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Epilepsy Flashcards

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1
Q

What is epilepsy?

A

A disorder of the CNS characterized by recurrent, sudden, large increases in electrical activity (electrical seizures) that may be localized or generalized

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2
Q

What determines Neuronal output (fire action potential or not)?

A

– Determined by number of excitatory and inhibitory synaptic inputs – Strength of individual inputs
- Integrated response

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3
Q

What can synapse transmitters do?

A

• Synaptic transmitters can:
– Excite neurons – depolarize
- Inhibit neurons – ‘hyperpolarize

• Also can modulate activity ion channels involved in: – Transmitter release (voltage gated calcium channels)
– Controlling membrane excitability (potassium channels)
• Changes frequency/number of action potentials

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4
Q

What is the role of glutamate in the CNS?

A
  • Glutamate – major excitatory transmitter in CNS
  • Mediates most of fast excitatory neurotransmission

– ~70-90% of CNS synapses - glutamatergic

• Principle mediator of sensory information, motor coordination, emotions, cognition (including memory)

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5
Q

Where does glutamate act?

A

Acts on specific receptors – Ionotropic receptors (ion channels)

Metabotropic receptors (G protein coupled receptors)

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6
Q

What does aspartate do in the CNS?

A

– mediates transmission at a small number of central synapses

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7
Q

How is the brains glutamate supply maintained?

A

– Non-essential amino acids – Do not cross blood-brain barrier not supplied by circulation

– Synthesized in brain from metabolism of glucose

  • Also from glutamine synthesized by astrocytes
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8
Q

What happens to glutamate after it has been released into the synapse?

A

Released glutamate taken up primarily by astrocytes

Glutamine Synthase – Converted into glutamine by glutamine synthase

– Glutamine transported out of astrocytes

– Glutamine uptake by neurons (transporter)

– Converted back to glutamate by the enzyme, glutaminase

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9
Q

Which molecule of the TCA cycle is converted into glutamate?

A

Alpha-Ketoglutarate

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10
Q

How do synaptic vesicles accumulate glutamate?

A

– electrical gradient created by different concentrations of H+
across vesicle membrane (i.e. inside vesicle and in cytoplasm)

• Vesicle positive potential with respect to cytoplasm

– Electrical potential gradient generated by vesicle ATP proton (H+) pump

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11
Q

What is the synaptic vesicular concentration of glutamate?

A

• Vesicle concentration >20mM

– 1,000 – 2,000 molecules per vesicle

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12
Q

Describe the sequence of events of Release and reuptake of synaptic glutamate

A

• Action potential in pre-synaptic neuron
– Depolarizes the pre-synaptic terminal
– Depolarization opens voltage gated calcium channels
– Calcium flows into terminal
– High local concentration of intracellular Ca2+
– Triggers exocytosis of synaptic vesicle contents ok

• Glutamate diffuses across synaptic cleft
– Interacts with specific receptors
– Multiple receptor types

• Reuptake of glutamate (and aspartate)
– Excitatory Amino Acid Transporters (EAATs)
– Reduces the extracellular concentration
– Terminates transmitter action

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13
Q

How does glutamate reuptake work?

A

• Glutamate transporters drive uptake through EAAT
– Co-transport of (2-3) Na+ and H+ into the cell
– Counter-transport of K+

• Most transporters located on
– Glial cells (astrocytes)
– Post-synaptic neurons (lesser extent)

Post-synaptic Exocytosis
• Some glutamate may diffuse to act at adjacent synapses

(• Km for glutamate ~low micromolar
– Keeps extracellular concentration low
• ~15,000 – 20,000 transporters per synaptic bouton –
Effective uptake process)

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14
Q

Outline the different types of glutamate receptors?

A

• Two large families of receptors

• Ionotropic receptors
– ion channels Ionotropic
– Binding site located on channel
– Agonist binding promotes channel opening
– Role in fast synaptic transmission
– 3 classes:
• NMDA (N-methyl-D-aspartate) receptors AMPA
• AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors
• Kainate receptors (kainate found in some seaweeds)
• Names based on ability of these drugs to selectively activate channels
• Glutamate is the natural transmitter at all receptors

• Metabotropic receptors
– G protein coupled receptors
– Modulatory effects on neuronal function and synaptic transmission

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15
Q

See page 12 of glutamate excitatory lecture for a table?

