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Medsci305 > Lecture 13: epilepsy and schizophrenia > Flashcards

Lecture 13: epilepsy and schizophrenia Flashcards

1
Q

What are the different lobes of the brain?

A

frontal
parietal
occipital
temporal

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2
Q

Where is the cerebellum and what is it involved in?

A

located at the back of the brain, invovled in movement and balance

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3
Q

What is the frontal cortex?

A

the part of the brain that is scrunched and squeezed against the skull
-this is also broken up tino different regions

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4
Q

What parts of the brain are in the ‘middle’?

A

hippocampus- invovled in learning and memory

basal ganglia- involved in movement, initiation and control of purposeful movement
this is affected by parkinson’s

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5
Q

What is the function of the brain stem?

A

primitive control like heart rate and breathing

this runs down to the spinal cord.

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6
Q

How do brain cells communicate wth each other?

A

An AP is generated which opens V-gated calcium channels to cause the release of vesicles containing neurotransmitters

  • these are released into the synaptic cleft
  • the neurotransmitters then bind to receptors in the post synaptic cell, or are taken up by a transporter.
  • they can also be recycled back into the presynaptic cell
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7
Q

what is epilepsy?

A

-chronic disorder characterised by recurrent seizures which affects 0.5% of the population

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8
Q

What are the causes of epilepsy?

A
  • genetic (rare)
  • birth/perinatal injuries
  • children undergone febrile seizures
  • after head injury, trauma or vascular event affecting an area of the brain
  • congenital abnormalities or metabolic disorders where there are imbalances in the brain
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9
Q

What is the characteristic event of epileptic seizures?

A

-seizures which are assoc with an episodic high frequency discharge of brain cells

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10
Q

What are the two types of seizure activity?

A
  1. generalised

2. partial

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11
Q

What are generalised seizures?

A
  • these affect both sides of the brain
  • can start in one hemisphere, but seizure activity is strong enough to spread across the corpus callosum to the other side
  • usually results in loss of consciousness of patients
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12
Q

What are partial seizures?

A
  • one hemisphere or one localised region exhibits the seizure activity
  • does not spread to the other hemisphere,
  • patients do not tend to lose consciousness
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13
Q

What is the mechanism on the spread of seizure activity?

A
  • not fully understood and involves multiple mechanisms
  • stems from abnormal neuronal activity in an area (focus) which could be due to damage or where a pathological event has occurred
  • These cells have abnormal electrical properties so the V gated (sodium and calcium) channels are abnormal
  • within this focus, you get these cells firing at a very high frequency due to constant depolarisation
  • can get abnormal activity of receptor gated channels resulting in the release of excitatory neurotransmitters and a reduction in the release of inhibitory transmitters
  • this imbalance contributes to the high frequency discharge.
  • cells then go into synhronisation resulting in full seizure activity
  • abnormal v gated channels and abnormal flow of Na and Ca ions results in abnormal extracellular environment- further promoting synchronisation
  • helps seizure activity spread to adjacent neurons (dependent on how many connections these neurons have made)
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14
Q

What is the problem with continual excitation and reduced inhibiton?

A
  • high levels of glutamate may accumulate.
  • this is toxic. -> loss of brain cells
  • cells will become abnormal which spreads the focus area of the seizure
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15
Q

What has research suggested regarding the seizure spread?

A
  • the seizure spread is determined by the delicate balance of excitation and inhibition.
  • increased excitation and reduced inhibition results in the synchronisation and further spread of seizure activity
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16
Q

What are the limitations regarding the biochemical balance theory of seizure spread?

A
  • when looking at animal models and in epileptic patients, there are no major abnormalities in the enzymes involved in the synthesis of glutamate/GABA
  • there are also no significant receptor abnormalities
  • but definitely considered that some of epilepsy is due to damage and repair process
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17
Q

What could the focal injury due to head injury or trauma represent?

A

surviving neurons making connections which are not successively connecting.

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18
Q

What are the aims of anti-epileptic agents?

A
  • block initiation of seizures in the focus
  • prevent synchronisation from occurring
  • lessen the extent of seizure activity
  • prevent propagation or spread of seizure activity
19
Q

What are the three main mechanisms of anti-epileptic agents?

A
  1. inhibition of sodium channel function
  2. enhancement of GABA action
  3. inhibition of calcium channel function
20
Q

What are the sodium channel inhibitors?

A

e. g. carbamazepine, phenytoin, valproate.

- these undergo a use dependent block of V depdent sodium channels

21
Q

What is a use dependent block?

A
  • we know that V-gated sodium channel goes through resting, open and inactivation stages
  • in the resting stage, the channel waits for depolarisation. THis means it is primed and ready to go
  • agents working by use dependent block will block the channels predeominantly in inactivated and open states
  • this stabilises the channel in its inactive or open state so that sodium does not go through
  • it also does not allow the channel to go back into resting state so the channel is no logner primed to respond to depolarisation
  • alters membrane potential and prevents cell depolarisation/excitation
22
Q

What are the effects of sodium channel blockers?

A
  • reduces and stops repetetive firing of neurons
  • prevents seizure initiation
  • this is important as it is targeting the drug to cells which fire abnormally thus selectively picking which sodium channels need to be blocked
23
Q

What are GABA enhancers?

A

-GABA is the inhibitory neurotransmitter.

  • GABA is stored in vesicle terminals but released into the synaptic cleft.
  • There are 2 main types of receptors (we are itnerested in GABA-A)
  • Diazepines bind to the alpha subunit on gaba A receptor
  • barbituates bind to the alpha subunit on GABA-A receptor and potentiates the receptor to GABA resutling in more chloride channels opening and more chloride entering the cell to inhibit the post synpatic neuron.

