Epilepsy (Glutamate/GABA signalling)

What are the two main types of epilepsy?

• Generalized, whole brain seizure

• Partial / focal

What can cause epilepsy, in general?

• Increased glutamate excitation or decreased GABA inhibition

• Train of action potentials mimics NMDAR activation, suggesting prolonged glutamate release

• Repeated seizures cause neuronal death - excitotoxicity involvement

As epilepsy treatment is lifelong, what does this mean for drug development?

• Minimizing side effects is a priority, which is hard as Na+v, Ca2+v and GABAergic neurotransmission disruption is expected to

Describe how GABA-A can be targetted by anti-epileptics

• Clonazepam, but unsuitable long term as causes sedation and dependence

• Diazepam is IV for rapid treatment of prolonged seizures that require emergency intervention (too long = excitotoxicity = neuronal death)

Describe how GABA neurotransmitter itself can be targeted by antiepileptics

• Prevent breakdown or decrease reuptake

• Tiagaine inhibits GAT1, decrease reuptake

• Vigabatrin blocks GABA transaminase to increase [GABA] released upon depolarization, but sometimes impairs visual field and has to be given 2x day due to half life so only in refractory

Describe how Na+v can be targeted by anti-epiileptics, name two

• Inhibit the incoming action potential (requires Na+v to open to allow influx and depolarization, if this cant happen then AP propagation halted)

• Stabilize the inactivated state of the neurone, which is only seen after the ‘open’ state after an AP

• Therefore only blocking high frequency firing neurones, such as those active in a seizure

• Carbamazepine, phenytoin

What needs considering when prescribing Na+v inhibitor carbamezapine?

• Widely used

• Ataxia, drowsiness, increase hepatic enzyme expression so faster metabolism of other drugs

What needs considering when prescribing Na+v inhibitor phenytoin?

• PK unpredictable, 90% plasma protein bound but other drugs can increase its detachment from plasma proteins and increase hepatic clearance

• Plasma concentration is not proprotional to dose as hepatic metabolism also shows saturation, but too high a dose can actually increase seizure frequency

• Rashes, osteoperosis

Describe how Ca2+v can be targeted by anti-epiileptics, name three

• Decrease Ca2+ influx at preSN can decrease amount of exocytosis of neurotransmitter-containing vesicles, esp. glutamate

• Ethosuximide, valproate, gabapentin

Discuss ethosuximide as an anti-epileptic

• Block T-type Ca2+v, which are especially involved in absent seizures where there is rhythmic firing

Discuss valproate as an anti-epileptic

• Ca2+v blocker, but also inhibits Na+v (stops AP propagation in highly active neurones) and GABA transaminase (increase GABA activity, increase inhibition)

• Can cause hair thinning

• Rare but possible for hepatotoxicity

Discuss gabapentin as an anti-epileptic

• Binds alpha2elta1 subunit of L-type Ca2+v

• Also decreases Ca2+v expression long term

• Decreases Ca2+ influx, decreases exocytosis in neurotransmission e.g. of glutamate

How can AMPAR be targetted as an anti-epileptic?

• Topiramate

• Blocks Na+v, Ca2+v and AMPAR

• Decreases glutamate release and decreases response of neurones to glutamate (competitive)

Describe different drug targets for epilepsy, giving an example for each

• Na+v (prevent AP propagation) - phenytoin

• L-type Ca2+v (prevent glutamate exocytosis in response to AP) - gabapentin

• T-type Ca2+v - valproate

• AMPAR (prevent glutamate activation) - Topiramate