NMDA Receptors & Stroke Therapies Ajay Chahal Vivian Tang Anushya Vijayaraghevan Chelsea Geen PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson
Dec 17, 2015
NMDA Receptors&
Stroke Therapies
Ajay Chahal
Vivian Tang
Anushya Vijayaraghevan
Chelsea Geen
PHM142 Fall 2014Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson
Stroke
• Caused by lack of blood flow to brain
• Variety of effects
– Partial paralysis, vision loss, dizzyness ect.
• Risk factors are:
– hypertension obesity, diabetes, excessive alcohol
consumption, smoking and stress.(Heart and Stroke Foundation, 2014)
NMDA Receptor
• N-methyl-D-aspartate Receptor
• Found in synaptic cleft
• Glutamate-gated ion channel
– Calcium
– Sodium
• Activation: ligand binding and depolarization
(Li & Tsien, 2009)
NMDA Receptor: Mechanism of Action
• At resting potential, the channel is blocked
by a Mg2+ http://www.sumanasinc.com/webcontent/animations/content/receptors.html
(Blanke & VanDongen, 2009)
NMDA Receptor: Mechanism of Action
• Electrical stimulation of presynaptic neurons
releases glutamate into the synaptic cleft. The
glutamate binds to the receptor.http://www.sumanasinc.com/webcontent/animations/content/receptors.html
glutamate
(Blanke & VanDongen, 2009)
NMDA Receptor: Mechanism of Action
• Receptor does not activate because
insufficient depolarization http://www.sumanasinc.com/webcontent/animations/content/receptors.html
(Blanke & VanDongen, 2009)
NMDA Receptor: Mechanism of Action
• During sufficient depolarization, the Mg2+ is
dislodged from channel and activateshttp://www.sumanasinc.com/webcontent/animations/content/receptors.html
Mg2
+
(Blanke & VanDongen, 2009)
NMDA Receptor: Mechanism of Action
• Activated channel results in influx of Ca2+
Acts as a secondary messenger to activate
intracellular signaling cascade(Blanke & VanDongen, 2009)http://www.sumanasinc.com/webcontent/animations/content/
receptors.html
Mechanism of Ischemic Cell Death
(Breton and Rodriguez, 2012)
Effects of High Ca2+ Concentration in Neurons after Ischemia
Rama
(Breton and Rodriguez, 2012)
Excitotoxic Signaling by Overstimulation of NMDA Receptor
(Breton and Rodriguez, 2012)
(R&D Systems, 2012)
NMDA & Stroke: Therapeutic Attempts
Only therapy currently
available:
thrombolytic recombinant tissue
plasminogen activator (rt-PA)
• give within 3 hrs
– most patients (95%) don’t
receive (eg delay to hospital)
– increases intracranial
haemorrhage risk(Reviewed in Green and Shuaib, 2006)Image http://www.thetimes.co.uk/tto/news/uk/scotland/article3796905.ece
Neuroprotective AgentsAnother approach!
– attempt to interfere with ischaemic cascade
mechanisms and decrease tissue damage
– have been studied
• but every one to reach clinical trials…
(Reviewed in Green and Shuaib, 2006)Image http://fightingclean.com/2014/07/kevin-casey-robert-drysdale-fail-post-fight-drug-tests/
Failed Attempts…
Table 1: Compounds that have failed clinical trials for acute ischaemic stroke treatment (Green and Shuaib, 2006).
There is still hope!
• New
neuroprotective
compounds
being
investigated
– But none
currently on
market
(Reviewed in Green and Shuaib, 2006)
Example: DAPK1 and NMDA
• DAPK1: death-associated protein kinase 1
– Found to be important part of neuron death
signaling cascade downstream of NMDA
– Could be a target for neuroprotective drug
development!
