Behavioural Brain Research 154 (2004) 149–153
Research report
Treatment with reduced nicotinamide adenine dinucleotide (NADH)
improves water maze performance in old Wistar rats
André Rex∗ , Markus Spychalla, Heidrun Fink
Institute of Pharmacology and Toxicology, School of Veterinary Medicine, Freie Universität, Koserstr. 20, 14195 Berlin, Germany
Received 6 October 2003; received in revised form 29 January 2004; accepted 3 February 2004
Available online 16 March 2004
Abstract
Age-associated cognitive impairment and related neurodegenerative disorders are an increasing major public health problem. Nicotinamide adenine dinucleotide (NADH), a co-substrate for energy transfer in the mitochondrial respiratory chain, is speculated to induce
positive effects in some of these diseases. Studies showed diminished mitochondrial function in patients with M. Alzheimer. In a preliminary
clinical trial NADH given peripherally improved cognitive function in Alzheimer disease.
Previous own experiments revealed an increased NADH level in the rat brain following peripheral application of NADH (10–100 mg/kg,
i.p.+ i.v.). Therefore, we wanted to know, whether or not NADH has an effect on cognitive function in animals. We analysed the effect
of repeated i.p. injection of NADH on the performance of 3-month-old and 22-month-old Wistar rats in the Morris water maze and in the
rota-rod test of motor coordination. The rats were injected for 10 days once daily with the doses of NADH used in the bioavailability study
(10–100 mg/kg) or vehicle 20 min before the behavioural tests. The repeated administration of NADH improved the performance of old
rats in the acquisition phase (place version) and the spatial probe of the Morris water maze compared to vehicle-treated controls. The effect
of NADH on learning-related processes is supported by the lack of effects on motor performance on the rota-rod. In summary, our results
suggest cognitive enhancing properties of NADH in learning impaired old rats.
© 2004 Elsevier B.V. All rights reserved.
Keywords: NADH; Learning; Memory; Morris water maze; Rota-rod; Old rat
1. Introduction
Age-associated cognitive impairment and related neurodegenerative disorders are an enormous public health and
socio-economic burden and therefore a major problem for
health systems. The full pathological process is not fully
understood yet.
Therapeutic interventions aimed at either finding a cure
or prevention of progression of age-related or pathological
decline in cognitive function cannot be overstated.
Mitochondrial dysfunction could be a factor for predisposition to neurodegeneration, and may accelerate cell dysfunction and loss. While probably not having a primary role
in pathoaetiology, respiratory chain dysfunction may still be
an important risk factor for development of late life neurodegenerative disorders and an important effector mechanism in
neuronal dysfunction [5]. A recent study showed alterations
of mitochondrial function in patients with M. Alzheimer [4].
∗ Corresponding author. Tel.: +49-30-83853512;
fax: +49-30-83853112.
E-mail address: [email protected] (A. Rex).
0166-4328/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbr.2004.02.001
Furthermore, there is increasing evidence for diminished
cerebral mitochondrial metabolism in Alzheimer patients
[6].
Considering the relatively small safety margin between
energy supply and neuronal function [1] and the known
age-related changes in mitochondrial function, it has been
thought that an exogenous supply with reducing equivalents for the energy metabolism could counteract age-related
deficits in cognitive function.
Nicotinamide adenine dinucleotide (NADH), a cosubstrate for energy transfer in the mitochondrial respiratory
chain, is speculated to induce positive effects in some degenerative disorders of the central nervous system. Clinical
studies demonstrated positive effects of peripherally given
NADH on serious disorders such as Parkinson’s disease
and chronic fatigue syndrom. [3,10].
Effects of oral NADH treatment in patients with cognitive impairment are ambivalent. While one study showed
promising results [2] another study was unable to replicate
the NADH-induced effects [26].
A criterion for a possible central action of a drug is the
cerebral bioavailability. Previous own experiments in rats
150
A. Rex et al. / Behavioural Brain Research 154 (2004) 149–153
revealed an increased NADH level in the CNS following peripheral application of NADH [27], which raises the question whether NADH may induce an effect in an behavioural
test of cognitive function.
The Morris water maze is the most common animal test
in behavioural neuroscience to investigate spatial learning
in laboratory animals [7,16,23]. Compared to the radial arm
maze and often used passive avoidance procedures the water
maze test has advantages [22] since it needs neither appetitive stimuli nor additional punishment which may interfere
with memory processes, although the animals behaviour is
partly aversively motivated.
However, changes in motor abilities can affect the performance of the animals in the Morris water maze. The rota-rod
provides a relatively easy way to test the motor function
in rodents. Central nervous system damage, drug effects on
motor coordination or fatigue can be assessed by measuring the time during which the animal remains walking on a
rotation drum [8,19].