A

-

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16
Q

Three agonists that work at AMPA receptors?

An antagonist?

A

Glutamate
AMPA
Kainate

CNQX

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17
Q

Three agonists that work at NMDA receptors?

An antagonist?

A

Glutamate
Aspartate
NMDA

D-AP5, D-APV, MK-801
Ketamine
Phencyclidine

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18
Q

How are glutamate receptors distributed in the brain?

A

• AMPA & NMDA receptors often co-localise at functional excitatory synapses
– Ratios at individual synapses varies greatly
– Some can contain only one sub-type
– Some can contain only one sub-type

• Only small number of kainate receptors in most CNS regions

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19
Q

What is the structure of ionotropic glutamate receptors?

A
  • Each subunit has 3 transmembrane spanning domains
  • Large extracellular N-terminus
  • Receptors made up of 4 subunits
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20
Q

What type of excitatory transmission are AMPA receptors involved in?

A

• AMPA receptors
- fast excitatory synaptic transmission
– Fast synaptic current
– Fast decay due to relatively low affinity (Kd ~200nM)

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21
Q

What type of excitatory transmission are NMDA receptors involved in?

A

• NMDA receptors
Fast excitatory neurotransmission
– Slower onset than AMPA
– Slower decay (up to several hundred msecs) – why?
– Higher affinity glutamate binding (Kd ~ 5nM)
- glutamate Stays on receptor even after synaptic clearance of glutamate - goes between open and closed state

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22
Q

What a AMPA receptors assembled of?
What is the relative synaptic current speed?
To what are they permeable?

A
  • Assembled from GluR1-4 – Tetramers
  • Fast synaptic current

• All permeable to Na+ & K+ (some also Ca2+-permeable)
– Depolarizes towards reversal potential, ~0mV
- Activation depolarizes neuron
– Activation depolarizes neuron

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23
Q

To what ions are NMDA receptors permeable?

A

• NMDA receptors are permeable to Na+, K+ and Ca2+

– Ca influx can also activate 2nd messenger systems and Ca dependent enzymes

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24
Q

What does the slower action of the NMDA receptor allow?

A

• Slower action of NMDA receptors
– Provides mechanism for spatial & temporal summation

