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PMCOL 412 > Excitotoxicity II > Flashcards

Excitotoxicity II Flashcards

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1
Q

Competitive antagonists of the NMDA receptor can bind at

A

either the:

Glycine site OR Glutamate site

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2
Q

Side effects of antagonizing the NMDAR

A

Significant side effects: agitation, confusion, hallucination, hypertension, death
Due to poor selectively (across receptor subtypes)

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3
Q

T/F: antagonizing the NMDAR is a good treatment option

A

FALSE

Clinical trials stopped because of the serious adverse effects (agitation, confusion, hallucination, death)

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4
Q

How traditional channel blockers work

A
  • Require prior activation of the receptor (as they bind within the channel and need an open pore to enter)
  • Act in a voltage-dependent manner
  • Do not generally discriminate between NMDAR subtypes
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5
Q

Examples of Traditional Channel blockers

A
  • Dizocilpine (MK801)
  • Phencyclidine (PCP)
  • Ketamine
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6
Q

Dizocilpine (MK801)

A
  • Potent anti-convulsant with dissociative anesthetic properties
    NOT used clinically due to:
  • Unacceptable toxicity and side effects (cognitive disruption, psychotic-spectrum reactions)
  • Low specificity. It is also an antagonist of nicotinic acetylcholine receptors, and inhibits serotonin and dopamine transporters.
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7
Q

Phencyclidine (PCP)

A
  • Originally developed as dissociative anesthetic.
  • Discontinued use due to serious side-effects (including delirium, psychosis and agitation)
  • decreases bp, pulse rate and respiration with high doses
  • increases strength and decreases inhibitions = dangerous behaviours
  • Used as “street drug” (angel dust)
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8
Q

Ketamine

A
  • Used for dissociative anesthesia in minor
    surgical procedures in the pediatric population and in veterinary.
  • High incidence of dysphoria, hallucinations, psycosis etc.
  • short half-life and low potency compared to PCP and MK801
  • causes psychological dependence
  • depresses consciousness and breathing at high doses
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9
Q

Ketamine vs. other traditional channel blockers

A

Short half-life and low potency make ketamine safer than MK801 or phencyclidine

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10
Q

Traditional NMDAR-based strategies fail because

A

… of lack of specificity across NMDAR subtypes

  • Can’t discriminate between synaptic and extrasynaptic receptors
  • inhibits both pro-apoptotic and pro-survival signals
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11
Q

Current therapies for excitotoxicity

A
  • Voltage-gated Na+ or Ca++ channel inhibitors
  • Glutamate re-uptake enhancer
  • Low affinity open channel blockers
  • Extrasynaptic signaling modulators
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12
Q

Voltage-gated Na+ or Ca++ channel inhibitors examples

A

Riluzole

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13
Q

Glutamate re-uptake enhancer examples

A

Riluzole

Ceftriaxone

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14
Q

Low affinity open channel blockers

A 
At synaptic receptors: 
- Amantadine
- Memantine
- Riluzole
At extrasynaptic sites
- Memantine
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15
Q

Extrasynaptic signaling modulators

A

Tat-NR2B9c

ZL006

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16
Q

Riluzole mechanism

A

has various mechanisms of action and more
favorable and safer clinical profile than classical NMDAR antagonists:
i) Decreases presynaptic release of glutamate via inhibition of pre-synaptic Na+ channels.
ii) Blocks NMDAR activation, preventing Ca++ entry through the channel. Binding site not identified
iii) Potent activator of glutamate re-uptake.

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17
Q

Riluzole in ALS

A
  • It is one of only two drugs with some (modest) beneficial effect in ALS (FDA approved).
  • It slows down progression and increases survival by 3-5 months.
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18
Q

Riluzole in HD & PD

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A

Not effective in clinical trials in HD and PD

19
Q

Differences in efficacy of riluzole in ALS vs HD/PD

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A

ALS target likely the SC, whereas HD/PD is the brain
Mechanism of action on the spinal cord may be different from action on brain.
OR excitotoxicity may be more relevant in ALS than HD/PD

20
Q

CEFTRIAXONE mechanism

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A
  • β-lactam antibiotics (penicillin, amoxicillin, ceftriaxone, etc.) increase EAAT2 protein expression –> increase glut reuptake
  • a glut reuptake enhancer (increase EAATS protein expression)
21
Q

CEFTRIAXONE efficacy

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A

Increases survival of ALS mice.

Currently in clinical trial for the treatment of ALS

22
Q

Open-channel blickers

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A

Open-channel NMDAR blockers bind to and block the receptor only during depolarization and opening of the channel.