(Reviewed in Martin and Wang, 2010)
Mechanism of Potential Therapeutic Action
(Reviewed in Martin and Wang, 2010)
Normal synapse:
Activate NMDA receptor neuronal survival signaling complex (SSC)
(Reviewed in Martin and Wang, 2010)
Increase Ca2+ influx through NMDA receptors activates DAPK promotes DAPK bind and phosphorylation of NR2B
Activated DAPK promotes neuron death signal complex (DSC) that shuts off SSC
Using an NR2B interference peptide inhibit aDAPK binding to NR2B blocks phosphorylation, decrease DSC activation avoid exitotoxic damage induced by stroke!
STROKECONDITIONS:
http://www.today.com/id/7466911/ns/today-today_entertainment/t/darth-vader-lives/#.VE8mIYvF9-g
Darth Vader = DAPKLightsaber = Ca2+
Darth Vader + Lightsaber = activated DAPK
Darth Vader + Lightsaber:
gives into anger (phosphorylation) and joins the dark side (binds NR2B)
promotes neuron death signal complex (DSC) shutting off survival signal complex (SSC)
Luke Skywalker = NR2B interference peptide
Luke Skywalker stops Darth Vader and his lightsaber (aDAPK) from joining the dark side (binding NR2B), blocking Darth Vader’s anger (phosphorylation)
Since Darth Vader is no longer angry, death signal complex (DSC) is decreased
http://www.comicvine.com/forums/battles-7/anakin-skywalker-vs-luke-skywalker-read-op-576670/
SummarySTROKE• Caused by an event that limits or stops blood flow to the brain
– ischemia or hemorrhaging– 2 kinds of ischemic stroke:
1) Thrombotic stroke: blood clot in an artery leading directly to brain2) Embolic stroke: clot forming somewhere else in the body, travels through blood stream to the brain.
• Risk factors: hypertension, obesity, diabetes, excessive alcohol consumption, smoking and stress
NMDA RECEPTOR• A glutamate-gated ion channel - activated when both glutamate is bound to
receptor and adequate depolarization occurs• Results in Ca2+ ion influx
• NMDA receptors excessively activated resulting in increased Ca2+ influx – after ischemia, cytoplasmic Ca2+ levels rise and can trigger many downstream
neurotoxic cascades including the activation and overstimulation– the results include activation of several signalling pathways mainly causing an
overproduction of free radicals, dysfunction of mitochondria, cell membrane disruption and DNA fragmentation, which together induce neuron death
THERAPY• Currently only rt-PA for ischaemic stroke (within 3 hours)• Neuroprotective agents still being investigated, although most have failed
clinical trials
ReferencesBlanke, M. L., and VanDongen, A.M.J. (2009). "Activation Mechanisms of the NMDA Receptor." Biology of the
NMDA Receptor. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK5274/.
Breton, R.R., and Rodriguez, J.C.G. (2012). Excitotoxicity and oxidative stress in acute ischemic stroke. Stroke, 8, 9. http://cdn.intechopen.com/pdfs/26258.pdf.
Green, A.R., and Shuaib, A. (2006). Therapeutic strategies for the treatment of stroke. Drug Discovery Today, 11:15/16. doi:10.1016/j.drudis.2006.06.001.
Heart and Stroke Foundation. (2014). “Stroke.” Web. 27 Oct. 2014. Retrieved from http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483933/.
Li, F, and Tsien J.Z. (2009). Memory and the NMDA receptors. New England Journal of Medicine, 361(3): 302-3. doi: 10.1056/NEJMcibr0902052.
Martin, H.G.S., and Wang, Y.T. (2010). Blocking the deadly effects of the NDMA receptor in stroke. Cell, 140: 174-176. DOI 10.1016/j.cell.2010.01.014.
R&D Systems. “Neuronal Death by Glutamate Excitotoxicity: Protein Mediators & Strategies for Inhibition.” (2012). Retrieved from http://www.rndsystems.com/mini_review_detail_objectname_neuronal_death_by_glutamate_excitotoxicity_article.aspx.