMP+blocks mitochondrial complex I, which reduces ATP production, increases oxidative stress, and eventually causes cell death and neuroinflammation. Similar to what is seen in PD
Why is MPTP not good for rats
EXTRA READING -Konnova 2018
rats are resistant to moderate doses of MPTP, while higher doses increase the mortality rates
It doesnt have this affect on mice so good to use.
