Download EEG Gamma Power Changes Following Administration of NMDA

EEG Gamma Power Changes Following Administration of NMDA Receptor Antagonists
Maninder Chopra1, Michael Quirk1, Ray Rothstein2, John Roberts3, Mary J Bock3, Ed Christian1, Russell Bialecki2 and Carlos Fonck2
Neuroscience Biology1, Safety Assessment2, DMPK3, Astrazeneca R&D, Wilmington, DE.
750.1/V36
RESULTS
Ketamine
50
12
45
40
10
40
35
8
30
6
25
20
4
Frequency (Hz)
45
5
0
20
40
60
Time (minutes)
60 mg/kg
55
80
100
20
60
Time (minutes)
100 mg/kg
55
80
100
25
20
2
15
10
0
5
20
40
120 mg/kg
55
60
Time (minutes)
80
100
-2
8
40
6
35
30
4
25
20
2
15
10
0
5
0
20
40
60
Time (minutes)
Mouse plasma concentrations for Ketamine and Traxoprodil
were determined by LC/MS. For the Ketamine PK/PD modeling,
PK was fitted simultaneously across 30 and 120 mg/kg doses.
Predicted concentrations were then used to fit EEG responses
to a sigmoidal Emax link PK/PD model for determination of
EC50, Emax and keo.
80
100
60
Time (minutes)
80
-2
100
Z-map
10
8
45
40
6
35
30
4
25
20
2
6
35
30
4
25
20
2
15
10
0
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Plot comparing the γ band power changes for nonselective NMDAR anatgonists (ketamine,
remacemide) and NR2b-selective allosteric
antagonist, traxoprodil.
0
5
0
20
40
60
Time (minutes)
80
100
-2
0
10
45
40
60 mg/kg
55
Heat maps showing power
spectrum changes following
administration of ketamine (left
column, 30, 60 and 120 mg/kg),
Remacemide (middle column, 30
and 100 mg/kg) or Traxoprodil
(Right column, 30, 60 and 100
mg/kg).
20
40
100 mg/kg
Z-map
50
20
50
5
0
-1
55
8
15
10
0
0
Frequency (Hz)
4
Frequency (Hz)
30
1
20
5
40
35
2
25
Z-map
45
6
3
30
0
50
8
4
35
10
5
40
5
15
10
20
Spectrogram
40
15
0
40
Frequency (Hz)
40
45
25
Z-map
45
Frequency (Hz)
50
20
5
10
45
25
-2
50
55
30
30
10
0
50
35
35
15
2
Traxoprodil
30 mg/kg
Spectrogram
Frequency (Hz)
14
10
EEG recordings
PK/PD methods
55
15
Surgical implantation of EEG electrodes.
Continuous EEG recordings were performed with a Pinnacle
Technology system (Lawrence, Kansas). A baseline
electrophysiological response was recorded for a period of 30
min prior to drug administration. Test or reference compounds
were administered intra-peritoneally, except Traxoprodil, which
was administered sub-cutaneously. EEG data was collected for
90 minutes following drug administration. At the end of each
experiment, plasma from blood was collected for bioanalysis.
Fast-Fourier analysis was applied to EEG data in MATLAB to
generate time-frequency series. Z-score maps from individual
animals were averaged to obtain average maps shown. The
power specific to a band was averaged post-drug
administration across 90 minutes to generate response curves.
Remacemide
30 mg/kg
Z-map
50
EXPERIMENTAL PROCEDURES
Male C57BL/6 mice were anesthetized and a head-mount with
four screw electrode holes was placed on top of the skull and
centered along the midline, with frontal screw positioned 1-1.5
mm anterior to Bregma. The head-mount assembly was
cemented onto the skull with dental acrylic. Animals were
allowed to recover from surgery for at least 10 days and were
used for upto 4 months after surgery.
30 mg/kg
55
Frequency (Hz)
Quantitative EEG (qEEG) offers an opportunity to provide a
pharmaco-dynamic, mechanistic and potentially translatable
biomarker for various drug-induced and disease states.
Changes in electroencephalogram (EEG) gamma band power,
defined as frequencies ranging between 30 and 80 Hz, have
been linked in humans to enhanced cognitive function, but
also to pathological states such as schizophrenia, druginduced hallucinations, epilepsy and Alzheimer’s disease.
Thus, the ability to pharmacologically modulate gamma power
may be of therapeutic interest. The EEG provides temporal
resolution in the milliseconds range, and the ability to detect
both excitatory and inhibitory neuronal activity. Here we
study effects of NMDA receptor blockers on mouse EEG, with
an overall aim to develop a useful biomarker for this
compound class, with a potential for forward and backtranslation.
60
Time (minutes)
80
-2
100
Spectrogram
5
50
4
45
40
Frequency (Hz)
INTRODUCTION
-2
3
35
2
30
25
1
20
0
15
10
-1
5
0
20
40
60
Time (minutes)
80
-2
100
Plots showing average fold-change in the γ
frequency band power 90 minutes
following drug administration as a function
of Cmax (Left, ketamine; Right; traxoprodil)
Clinical ranges were simulated or quoted
from listed references.
SUMMARY
‰ Non-selective NMDA receptor open channel
blockers, ketamine and remacemide increased β
and γ-power in a dose- and exposure-dependent
manner
‰ In contrast, traxoprodil, an NR2b specific allosteric
antagonist showed a small decrease in γ-power.
‰ Differences in the effects on EEG γ-power caused
by the two types of NMDA receptor antagonists
may be explained by differences in blocking
mechanism (open-channel pore blocker vs
allosteric antagonist) subtype-selective effects,
and/or a yet unexplored polypharmacology.
REFERENCES
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Gamma EEG Power
White PF, Ham J, Way WL, Trevor AJ (1980) Pharmacology of ketamine isomers in surgical
patients. Anesthesiology 52:231.
15 mg/kg
30 mg/kg
60 mg/kg
120 mg/kg
Parameter
Value
%CV
Emax
4.15
19
EC50 (μM)
28
23
Keo (min-1)
0.61
18
Hill slope
1.48
7
PK/PD parameter estimates for
ketamine were obtained using
WinNonlin 4.1.
Diagram showing position of the head-mount implant
Ketamine concentrations
peak and decline rapidly
following 30 mg/kg dose
while onset of peak effect
is slightly delayed in time.
At higher doses of ketamine
(120 mg/kg) evidence of a
prolonged active metabolite
contribution or mechanism
related indirect effect was
observed.
Time (min)
Plot showing actual and predicted
PK/PD fits to ketamine gamma EEG
using a link model.
Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, Aoyama T, Yamamura Y,
Yamada Y, Iga T. (2003) Plasma Concentration Profiles of Ketamine and Norketamine after
Administration of Various Ketamine Preparations to Healthy Japanese Volunteers Biopharm.
Drug Dispos. 24: 37.
Zarate CA Jr, Singh JB, Carlson PJ, Brutche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji
HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant
major depression. Arch Gen Psychiatry 63: 856.
ACKNOWLEDGEMENTS
We wish to thank Mark Eisman and Bernie Lanoue for DMPK support, and
Frank McGrath and Lisa Leon for surgery support.