– Also voltage sensitive
• At membrane potentials

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25
What is meant by 'NMDA receptors act as ‘co-incidence' detectors (i.e. several inputs)'?
– Needs repetitive or multiple excitatory inputs from other AMPA receptors -depolarize the neuron and relieve the Mg2+ block depolarize the neuron and relieve the Mg block – Act to sense activity of many independent synaptic inputs on same neurone
26
What is the structure of an NMDA receptor?
• Tetramers | – 2 NR1 subunits plus 2 NR2 subunits
27
What factors are require to make an NMDA receptor function?
– Glutamate binds to the NR2 subunit – Binding of glycine ( or D-serine) to a site on NR1 – (not to be confused with inhibitory glycine receptors) * Glycine concentration in brain saturating for some sub-types * Potential site for drugs to act : drugs that prevent glycine binding will inhibit NMDA receptorsa
28
What drugs block NMDA receptors?
Phencyclidine Ketamine Dextromethorphan
29
What effects do NMDA receptor antagonists have in small concentrations?
• Psychotomimetic − Cognitive defects − Hallucinations − Delusions
30
What effects do NMDA receptor antagonists have in higher concentrations?
• Dissociative anaesthetics − Sensory dissociation − Analgesia - amnesia
31
What is the the NMDA antagonist Dextromethorphan used as?
Cough suppressant
32
What type of drug is ketamine and what is it used for?
NMDA receptor antagonist Ketamine: anaesthetic/analgesic -pediatric anaesthesia, emergency surgery, (usually with sedative drug e.g. Diazepam). Suppresses breathing less than most other anaesthetics and increases cardiac output.
33
How many Metabotropic Glutamate receptors are there?
* 8 receptors known mGluR1 8 | * 7 transmembrane G-protein coupled receptors
34
Are metobotropic glutamate receptors made up of subunits?
• Not formed of subunits – One molecule = one receptor
35
How are metobotropic glutamate receptors grouped?
• Grouped into 3 groups according to: – Amino acid sequence homology – Agonist pharmacology – Signal transduction pathways – Group I, II & III
36
Where are metobotropic glutamate receptors located?
Located in different regions of CNS – Pre-synaptic – Post-synaptic
37
Which metobotropic glutamate receptors are in Group I, and what is the pathway that they activate?
``` Group I: mGluR1, mGluR5 - Activates Phospholipase C - production of IP3 and diacylglycerol (DAG) • IP3 - Ca2+ release -increase intracellular Ca2+ concentration • DAG activates Protein Kinase C protein phosphorylation Modifies ion channel activity ``` (Beta-gamma complex dissociated can interact with ion channels directly)
38
Which metobotropic glutamate receptors are in Groups II and III and what is the pathway they are in?
Group II: mGluR2, mGluR3 Group III: mGluR4, mGluR6-8 - Inhibits adenylate cyclase - decrease cAMP levels - Modifies ion channel activity (Beta-gamma complex dissociated can interact with ion channels directly)
39
What are the modulators effects of pre-synaptic metobotropic glutamate receptors?
– Inhibit voltage-gated Ca channels – reduce transmitter release • Primarily group II & III receptors – Glutamatergic terminals (inhibitory autoreceptors) – Terminals that release other transmitters
40
What are the modulators effects of post-synaptic metobotropic glutamate receptors?
• Post-synaptic effects - variable – Inhibit some K+ channels – increase excitability – Increase activity of some K+ channels – decrease excitability – Effects depend on cell type involved
41
View second to last page of glutamate excitability lecture
-
42
What do you you know about the link between calcium influx and excitotoxicity?
• Many ionotropic glutamate receptors are permeable calcium – Greatly increased glutamate release seen with a seizure or in ischaemia/reperfusion with e.g. stroke – Intense receptor activity • Large Ca2 influx – Overwhelms normal Ca2+ buffering & sequestration into intracellular organelles * Increased intracellular Ca2+ concentration – Normally used as a signalling pathway e.g. activate some enzymes * Protein kinase C, Phospholipase C – BUT large Ca2+ increase • Activates Ca2+-dependent enzymes that cleave proteins (proteases) • Generates damaging – Lysophospholipids - compromise membrane integrity – Oxidative stress (free radicals) • Leads to cell death (Why they want an NMDA antagonist - Limit the effects of stroke - would have to be given v. Soon after event though)
43
What is the major inhibitory neurotransmitter in the brain?
* GABA: gamma-amino butyric acid * GABA occurs in brain tissues but not in other mammalian tissues at significant concentrations • GABA functions as major inhibitory transmitter in many CNS pathways – Functions throughout brain • Transmitter at ~30% of all synapses in CNS
44
How is GABA synthesised?
• GABA formed from glutamate by action of enzyme – Glutamic acid decarboxylase (GAD) – Enzyme found only in GABA-synthesizing neurons (• GABA destroyed by GABA Transaminase within cells)
45
What do you know about vigabatrin?
