Brain Diseases

Question 1

What are the positive and negative symptoms of Schizophrenia?

Answer 1

Positive symptoms: psychosis, hallucinations, delusions, paranoia
Negative symptoms:
social withdrawal, lack of motivation, cognitive and attention impairment

Question 2

What does the treatment of Schizophrenia entail?

Answer 2

• treatment with antipsychotic drugs
• interfere with dopamine function
• chlorpromazine blocks dopamine receptors
• reserpine

Question 3

How does the drug Reserpine work against schizophrenia?

Answer 3

• lowering neurotransmitter levels
• inhibitor of vesicular monoamine transporters (VMAT)
• this block neurotransmitter recycling thus depleting levels of neurotransmitters
• can cause low dopamine therefore causing Parkinsonism

Question 4

How does the drug Chlorpromazine work against schizophrenia?

Answer 4

• blocks dopamine receptors

- can cause low dopamine therefore causing Parkinsonism

Question 5

What are the causes of schizophrenia?

Answer 5

• reduced function of NMDAR
• strong genetic contribution
• may be a developmental disorder of brain organisation resulting in thinning of the prefrontal cortex. Due to excessive synaptic pruning.

Question 6

How are mood disorders treated?

Answer 6

Manipulating monoamine neurotransmitter metabolism

• MAO inhibitors
• Neurotransmitter re-uptake inhibitors

Question 7

How do antidepressants work?

Answer 7

Act by prolonging neurotransmitter action.

Question 8

How do Iproniazid antidepressant function?

Answer 8

inhibiting MAO thus increasing neurotransmitter levels at synaptic cleft

Question 9

How does Prozac antidepressant function?

Answer 9

blocks serotonin re-uptake

Question 10

How do selective serotonin re-uptake inhibitors (SSRIs) antidepressant function?

Answer 10

increase serotonin levels

Question 11

How are anxiety disorders treated?

Answer 11

1. Anxiolytic drugs that enhance GABA transmissions
   - neurotransmitter for inhibiting synapses
   - used to use barbiturates to activate GABA but overdose is lethal so instead use benzodiazepine
2. decrease glutamate concentration/ transmission
   - drugs that inhibit the glutamate pathway

Question 12

How can you modulate GABAergic inhibition to treat anxiety disorders?

Answer 12

GABA receptors have 5 subunits, 2 α, 2 β and a γ. GABA binds between α and β and benzodiazepine binds between α and γ. When they both bind, this enables the GABA receptor to stay open for longer and Cl ions are able to come in and be inhibitory.

Question 13

Define drug addiction.

Answer 13

“compulsive drug use despite long-term negative consequences, loss of self-control and propensity to relapse”

Question 14

How does drug addiction happen?

Answer 14

• addictive drugs hijack the brains reward system by increasing the concentration of dopamine in targets of VTA neurons (ventral tegmental area)
• overall there will be more dopamine than usual

Question 15

How does nicotine enhance dopamine production?

Answer 15

Activates ACh receptors to excite dopamine neurones

Question 16

How does opium and cannabinoids enhance domaine production?

Answer 16

• opium and cannabinoids inhibit the GABAergic neurons, causing disinhibition of dopamine neurons

Question 17

How does cocaine enhance dopamine production?

Answer 17

Cocaine blocks the plasma membrane dopamine transporter and dopamine re-uptake

Question 18

How does Ecstasy enhance dopamine production?

Answer 18

reverse the dopamine membrane transporter, causing vesicle-independent release of dopamine
- increase dopamine synthesis and prevent its degradation

Question 19

Why are drugs addictive?

Answer 19

• if dopamine neurons signal a reward, the action that preceded the reward is reinforced through dopamine regulation of neural circuits
• drugs hijacks the brains reward system

Question 20

What is epilepsy?

Answer 20

Disorder of neural network excitability

• abnormal balance between the actions of excitatory and inhibitory neurones
• dysfunction of synapses
• chronic condition with recurrent seizures

Question 21

What can cause epilepsy?

Answer 21

• head injury, infection, stroke, brain cancer, drug abuse
• genetic predisposition (mutation in channels)
• seizure predisposes to having future seizures

Question 22

What treatment can be given to people who suffer from epilepsy?

Answer 22

• drugs that inactivate Na+ channels to reduce excitation
• drugs that inhibit Ca2+ channels to reduce synaptic transmission
• brain surgery
• GABAa receptor agonists (benzodiazepine)

Question 23

What is autism?

