Lecture 28

Question 1

Antiseizure drugs and other treatments

Answer 1

Most common treatment. Controls seizures in 70% patients therefore need for new treatment. Surgery removes active brain region where seizures originate/spread from, ketogenic diet used in children, vagus nerve simulation. ASDs change chemical levels in brain and prescribes on patient profile and seizure classification.

Question 2

Vagus nerve and deep brain stimulation

Answer 2

Manages refractory epilepsy esp in ASD non-responsive patients. Increases inhibitory neurotransmission to decrease seizure frequency and severity. >4 yrs old. Permanent, patient stimulates VN when seizure is about to occur. DNS occurs in adolescents/after brain development. Signals sent to hippocampus/thalamus to modulate activity. Decrease abnormal firing, decrease seizure frequency.

Question 3

Ketogenic diet

Answer 3

Decrease seizures in drug-resistant kids. Induces ketosis where ketones are main energy source which may increase inhibitors. Increase GABAergic activity, decrease excessive neuronal firing. Close medical supervision and side effects.

Question 4

AED action

Answer 4

Na+ influx triggers AP where neurotransmitters diffuse across synapse and bind to receptors on the post-synaptic membrane. Uncontrolled AP cause epilepsy therefore, AED must work on receptors involved in AP. Drugs can inhibit voltage-gates Na+ channels, decrease Na+ influx, increase K+ efflux and Ca2+ influx inhibition. GABA(A) receptors increase inhibition. All ain to decrease AP generation. GAT1 inhibition keeps GABA in circulation. Most drugs are ‘dirty drugs’ i.e have multiple sites of action.

Question 5

GABA mediated and GABA(A) receptors

Answer 5

GABA is synthesized from glutamate by GAD. GABA uptake inhibitors block the reuptake of GABA, increasing its availability in the synaptic cleft. Benzodiazepines bind to GABA(A) receptor to enhance GABA activity. Barbituates also bind to GABA(A) to increase duration receptor is open, GABA transaminase stops GABA breakdown.

Question 6

Functional outcome of genetic variants

Answer 6

Variants impacts course of treatment. If genetic variant increases Na+ channel activity = increases Na+ influx but if it dampens receptors, decreases [Na+]. Na+ channel blockers would not be used if variant dampens Na+ channels, you would need to use one that modulates Na+. If it causes Na+ influx increase, Na+ channel blockers would be appropriate.

Question 7

Cannabinol

Answer 7

Cannabis. Used for Na+ channel LOF variants

Question 8

Vinpocetine

Answer 8

LOF GABA(A) variants. Derivative of vincamine

Question 9

4-Phenylbutyrate

Answer 9

Used in other treatments but now found to treat GABA(A) LOF.

Question 10

Antisense oligonucleotides, SiRNAs and splice-switching ASOs

Answer 10

Piece of RNA binds to defective gene to break it up and enhance exposure of beneficial gene (both exist)

Question 10

Antisense oligonucleotide, gapmer ASO

Answer 10

Binds to target RNA forming DNA-RNA complex and recruits RNAse H to cleave mRNA enabling good gene to express functional proteins. Targets Na+ channels. Difficult to cross BBB and travel to correct region, cost and accessibility concerns. Very precise and is a cure.

Question 11

SiRNA

Answer 11

Enter cell as double-strands and use RISC to unwind, bind to target mRNA and cleave genes involved in seizures. Decrease in half-life and hard to cross BBB.

Question 12

ssASOs

Answer 12

Bind to premRNA and modulate splicing so that variant is spliced.