• Vigabatrin – synthetic analogue of GABA – Inhibits GABA Transaminase by irreversible covalent binding – Long lasting effect despite short plasma half-life Increases GABA concentration in brain – Increases GABA concentration in brain – Effective in epileptic patients (resistant to other drugs) – Generally well tolerated and relatively free from side effects • Main drawback – depression and occasional psychotic episodes in minority of patients
46
Ae drugs that increase GABA activity effective in treatment of abscence seizures?
– Absence seizures are paradoxically often exacerbated by drugs that enhance GABA activity • Better treated by drugs acting by different mechanisms
47
What does GABA transaminase convert GABA into and what can then happen to this?
Succinic semialdehyde | - can become succinate and enter TCA
48
How is GABA concentrated in vesicles?
• Vesicular packaging via a transporter – Like glutamate - transporter dependent on electrical potential across vesicle membrane • Potential generated by ATP-dependent proton pump
49
How is GABA taken up from the synapse and by what?
• Released GABA taken up by transporters – Uses energy from Na+ gradient to drive uptake (co-transport) – In pre-synaptic neurons : reutilized – In post-synaptic neurons & glia
50
What does Tiagabin do?
– inhibits GABA uptake and therefore increases GABA concentration
51
What are the 2 main functional groups of GABA receptors?
• Ionotropic GABA receptors – post-synaptic – Site of action of benzodiazepine drugs • Metabotropic GABAB receptors – pre- & post-synaptic – G protein coupled receptors • GABA receptors identified in all regions of the brain
52
How are GABA receptors structured?
* Each receptor made up 5 subunits * Each subunits has 4 transmembrane spanning domains Most likely composition is 2alpha 2Beta 1gamma ``` Most prevalent combination in brain: alpha1, beta2, gamma2 (60%) Others: alpha2, beta3, gamma2 (15-20%) alpha3, beta3, gamma2 (10%) ``` GABA binding sites (2) at interface of alpha & beta subunits Benzodiazepine binding site at interface of alpha & gamma 2 subunits Expression of each subtype varies in different brain regions (e.g. alpha6 expressed almost exclusively in b ll ) cerebellum)
53
How do GABA receptors basically work?
• GABAA receptors are Cl- selective ion channels – Reversal potential near 70mV – Hyperpolarize neuron or ‘clamp' voltage near resting potential • Inhibit depolarization responses to excitatory inputs
54
Name a GABA receptor agonist?
• Muscimol from hallucinogenic mushrooms
55
2 GABA antagonists?
• bicuculline - Convulsant alkaloid - inhibits GABAA receptors by binding to the GABA binding site • picrotoxin - Another convulsant - blocks the chloride channel
56
Types of GABA modulators drugs?
* Benzodiazepines * Barbiturates * Neurosteroids (e.g. pregnenelone, alphaxolone) * Ethanol * Anaesthetics
57
How do benzodiazepines work?
Benzodiazepines – Selectively potentiate GABA effects on GABAA receptors – Bind to an accessory site – not the GABA binding site * Located at a site of alpha subunit interaction with gamma subunit * Facilitates binding of GABA by allosteric action * Enhances effect of GABA Enhances effect of GABA • Increase probability of channels opening – no effect on channel conductance or open time
58
What three GABA agonists of the benzodiazepine family do you know? What are their relative durations of action?
* Diazepam – long lasting as metabolized to active metabolite * Clonazepam – long lasting parent compound * Lorazepam, Temazepam – short lasting, no active metabolite
59
What is a GABA antagonist, can act as a convulsant and can be used as an antidote to benzodiazepine overdoses?
• Flumazenil – can act as a convulsant • Used as antidote for benzodiazepine overdoses
60
What are the clinical effects of benzodiazepines?
– Anxiolytic • Used mainly for acute anxiety • Use reducing in favour of antidepressant drugs and Cognitive Behavioural Therapy. – Sedative • Decrease time to sleep onset & increase time asleep • Sleep effects tend to decline when drug taken for 1-2 weeks – - Reduction of muscle tone • Feature of anxiety in humans • Contributes to aches, pain and headache in anxious patients • Possible without appreciable loss of coordination – Anticonvulsant • Diazepam (i.v.used to treat status epilepticus) – Acts rapidly compared to other drugs • Clonazepam claimed to be relatively selective anti-convulsant – Sedation a concern – Withdrawal may exacerbate seizures – Amnesia • Reduced memory of events experienced while taking Benzodiazepines • Minor surgery without unpleasant memories
61
What are the side effects of benzodiazepines during use?
– Drowsiness – Confusion – Amnesia – Impaired coordination – High degree of tolerance and dependence
62
What happens in acute toxicity from benzodiazepines?
– Overdose less dangerous than other anxiolytic/hypnotic drugs – Prolonged sleep without depressing respiration/cardiovascular function – With alcohol – respiratory depression • Treated with antagonist, Flumazenil
