anticonvulsants and epilepsy

Question 1

what is epilepsy?

Answer 1

Unprovoked seizures with different properties depending on underlying cause
Seizure = high frequency discharge by a group of neurons (high rate of APs)
Seizure usually starts at the ‘focus’ and can then spread (or not)

diagnosed by EEG

Question 2

what are the different kinds of seizures?

Answer 2

partial = No spread/localised

Generalised = if it spreads across both hemispheres and all lobes

includes petit mal, which are absence seizures
grand mal, which are clonic/tonic, or contraction relaxation typical seizures

some people experience an ‘aura’ - some kind of pre-warning before a seizure occurs

Question 3

what can trigger a seizure?

Answer 3

Triggers = lack of sleep/excess stress, flashing lights, alcohol, loud music, changes in blood glucose levels

Question 4

what are the causes of epilepsy?

not triggers, genetic and non-genetic

Answer 4

Gene mutations, can be inherited or not, usually in ion channels such as:
Na+ channels - when a mutation increases how easy it is for them to open

or K+ channels (when a mutation causes loss of function)

Also can be cause by many mutations in proteins involved in mediating synaptic transmission

non-genetic causes = head injury, tumours etc…

Question 5

what animal models have been used for epilepsy?

Answer 5

induce epilepsy in animals using chemicals/small molecules (inc. penicillin and kainate a glutamate agonist)

Kindling model - low level electrical stimulation causing genetic changes leading to hyperexcitability

Genetically modified animals

Question 6

what are the different targets for treating epilepsy?

Answer 6

1. increasing inhibitory transmission by increasing GABA/reducing GABA metabolism/blocking GABA reuptake
2. limiting overexcitability/excess transmission in focuses of seizures by -
   - limiting secretion of glutamate
   reducing open time of glutamate receptor Na+ channels
   -inhibiting t type Ca channels in neurons responsible for oscilatory behaviour seen on EEGs

Question 7

in terms of increasing inhibitory transmission to treat epilepsy, which drugs do what (mechanism)?

Answer 7

GABAa receptor agonists/PAMs like benzodiazepines

block GABA reuptake - tiagabine

inhibit breakdown (metabolic inhibitor) of GABA = vigabatrin and valproate

Question 8

how do valproate and vigabatrin work?

Answer 8

GABA is made from a Kreb’s cycle by-product:
Glutamate must be acted on by GAD (glutamate decarboxylase) to give GABA, which is then acted on by GABA transaminase to turn it into something else

valproate and vigabatrin inhibit GABA transaminase (so GABA isn’t broken down)

Question 8

how is vigabatrin a bit of an issue?

Answer 8

has shown side effects of depression, is a suicide inhibitor (binds covalently)

Question 8

valproate doesn’t only inhibit GABA transaminase - what other uses does it have?

Answer 8

valproate can treat epilepsy via another two mechanisms -
at low concentrations it may affect HDACs (histone deacetylase enzymes) to cause increased transcription of enzymes like GAD involved in GABA production

• can act as a t-type calcium channel inhibitor

Question 9

how can excitatory transmission be limited by going after glutamate receptors? (hint = inactivating particle)

Answer 9

In APs, eventually Na channels become blocked by the ‘inactivating particle’, which stops ions, but must move and allow the channel to close before the channel can reopen again

In seizures - high rate of APs - there begins to be an accumulation of inactive Na+ channels with the inactivating particle stuck in the way

certain drugs preferentially bind to channels in this blocked inactive state, so are binding to neurons that are firing too many APs - like in the focus of a seizure
So these drugs are meant to protect from abnormal increased firing in a focus while not affecting the rest of the brain

Examples include carbamazepine (most popular)

Question 11

what does carbamazepine do?

Answer 11

a use-dependent sodium channel inhibitor for epilepsy treatment - binds preferentially to glutamate channels blocked by inactivating particle, preventing them from re-opening so reduces glutamate excitatory transmission in overactive neurons while not affecting the rest of the brain as much

Question 12

how can calcium channels be targeted to treat epilepsy?
x2

include what kind of seizures they are particularly involved in

Answer 12

Drugs that inhibit t type Ca channels may be useful in managing seizures, particularly absence seizures, as these channels are found in neurons responsible for the oscillatory behaviour seen on EEGs in absence seizures
1. drugs that do this (inhibit) = ethosuximide, Valproate works here as well

2. control trafficking:
   GABApentin and pregabalin - control the trafficking of V.gated Ca channels into nerve endings by binding to alpha-2-delta subunit of the channel. Can be used for pain disorders

Question 13

new drug targets - what is the up and comer for epilepsy?

Answer 13

Levetiracetam - binds to protein SV2 on vesicles storing glutamate
Mechanism not understood, but drug limits amount of glut stored in the vesicles - less glut = less excitability

Question 14

what do GABApentin and pregabalin do?

Answer 14

bind to a-2-d subunit of t-type calcium channels to control their trafficking/prevent insertion into neuron endings, reducing excitatory transmission to treat epilepsy particularly absence (patit mal) seizures

can be used to treat pain disorders

Question 15

what controversial treatment has been seen to be effective for epilepsy?

Answer 15

cannabinoids (specifically cannabidiol) for severe epilepsy mostly

Question 16

what other kind of approach is being investigated for epilepsy?

Answer 16

genetic approach using biological therapies - in animal models using a GM virus to do something like increase expression of K+ channels to hyperpolarise abnormally active neurons for example