23
Q

New vs. old channel blockers

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A
  • NEW are characterized by lower affinity and faster dissociation than classic NMDAR channel blockers.
  • These properties decrease side effects and toxicity
  • new: amantadine, memantine
24
Q

Memantine: key properties

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A

Key therapeutic properties of memantine: UFO drug

  • Uncompetitive antagonist
  • Fast “Off-rate”
25
Low doses of memantine
At low doses memantine preferentially blocks stimulation of extrasynaptic NMDA receptors, while sparing synaptic receptors
26
Uncompetitive vs. noncompetitive inhibitors
Uncompetitive--> icnreased binding with increased conc of the agonist (NMDA) Noncompetitive--doesn't compete, binding rate is consistent/independent of angonist concentration
27
Memantine and glut/NMDA concentration
Uncompetitive agonist | works well when glut is raised for longer periods
28
Memantine at synaptic vs extrasynaptic receptors
Synaptic receptors--> glut is only high for miliseconds --> memantine doen't work great Extrasynaptic --> prolonged channel activity, with elevated glut over minutes = memantine is more effective allows selectivity for extrasyn receptors
29
Memantine binding site
Binding site is within the channel and on the NR1 subunit. Little preference for the NR2 subunit.
30
Binding affinity of memantine
Low affinity: it rapidly binds and dissociates from the receptor = fewer side effects
31
T/F memantine has effects at sites other than the NMDAR
TRUE | Also inhibits a7 nicotinic acetylcholine receptors
32
Memantine efficacy for Dementia
Beneficial effects, although modest, in AD and vascular dementia. However, it does not appear to be able to modify disease course. Currently in clinical trials in PD, ALS, HD, frontotemporal lobar degeneration, dementia associated with traumatic brain injury
33
Memantine action at a7 nicotinic acetylcholine
Intially Inhibition of a7 nicotinic acetylcholine receptors (nAChR) --> worsening of cognitive function at the beginning of treatment Over time Inhibition of nAChR induces receptor upregulation over longer time --> might contribute to the cognitive-enhancing effects of chronic memantine treatment
34
Tat-NR2B9c structure
20 amino acid-long peptide that includes: - -> the NR2B C-terminal sequence that binds PSD95 - -> the membrane transducing domain of the HIV1 Tat protein (which makes the peptide membrane permeable)
35
How Tat-NR2B9c works
Binds PSD95 instead of NMDARs (acts as a decoy) | In excess will compete with receptor binding for PSD95 --> inhibit NO release and block downstream signalling
36
ZL006
small molecule drug that interferes with the binding of nNOS to PDS95 nNOS binds to ZL006 instead of PSD95
37
ZL006 & Tat-NR2B9c
Both strategies have been successfully used to reduce stroke damage in animal models by Inhibition of protein-protein interactions at extrasynaptic NMDA receptor signaling platforms
38
Inhibition of protein-protein interactions at extrasynaptic NMDA receptor signaling platforms: normal
- PSD95 and nNOS bind --> release NO --> signalling of excitotoxicity - protein-protein interactions at extrasynaptic NMDA receptor
39
Tat-NR2B9c in non-human primates
- Induction of stroke by surgical middle cerebral artery occlusion + Intravenous administration of Tat-NR2B9c peptide after 1 hour - Tat-NR2B9c treated animals showed decreased infarct and lower stroke scale scores after 7, 14-days compared to placebo
40
Tat-NB29c peptide is neuroprotective in | patients with iatrogenic stroke
- Evaluating Neuroprotection in Aneurysm Coiling Therapy (ENACT) Phase II trial - Decreased numbers of stroke lesions in patients taking Tat-NR2B9c--fewer lesions after TAT-NR2B9c compared to placebo - Benefits of Tat-NB29c administration in combination with classic thrombolytic therapies needs to be assessed.
41
Iatrogenic stroke
stroke caused by a medical procedure (ex. endovascular aneurysm repair)
42
ZL006 development
- researchers found that nNOS is in complex with PSD-95 and active NMDA NR2B subunits after stroke and that this complex is crucial for neuronal death. - Found that peptides that destroy PSD-95 – nNOS binding are protective - Used rationalized drug design to prevent crucial amino acids interactions for PSD-95-nNOS binding --> developed ZL006 as potent inhibitor of nNOS – PSD95 binding and excitotoxicity, without side effects
43
Structural underpinning of PSD95-nNOS interaction
- A beta-finger domain in nNOS is important for interaction with PSD95 - this domain is stabilized by he interaction between Arg121 and Asp62 of nNOS - ZL006 is designed to bind Arg121, preventing its interaction with Asp62
44
Treatment of cerebral ischemia by disrupting ischemia induced interaction of nNOS with PSD-95
ZL006 decreased infarct size and neurological score by almost 50% compared to placebo

PMCOL 412 (35 decks)

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