63
What are the withdrawal symptoms for benzodiazepines?
– Anxiety, increase in irritability and aggression – Tremor and dizziness
64
How might it be possible to separate the undesirable affects of benzodiazepines from the desirable effects?
• Action at alpha1 subunits leads to unwanted side effects (sedation) – Action at alpha2 and/or alpha3 containing receptors responsible for desirable anxiolytic effects without side effects – Prospect that selective alpha2/3 acting ligands could be superior anxiolytic drugs
65
What are barbiturates?
• Barbiturates discovered in the early 20th century • Bind to GABA receptor at different site to benzodiazepines – Potentiate GABA effect * Less specific receptor activity than Benzodiazepines * Widely used as sedatives until 1960s
66
What can result from barbiturate overdose?
- death from respiratory and cardiovascular depression
67
Clinical effects of barbiturates?
– Sedative effects - impaired cognition - motor coordination
68
Why are barbiturates rarely used?
– High degree of tolerance and dependence – Strongly induce hepatic cytochrome P450 enzyme • Enzymes that break down many drugs • Drug drug interactions
69
What three barbiturates do you know and when they are used, what is it for?
• Pentobarbital - occasionally used for sleeping pills and anxiolytic but less safe than benzodiazepines * Phenobarbital – still used for anticonvulsant activity * Thiopental – used as an intravenous anaesthetic
70
Where are neurosteroids made and when are their levels increased?
* Neurosteroids (e.g. allopregnanolone) * Locally synthesized in CNS in glial cells from cholesterol or steroidal precursors • Increased synthesis of endogenous neurosteroids in the brain during – stress - pregnancy - after ethanol consumption
71
How do neurosteroids affect GABA activity?
• Two binding sites on alpha sub-unit – Potentiates – Recent evidence that can also directly activate channel • Enhance GABA-mediated chloride currents
72
What synthetic neurosteroid do you know?
• - alphaxolone - developed as anaesthetic agents | – Veterinary usage
73
Disrupted steroid regulation of GABAergic transmission is implicated in several debilitating conditions. What are these?
- panic disorder - depression - schizophrenia - some forms of epilepsy
74
How does ethanol affect GABA receptors?
– Multiple sites of action in CNS – Acute GABA receptor potentiation similar to benzodiazepines – Longer term modifications (receptor location, subunit composition, neurosteroids etc) – Other sites include - Voltage gated Ca2+ channels
75
Do anaesthetics work on GABA receptors?
– GABA receptors one site of action for some general anaesthetics - Etomidate - propofol - thiopental – Act at different site to benzodiazepines • Volatile anaesthetics (e.g. isoflurane, enflurane)
76
He does GABA inhibit nervous transmission presynaptically?
– Inhibition of voltage-gated Ca2+ channels - decrease transmitter release – Occurs on glutamate, GABA and other transmitter containing pre-synaptic terminals
77
He does GABA inhibit nervous transmission presynaptically?
– Increased opening of K+ channels - reduced firing of post-synaptic neurone
78
Outline how glycine involved in the CNS as an NT
• A major inhibitory transmitter in vertebrate CNS – Especially in spinal cord and brainstem – Critical for regulation of motoneurons Functions in: - retina - auditory system - sensory systems
79
What is glycine made from and by what enzyme?
- Serine | - Serine hydroxymethyl transferase
80
How is glycine stored presynaptically and what takes it up from the synapse?
• Small pool of glycine packaged into synaptic vesicles – H+-dependent vesicular inhibitory amino acid transporter (VIAAT) • Released glycine taken up by transporters (GLYT1 & GLYT2) – Astrocytes – terminates transmitter action – Pre-synaptic neurons – replenishes pre-synaptic pool – Driven by Na+ & Cl- gradients
81
How are glycine receptors structured?
* Like GABAA receptors – pentameric (5 subunits) * Four types of alpha subunits; one type of beta subunit known • Composed of alpha (3) & beta (2) subunits or alpha (2) & beta (3) – Each 4 transmembrane spanning domains
82
What compounds that affect the glycine receptors do you know?
- Strychnine (antagonist) - glycine (agonist) Both of above bind to alpha subunit • Picrotoxin – non-competitive inhibitors at glycine receptor alpha subunit
83
What specifically makes glycine receptors inhibitory?
• Ion channels permeable to Cl- – Activation generates a hyperpolarizing ipsp
84
What therapeutic drugs do you know that act on glycine receptors?
• No therapeutic drugs act specifically on glycine receptors
85
Do you know a condition caused by a mutation in the glycine receptor?
Hyperekplexia – Rare dominant mutation - single amino acid on alpha1 subunit – Leads to 100-fold decrease in glycine affinity – Greatly reduced glycine sensitivity – Increased muscle tone, increased startle reflex

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