Transcript High-Impact AMPAKINEs and Neuroprotection

AMPAKINE Compounds for the
Treatment of Rett Syndrome
Mark A Varney
Chief Scientific Officer
Hypothesis
• Depressed Levels of BNDF Contribute
to the Phenotype of Rett Syndrome
– Lifespan
– Motor Activity
– Cortical Layer V Firing
– Breathing Abnormalities
• Increase Brain BDNF to Attenuate Rett
Symptoms
Chang et al, 2006. Neuron 49, 341–348
Wang et al, 2006. J Neurosci 26:10911–5
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BDNF – A Major Regulator of Synaptic
Plasticity
• Synthesized and stored in glutamatergic
neurons and is released in an activitydependent manner
• Critical for neuronal survival and differentiation
• Plays a role in fast excitatory synaptic
transmission and synaptic plasticity, including
LTP and LTD
• Critical for synaptic plasticity and memory
processing in the adult brain
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Strategy
• Treat with AMPAKINE Molecules to
Increase Endogenous BDNF Levels in
Specific Brain Regions
– AMPAKINEs are small molecules that
positively modulate the AMPA receptor
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AMPA Receptors Play a Key Role in
Glutamatergic Transmission
• Glutamate is the major
excitatory neurotransmitter
in the CNS
• Virtually all neurons express
glutamate receptors
• Fast excitatory transmission
is mediated by AMPA
receptors
Swanson et al. (2005)
Nat Rev Drug Dis 41: 131-144
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AMPAKINE Molecules
• AMPA receptors deactivate and/or desensitize
extremely rapidly (~2-10 ms)
• AMPAKINEs are allosteric positive modulators of the
AMPA receptor
– Attenuate deactivation and/or desensitization of AMPA receptors
– Strengthen synaptic transmission and facilitate long term
potentiation (LTP), widely regarded as the substrate for memory
– Stimulate BDNF production
1 ms Pulse
Baseline
Deactivation
+ AMPAKINE
Superimposed
Desensitization
500 ms Pulse
Baseline
+ AMPAKINE
Superimposed
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AMPAKINEs Have Acute and Chronic
Effects In Vivo
AMPAKINE Treatment
Acute Effects
Chronic Effects
(Lasts with the t½ of the
drug)
(Trophic induction lasting ≥
one day)
• Memory
• Cognition
• Psychiatric disorders
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Memory
Cognition
Psychiatric disorders
Degenerative diseases
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Chronic Effects of AMPAKINEs
1. Brief treatment with
AMPAKINE causes long
lasting increases in BDNF
2. Use daily injections of short half-life AMPAKINEs to
chronically increase BDNF levels.
3. BDNF then promotes plasticity and
neuronal viability
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Chronic Effects of AMPAKINEs on BDNF
Rat Cortical Cultures Cultured Hippocampal Slices
In Vivo
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Protein
mRNA
Protein
6 hr AMPAKINE pulse,
protein at 24 hrs
3 hr AMPAKINE pulse,
mRNA at 18 hrs
1 injection/day for 7 days,
Hippocampus collected 24
hrs after last treatment
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Huntington’s Disease (HD)
• Progressive, hereditary brain disease that
causes changes in movement, thinking and
behavior
• Onset commonly between ages 30-50
• 30,000 people in US (~1/10,000)
• Caused by excessive CAG repeats in the
huntingtin gene
• Disturbances in executive function are
probably earliest manifestation
• Neuropathology, particularly in striatum, in
later phases
• BDNF levels are reduced in HD postmortem
brain and transgenic mouse models
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Reduced BDNF and Defective LTP in
Asymptomatic HD Knock-in Mice
TBS: 10 bursts of 4 pulses 100 Hz; separated by 200 msec
Lynch et al., J. Neurosci 2007
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AMPAKINE Treatment Paradigm
HD Knock-in Mice
CX929 selected because
of its short t½ of 15min
and robust effects on
BDNF
Injected with Vehicle or
CX929 at 5 mg/kg/day i.p. for
between 4 to 30 days
18-24 hours after the last dose, measure
• Hippocampal LTP
• Actin Polymerization
• Locomotor Effects
• BDNF Measurements
• Cognition
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CX929 Up-regulates Mature BDNF in HD
Knock-in Mice and Restores LTP
Mature Hippocampal
BDNF Protein
Hippocampal LTP
140
% Control Mean
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100
80
60
40
20
0
Normal
HD
HD+CX929
• Cognitive deficits restored and motor deficits prevented by CX929
Mature hippocampal BDNF and LTP assayed 18 hrs after the last of 30
daily treatments with CX929
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Current Studies
• Evaluate if AMPAKINE treatment
corrects Rett phenotypes in Mecp2-/y
mice
– Respiration
– BDNF levels
– Other behaviors
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Summary
• AMPAKINE molecules increase brain BDNF
levels
• Transgenic HD mice have deficits in BDNF
levels and deficits in hippocampal LTP
– The short acting AMPAKINE, CX929 can restore
depressed BDNF levels and hippocampal LTP
deficits
• Rett Mice have deficits in BDNF
• Currently testing AMPAKINEs in Rett mice to
see if it restores normal phenotype
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