Download Memantine and Neuroprotection

Dr. P.M. van Zyl
Department of Pharmacology
2010
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A major cause of disability and death
worldwide.
Economists: treatment of dementia will
consume the entire gross national product of
western countries by 2050.
Alzheimer’s disease: leading cause of
dementia, fourth in mortality in the US.
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Cholinergic hypothesis
Glutamate hypothesis
?Combination: Glutamate an executor of
neurodegenerative processes, and cholinergic
neurones one of the victims.
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Olney and coworkers (1998): two phases:
1. over activation of NMDA receptors
damage of neurones bearing this receptor
subtype - in particular GABAergic neurones
2. secondary hypofunctional state of NMDA
receptors ( due to cell loss).
Loss of inhibitory (GABA) neurones in brain
further neurotoxicity due to disinhibition.
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Main excitatory neurotransmitter
Rapidly convey sensory information, motor
commands
Thoughts and memories
Most neurons and glia contain high [glutamate].
Released for milliseconds to communicate with
other neurons via synaptic endings
3 classes of ionotropic channels: AMPA receptors,
kainate receptors and NMDA receptors.
NMDARs most permeable to Ca2+.
Schematic presentation of the glutamatergic synapse and major
ionotropic glutamate receptors – AMPA and NMDA.
NMDA channel activated for only brief periods due to relief of Mg2+
blockade, which occurs after cation influx into the neuron via
AMPAsensitive glutamate receptor channels
Synaptic plasticity in CNS : detection of relevant signal over existing
background noise  long lasting alteration in synaptic strength. NMDA
receptors plays central role in such alterations and an endogenous
“noise suppressant” is magnesium.
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Powerful:
◦ Too much, too long  excite cells to death
◦ Excessive activation of NMDAR  free radicals and
activation of proteolytic processes cell
injury/death.
◦ Cleared by glutamate transporters
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Ionic homeostasis energy dependent
◦ Energy compromised neurons become
depolarized (more positively charged) relieves
normal block of NMDARcoupled channels by Mg2+.
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Glutamate-related neuronal cell injury and
death
◦ occurs in part because of overactivation of Nmethyl-d-aspartate (NMDA)-sensitive glutamate
receptors, permitting excessive Ca2+ influx
through the receptor’s associated ion channel.
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Alzheimer’s disease
Parkinson’s disease
Huntington’s disease
HIV-associated dementia
Multiple sclerosis
Amyotrophic lateral sclerosis (ALS)
Neuropathic pain
Glaucoma
Stroke, CNS trauma and seizures
Glutamate and glycine bind  cell is depolarized to remove Mg2+
block
NMDAR channel opens  influx of Ca2+ and Na+.
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Potential therapeutic benefit in range of
neurological disorders.
Must leave normal NMDAR function relatively
intact
◦ LTP in hippocampus: cellular–electrophysiological
correlate of learning and memory formation.
◦ Reticular activating system in brainstem: if
compromised: drowsiness, even coma.
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Competitive antagonists of glutamate or
glycine block normal function, not
pathological function.
Displaced from receptor by the high local
concentrations of glutamate or glycine that
can exist under excitotoxic conditions.
◦ Neuroprotective dose of MK-801: coma
◦ Phencyclidine “Angel Dust” hallucinations
◦ Ketamine: narcosis
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Theoretic solution: ‘uncompetitive’
antagonist. (An inhibitor whose action is
contingent on prior activation of the receptor
by the agonist.): blocks higher concentrations
of agonist to a greater degree than lower
concentrations of agonist.
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Relatively low-affinity, open-channel blocker —
only enter channel when it is opened by agonist.
Relatively fast off-rate: prevents accumulation in
ion channels and interfering with subsequent
normal synaptic transmission.
Neuroprotection with minimal adverse effects.
Reported SE:
◦ occasional akathesia,
◦ rare slight dizziness at higher dosages.
– At high doses:
block 5-HT3 receptor-channels
(? cognition) and nicotinic receptor channels
(? glutamate release).
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Observed in cultures and animal models
Example: Rat model of stroke, memantine
brain damage by approximately 50%.
Proving neuroprotection in humans
Minimal adverse effects. Rare: dizziness,
restlessness/ agitation (@ higher doses: 40–
60 mg/ day).
Memantine work better for severe conditions.
◦ Neuropathic pain
◦ Alzheimer’s disease: FDA approval for moderateto-severe disease.
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Initial stage: disease progression +
symptom improvement
Later: NMDA receptors on functional neurones
fully preserved ( moderate affinity antagonist).
Zajaczkowski et al., 1997: in tonic activation of
NMDA receptors, memantine can reverse deficits
in synaptic plasticity, both at neuronal (LTP) and
behavioural (learning) level
Significant improvement in: cognitive processes,
daily activities and self care (Ditzler, 1991;
Görtelmeyer and Erbler, 1992; Winblad and
Poritis, 1999).
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Agents such as memantine which mimic
some of the features of the endogenous
antagonist magnesium may be an optimal
treatment combining both neuroprotective
activity with symptomatological
improvement.
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Memantine, an “un-competitive” NMDA antagonist.
Rationale for use: excitotoxicity as a pathomechanism
of neurodegenerative disorders.
Memantine acts as a neuroprotective agent
Promising for treatment of dementias, particularly
Alzheimer’s disease.
Combined with acetylcholinesterase
inhibitors(mainstay of current symptomatic treatment
of Alzheimer’s disease).
Therapeutic potential in other CNS disorders: stroke,
CNS trauma, Parkinson’s disease (PD), amyotrophic
lateral sclerosis (ALS), epilepsy, drug dependence and
chronic pain.
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Stuart A. Lipton. 2006. Paradigm shift in
neuroprotection by NMDA receptor blockade:
Memantine and beyond Nature Reviews Drug
Discovery | AOP, 20.
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W. Danysz, C.G. Parsons, H-J Möbius,
A.Stöffler and G.Quack. 2000.
Neuroprotective and Symptomatological
Action of Memantine Relevant for Alzheimer’s
Disease – A Unified Glutamatergic Hypothesis
on the Mechanism of Action. Neurotoxicity
Research, Vol. 2. pp. 85-97.