Download NMDA and stroke

PHM142 Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
STROKE THERAPIES &
THE NMDA RECEPTOR
Michael Haichin
Matin Shariatian
Roman Pelyavskyy
Niraj Maulkhan
CEREBROVASCULAR ACCIDENTS
Strokes
Hemorrhagic
Ischemic
• Bleeding within the brain
• Interrupt blood supply to a
• Resulting from blood vessel
region of the brain
rupture
• Caused by either thrombus
• Malformed or high blood
or embolus
pressure
• 87% of strokes are of the
ischemic type
THE NMDA RECEPTOR (NMDAR)
• N-methyl-D-aspartate receptor
• Ion channel
• Found in Nerve cells
• Allows positively charged ions through the cell membrane
• Has important roles in synaptic cell death following a
stroke
MECHANISM OF ACTION
• Has binding site for glutamate and
glycine
• Is voltage dependent
• Mg2+ ions block the channel pore
• Sufficient depolarization will dislodge
the magnesium ion and allow for
Ca2+ and Na+ permeability
• Therefore both the presence of
glutamate (and glycine) and sufficient
depolarization are required
• Has allosteric sites which allow for
potentiation
NMDAR AND CELL DEATH
FOLLOWING STROKE
Stroke
Interruption of blood supply to the brain
Oxygen and Glucose depletion
Na+/K+ transporters stop functioning
Neurons become depolarized
Glutamate is released
NMDAR is activated and Ca2+ and Na+ enter the cell
NMDAR AND CELL DEATH
• Overload of Sodium and calcium in the cell causes water
absorption
• This attracts microglial cells and makes them phagocytic
• Additionally overload of calcium can trigger several
downstream lethal pathways
• Nitrosative stress
• Oxidative stress
• Mitochondrial dysfunction (produces free radicals and induces
apoptosis)
• NMDAR is therefore an important drug target
FAILED NMDAR
STROKE THERAPIES
PROPOSED TREATMENT
• It was theorized that high concentrations of Glutamate
served only to destroy neurons
• Competitive and Non-competitive Antagonists for
Glycine and Glutamate
• THEORY: Blocking these NMDA Receptors entirely
should just fix the problem of neuronal cell death, right?
WHERE IT WENT WRONG
• Competitive Antagonists would block healthy brain regions first
• Inhibition of normal NMDAR functioning leads to unwanted side effects
• Drowsiness
• Hallucinations
• Coma
• NMDAR antagonism hinders endogenous, beneficial mechanisms
• Plasticity
• Long-term neuronal survival
• Neurodevelopment (through Brain Derived Neurotrophic Factor)
• Toxicity in humans
• Unable to replicate drug levels in animal models that lead to neuroprotection
DEVELOPMENT OF NEW THERAPIES
BUT WAIT THERE’S HOPE!
• Target downstream effects of the NMDAR rather than
blocking all of the NMDAR activity
• In vivo and In vitro studies have had success with this
approach
• Ex. Inactivation of PSD-95, a scaffolding protein that binds
NMDARs to neuronal nitric oxide synthase (nNOS)
THE ROLE OF PSD-95
• PSD-95 is a scaffolding protein that binds NMDARs
to neuronal nitric oxide synthase (nNOS)
• The calcium influx from the over activated NMDA
receptor causes the activation of nNOS
• Active nNOS results in the production of nitric
oxide (NO), a signaling molecule that mediates
NMDAR-dependent excitotoxicity
INACTIVATION ON PSD-95
• PSD-95 deletion/inhibition prevents NMDAR activity
from producing NO and thus suppresses
excitotoxicity
• NMDAR activity is unaffected by mutating PSD-95 in
vivo (no unwanted side effects of blocking NMDA
activity)
• Drugs are now being produced to inhibit the PSD95 signal pathway, thus preventing brain damage
resulting from stroke mediated by NO
SUMMARY
• Two major types of strokes:
• Hemorrhagic strokes are caused by bleeding within the brain, resulting from a ruptured blood
vessel.
• Ischemic strokes interrupt the blood supply to a region of the brain.
• NMDAR is an ion channel activate by glutamate and glycine binding
• Simultaneous depolarization is required to remove Mg+ ion from blocking its pore
• It is involved in cell death following stroke by its over activation due to excessive glutamate released by
depolarized cells.
• This causes Na+ and Ca2+ overload in the cells leading to swelling which attracts microglial cells
• Ca2+ overload also induces downstream lethal pathways that lead to free radical production and apoptosis
SUMMARY
• Complete inhibition of NMDAR leads to:
• Damage to healthy brain regions
• Unwanted side effects including drowsiness and hallucinations
• Inhibition of endogenous, beneficial mechanisms
• Early NMDAR antagonists produce low-dose toxicity in humans
• PSD-95 is a scaffolding protein that binds NMDARs to neuronal nitric oxide synthase (nNOS),
• nNOS is stimulated by the calcium influx from the over activated NMDA receptor resulting in
the production of NO, which can cause neuronal cell death
• PSD-95 deletion/inhibition prevents NMDAR activity from producing NO and thus suppresses
excitotoxicity without adverse side effects
REFERENCES
1.
Aarts M, Liu Y, Liu L, et al: Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 298. (2002): 846850
2.
Carlson, Neil R. Physiology of Behaviour. Harlow: Pearson/Education, 2012.
3.
Dawson,V. et al. "Resistance to Neurotoxicity in Cortical Cultures from Neuronal Nitric Oxide Synthase-Deficient Mice." The Journal of
Neuroscience 16.8 (1996): 2479-487
4.
Hoyte, L., P. Barber, A. Buchan, and M. Hill. "The Rise and Fall of NMDA Antagonists for Ischemic Stroke." CMM Current Molecular Medicine 4.2 (2004):
131-36.Web.
5.
Ikonomidou, Chrysanthy, and Lechoslaw Turski. "Why Did NMDA Receptor Antagonists Fail Clinical Trials for Stroke and Traumatic Brain Injury?" The
Lancet Neurology 1.6 (2002): 383-86. Web.
6.
Lipton, Stuart A. “Failures and Successes of NMDA Receptor Antagonists: Molecular Basis for the Use of Open-Channel Blockers like Memantine in the
Treatment of Acute and Chronic Neurologic Insults.” NeuroRx 1.1 (2004): 101–110. Print.
7.
Martin, H and Yu,T. "Blocking the Deadly Effects of the NMDA Receptor in Stroke."Cell 140.2 (2010): 174-76
8.
Moskowitz, Michael A., Eng H. Lo, and Constantino Iadecola. “The Science of Stroke: Mechanisms in Search of Treatments.” Neuron 67.2 (2010): 181-98.
9.
Ogden, Kevin K., and Stephen F. Traynelis. "New Advances in NMDA Receptor Pharmacology." Trends in Pharmacological Sciences 32.12 (2011): 726-33.
Web.
10. Shohami, Esther, and Anat Biegon. "Novel Approach to the Role of NMDA Receptors in Traumatic Brain Injury." CNS & Neurological Disorders - Drug
Targets 13.4 (2014): 567-73. PubMed. Web.
11. Tu W., et al. "DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke." Cell 140.2 (2010): 222-34.Web.
12. Vandongen, Antonius, and Marie Blanke. "Activation Mechanisms of the NMDA Receptor." Biology of the NMDA Receptor Frontiers in Neuroscience (2008):
283-312.Web.
13. Zhou, Li et al. "Treatment of Cerebral Ischemia by Disrupting Ischemia-induced Interaction of NNOS with PSD-95." Nature Medicine 16.12 (2010):
1439-443