Flashcards in CNS Drug Targets Deck (26):
Whats the hardest thing about developing drugs for the CNS?
Finding targets and modelling pathologies in the brain
What needs to be known to generate CNS drug targets?
- How pathological events affect cell survival/ disease progression
- Molecular and cellular events
- Identification of molecular events i.e the genes responsible for huntingtons disease
Lots of stuff to be learnt for CNS pathology
If molecular events are indentified, then what can this allow?
- Halt/ prevention of disease
- protect cells from dying (inflammation, bystander affect)
Whats an example of a CNS disease we want to treat?
What is huntingtons?
- Movement disorder
- selective loss of GABA spiny mdeium interneurons in the striatum / basal ganglia.
- Due to expanded CAG section in DNA normal 20 repeats, instead 36+
- Produces mutant huntingtin (Hh)
- Autosomal dominant
- Depression and psychiatric affects
What role does BDNF play in HD?
Transport of BDNF is impaired in HD
- Due to mutant Htt
BDNF supports and protects GABA medium spiny interneurons, Htt mutation can no longer transport BDNF from cortex to striatum and MSN die from excitotoxicity
This lack of BDNF means what?
BDNF may be a replacement target therapy option.
How is HD modeled?
IPS cells from HD patients used.
- Differentiate in MSNs
(in vitro disease model)
Removal of BDNF during MSN development leads to fast rate of neuronal death during HD disease.
In the HD disease model did replacement BDNF help?
yes it did
How did they model HD initially in vivo?
Using normal rats, they injected quinilonic acid, to create a lesion model of HD (selectively kills MSN) (QA is formed in HD)
They then administered BDNF
How was BDNF administered?
Cant cross the BBB therefore they injected directly into the model or used viral vectors. (AAV-BDNF)
How did they know the rats had HD in the normal rat model?
3 weeks post unilateral QA lesion, the rats performed a test and favored one paw and tested sensorimotor function for 8 weeks
(One subset of mice received BDNF from viral vector at 3 weeks, after they knew they had HD)
What was observed in the HD rats, between no BDNF and BDNF receiving rats?
BDNF protected MSN and prevented QA induced sensorimotor function impairment compared to the untreated rats, therefore from 3 weeks on those rats with BDNF suffered far less further HD associated degeneration.
What was the next step in experimentation once they had used normal rats but induced QA lesions to model huntingtons?
The use of Transgenic HD rats
Whats special about transgenic HD rats?
They were genetically bred to carry 51 CAG repeats
- therefore they will have progressive sensorimotor symptoms and cell loss starting around 6 months since birth.
(behavioral impairment first though)
What was the timeline for transgenic HD rats to recieve treatment?
At 3 months, presymptoms, some rats received the AAV-BDNF
Then till 18 months all rats were made to to sensorimotor function tests to observe differences.
(both male and female rats were used)
What was observed from the transgenic HD rats?
- AAV-BDNF prevented and reduced sensorimotor function impairment and the progressive loss of MSNs in tgHD rats
- Female rats had less sensorimotor loss and performed behavioral tests better. Also improved significantly better.
So what is the summery of these experiments for HD?
BDNF is a potential therapy.
tgHD rats have better validity in this instance
The next step is safety profile of this treatment
What is ms?
An autoimmune disease that results in brain degeneration
What is currently used to treat MS?
Anti-psychotic agents i.e clozapine as they have antinflammatory properties. (known as a dirty drug as works on a range of receptors)
Whats an in-vivo model of MS?
- progressive degeneration of WMT
What does clozapine do to the in vivo model?
Reduces disease progression and number of lesions
What in vitro model was used for MS?
Primary human cells. = LPS stimulated macrophages.
What was done in the in vitro model?
LPS stimulated macrophages produced IL-12 a proinflam marker. Modulates the immune system. Clozapine and respiradole reduced IL12 and increase IL10 (anti-inflam)
Based on invitro models what antipsychotic agent is being used in clinical trials in NZ?