Answer 23

neurodevelopment disorder. Deficits in communication and reciprocal social interactions, reduced emotions and difficulty adapting behaviour to a changing environment
- reduced neural synchrony patterns

Question 24

What is the predominant cause of autism?

Answer 24

Genetic

- mutation in genes to do with synapse development and function

Question 25

What is fragile X syndrome?

Answer 25

neurodevelopment disorder. intellectual disability and autism spectrum disorder - affects boys - defect in FMR-1 gene

Question 26

What does the FMR-1 gene do?

Answer 26

gene involved in the regulation of translation | - produces FMRP that represses protein translation that is required for learning

Question 27

What happens during the onset of Alzheimers?

Answer 27

Loss of memory and disorientation - affects the hippocampus Microglia dysfunction can occur

Question 28

What are the pathological features of Alzheimers?

Answer 28

increase in Aβ-Amyloid plaque formation and neurofibrillary tangles in the hippocampus, amigdala and cortex

Question 29

How does Amyloid β formation take place?

Answer 29

- precursor is APP (amyloid precursor protein) - Aβ-Amyloid is a product of the APP cleavage - cleavage occurs in two places, β-secretase and γ-secretase - α-secretase cleavage prevents the formation of Aβ-Amyloid

Question 30

What is familial Alzheimers cause by?

Answer 30

mutations in the amyloid precursor protein (APP) and Presenilin, increase β-Amyloid production - down syndrome patients have an extra copy of APP and develop Alzheimer's in the 40's

Question 31

What is ApoE in terms of Alzheimers?

Answer 31

Found high number of patients with alzheimers have a link to ApoE - ApoE is a component of high-density lipoproteins involved in lipid transport and metabolism - AD patients have ApoE-ε4 allele instead of ε3.

Question 32

What usually clears up β-Amyloid plaque aggregates?

Answer 32

microglia | - through phagocytosis

Question 33

How can microglia dysfunction be negative to humans?

Answer 33

- won't clear up aggregates | - can inflame and lose track of what to clear out and start attacking healthy neurons

Question 34

What is the treatment for Alzheimers?

Answer 34

aim to reduce the amyloid plaques and neurofibrillary tangles - drugs to reduce Aβ toxicity and increase clearance - done by inhibiting γ-secretase Biomarkers to detect Amyloid β deposits before symptoms are onset

Question 35

What is the general procedure from lab to clinic for drug to a disease?

Answer 35

1. determine the pathogenic process to intervene 2. use biochemical assays to identify a drug candidate 3. optimise the candidate for affinity, activity, safety in vitro and in animal models 4. test in human trials Phase 1 - safety Phase 2 - proof of concept Phase 3 - large patient population

Question 36

What happens during Parkinsons disease?

Answer 36

- tremor, rigidity, problems walking | - death of dopaminergic neurones of the substantia nigra

Question 37

What is the pathology of Parkinsons Disease like?

Answer 37

Presence of Lewy bodies, which is α-synuclein aggregates, clog up function of neurons and interfere with normal function

Question 38

Is Parkinsons inherited?

Answer 38

There is no clear inheritance pattern, mostly sporadic

Question 39

Where does α-synuclein aggregation begin in Parkinsons?

Answer 39

Starts in the brainstem and substantia nigra, then spreads throughout cortex - defective proteostasis - behave like prions - loss of vesicle release

Question 40

What does α-synuclein accumulation cause in Parkinsons?

Answer 40

Blocks vesicle trafficking, protein clearance and degradation and build up causing oxidative stress - the accumulation interferes with the priming of vesicles, decreasing the size of the releasable pool

Question 41

What other genes have seen to be involved with Parkinsons?

Answer 41

Pink1 - mitochondria-associated kinase Parkin - Uq-proteasome system for protein degradation. Regulate mitochondrial function, movement along microtubules and removal of damaged mitochondria. DNAJC6, GAK - endocytic pathways

Question 42

What is the treatment strategy for Parkinsons?

Answer 42

``` Boost dopamine levels - administer of L-Dopa - dopamine neurons keep dying Target the lysosome to increase lysosomal function Deep brain stimulation - can alleviate symptoms Cell Replacement Therapy - transplantation of dopamine neurons into the brain ```

Question 43

What are the challenges of cell replacement therapy for Parkinson?

Answer 43

- need Dopaminergic neurons in large amounts - no contamination from other cell types - immunosuppression - better to use stem cells to produce the dopaminergic neurons in vitro (iPSC's)