Valproate and vigabatrin inhibits GABA transaminase to stop the breakdown of GABA

Valproate also stimulates GAD activity to increase formation of GABA

24
Q

What are calcium channel blockers?

A
  • we are particularly interested in the t type calcium channels in the brain as they exhibit pacemaker ability.
  • ethosuzimide is a t type specific calcium channel blocker.
  • t type channels can act in the pathologically affected neurons seen in epilepsy
  • prevention of Ca influx into neurons prevents release of neurotransmitters and prevents further spread of the action potential
25
Q

What are the new anti-epileptic agents?

A 
lamotrigine
felbamate 
gabapentin
tiabine
topiramate

These have a mixture or slightly unkonwn mechanisms of action

26
Q

What is lamotrigine?

A

new AED

  • inhibits sodium channels via use dependent block
  • also inhibits release of excitatory amino acids like glutamate
27
Q

What is Felbamate?

A
  • new AED
  • mechanism not fully characterised
  • has weak effect on sodium channels
  • very little effect on GABA transmission
  • also shown to partially block the NMDA receptor for glutamate
28
Q

What is gabapentin?

A
  • new AED
  • unknown mechanism
  • analogue of GABA which was intended to mimic its action, but actually doesnt act on GABA receptors
  • binds to t type channels to block them and inhibits the excitatory process
29
Q

What is Tiagbine?

A
  • new AED
  • increases concentration of GABA in synaptic cleft
  • potentiates and prolongs GABA action
30
Q

What is topiramate?

A
  • new AED
  • complex mechanism
  • effective sodium channel blocker which prevents further depolarisation
  • also blocks AMPA glutamate receptors
31
Q

How does phenytoin work?

A

blocks sodium channels

32
Q

How do valproate and vigabatrin work?

A

they both inhibit transaminase.

valproate also stimulates gad

33
Q

What is schizophrenia?

A
  • clinically diagnosed as when a patient has the normal perceptions of the environment disrupted
  • very specific for different patient as to how the disease manifests
34
Q

What are some examples of presentations of schizophrenia?

A
  • auditory and visual hallucinations
  • paranoia
  • depersonalisation
  • attachment/obsessiveness in daily events.
35
Q

What does schizophrenia affect?

A
  • mainly frontal cortex, temporal lobe, hippocampus

- can be broken down into positive and negative symptoms

36
Q

What are the positive symptoms of schizophrenia?

A

-hallucinations, delusions, paranoia

37
Q

What are the negative symptoms of schizophrenia?

A

-apathy, social withdrawal, extreme inattentiveness, lack of motivation

38
Q

What is the need to separate positive and negative symptoms of schizophrenia?

A

agents can be effective on positive symptoms, but we have yet to develop therapy that affects negative symptoms

39
Q

What is the genetic basis for the cause of schizophrenia?

A
  • strong but incomplete hereditary tendency
  • identical twins have a 50% chance of developing it if one has it
  • currently a large number of gene wide association studies to try to identify genes involved
  • strongest evidence with chromosome 13 and 16,
  • clearly established that there is more than one cause
40
Q

What is the ‘natura’ disease progression of schizophrenia?

A
  • loss of brain matter
  • this is not seen in all patients
  • but there is a lot of evidence that supports the initial precipitating events may occur in utero and it may appear as a developmental disorder
  • quite possibly due to neurons forming inappropriate connections which are not seen until hormal levels increase in puberty
41
Q

What is the inflammatory hypothesis?

A
  • the suggestion that the patient may hold susceptibiltiy genes for schizophrenia
  • if the mother had an infection during pregnancy, this cause cause acute fetal inflammation which, over time may be suppressed.
  • this can lead to long term developmental dysfunction after birth
  • despite this, drugs for schizophrenia are based on the neuro-chemical hypothesis
42
Q

What is the dopamine hypothesis?

A

the suggestion that schizophrenia is due to an increase in dopamine in the bran

  • has been shown in animals that excessive dopamine can cause very specific behavioural events which mimic the positive symptoms of schizophrenia (paranoia, irrational fear responses)
  • also supported by potent D2 receptor agonists like amphetamine can produce schizophrenia like symptom and can exacerbate schizophrenia in patients
  • Also based on the fact that dopamine D2 receptor antagoinsts and drugs that block dopamine release like Ezertene, prevents the positive symptoms of schizophrenia
  • very positive correlation
  • anti-schizophrenic drugs must block 80% of receptors to have a clinical effect
43
Q

What are the neuro-chemical alterations with schizophrenia?

A
  • this is suggestive of the glutamate hypothesis
  • supported by the fact that patients taking PCP or angel dust have similar symptoms to schizophrenia due to this blocking MDMA receptor which inhibits glutamate activity
  • also managed to produce a transgenic mouse lacking these receptors which has shown to have schizophrenic behaviour
44
Q

What is the serotonin hypothesis with schizophrenia?

A
  • based on recreational drug use (LSD) which produces schizophrenia like symptoms.
  • no real biochemical evidence of serotonin involvement
  • however a number of anti-psychotic agents (like those that block Dopamine) also block serotonin receptors.
  • Although 5-HT has a modulatory effect on dopamine pathways, it is debateable whether affinity for 5-HT receptors contribute to clinical therapeutic benefit, or simply diminishes the undesired side effects which occur with D2 receptor antagonists.

Medsci305 (17 decks)

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