The aim of the present study was the assessment whether
or not NADH could counteract age-related cognitive performance deficits. Thus, young adult and old rats received for
10 days once a day intraperitoneal injections of NADH before testing in the Morris water maze and on the rota-rod
motor coordination task [15,33].
each animal, the submerged platform (transparent perspex:
16 cm × 16 cm) was placed in the centre of one quadrant
of the maze at 1.5 cm below water level. The location of
the platform was constant for each rat and was counterbalanced within groups. Rats were placed gently in the water
maze at a start point in the middle of the rim of a quadrant,
which did not contain the platform. The starting points for
the three trials of a rat varied randomly during the day so
that the same start point was not used twice in a rat during
a session. After reaching the platform, the rats could stay
on it for 30 s; the next trial started 1 min following this 30-s
period. If an animal failed to find the platform in 90 s, it was
placed on the platform for 30 s. Parameters measured were:
time needed to reach the platform, swim distance and swim
speed. On the ninth day, the platform was removed and the
animals were tested as described for the habituation session.
The parameter assessed during this 90-s spatial probe was
the time spent in each quadrant. On day 10, the animals were
observed for three additional trials in the visible-platform
version of the task. Rats were tested as described for the
hidden-platform task, with the exception that the platform
was made clearly visible and positioned 1.5 cm above water level in the quadrant opposite to its original location.
During the different versions of the maze, the animals were
tracked and the behaviour analysed with a computer aided
videotracking system (VideoMot, TSE, Germany).
2. Material and methods
2.4. Rota-rod test
2.1. Animals
In a separate experiment the motor coordination was evaluated with an accelerating rota-rod for rats (TSE, Germany).
The treadmill consisted of four rotating drums (7 cm diameter, 24 cm above ground), divided by flanges. The first day,
rats were familiarized with the apparatus; they were placed
for three 2-min runs on the constantly revolving drum (speed
4 min−1 ). If a rat fell off during the trials, it was immediately placed back onto the drum. On the next day, the rats
received either NADH or vehicle. Twenty minutes later the
rats were placed on the accelerating rotating drums (speed
4–32 min−1 ) for maximal 5 min. The latency until the rat
fell off the drum was registered.
Male Wistar (Shoe: Wist, Tierzucht Schönwalde GmbH,
Germany) rats 3 months old (250 ± 22 g, young adult)
and 22 months old (404 ± 5 g, old) were used. They were
group-housed, five per cage (45 cm×60 cm×25 cm), at room
temperature (22 ± 2 ◦ C) and under a 12 h-light/12 h-dark
cycle (light on at 06:00 h). Standard pellet food (Altromin
1326) and water were freely available. All rats appeared
healthy before testing.
2.2. Drugs and treatment regimen
NADH (10–100 mg/kg, Gerbu, Germany) as well as the
vehicle (NaHCO3 -buffer, pH 8.0) were administered intraperitoneally with an injection volume of 1 ml/kg. All
animals were treated with verum or vehicle once daily
20 min pretrial.
2.3. Apparatus and experimental protocol
The Morris water maze was a circular tank (200 cm) with
60 cm high walls filled to a depth of 42 cm with water at
22 ± 1 ◦ C. Young adult and old animals were habituated to
the water maze by lowering each rat into the apparatus for
90 s with no opportunity to escape. Commencing on the second day, rats were tested in the hidden-platform version of
the task on seven consecutive days (three trials per day). For
2.5. Statistics
The data were analysed using two-way ANOVA or
one-way ANOVA for multiple comparisons and the Holm–
Sidak method for the post hoc comparisons. Differences of
the means (P < 0.05) were considered significant.
3. Results
3.1. Morris water maze
Vehicle-treated old animals showed an impairment in
learning to navigate the maze compared with young adult
A. Rex et al. / Behavioural Brain Research 154 (2004) 149–153
151
cape latencies from the sixth day onward (P-values < 0.05
versus old controls). On the last testing day (day 8), the
escape latency of the old vehicle-treated rats was prolonged
compared to the NADH-treated old rats and all young
adult rats [F(7, 77) = 5.817, P < 0.001]. Based on the
present statistical methods, there was no significant difference between old NADH-treated rats and young adult rats
[F(6, 67) = 2.003, P = 0.079]. Nevertheless, there was a
trend for superior performance in the young rats.
The young adult controls showed a higher swim speed relative to vehicle-treated old animals [factor age: F(1, 29) =
5.6, P = 0.025]. The swim speed decreased in the young
adult animals over the days starting at day 6 [factor day:
F(6, 279) = 5.267, P < 0.001]. The treatment with NADH
did not affect the swim speed neither in the young adult rats
nor in the old rats [factor group: F(3, 279) = 2.226, P =
0.102] (Table 1).
During the free swim trials on the ninth day, the
vehicle-treated old controls spent less time in the quadrant
of the maze where the escape platform was located in the
hidden-platform task compared to vehicle-injected young
adult controls [factor age: F(1, 78) = 11.125, P < 0.001].
Treatment with NADH increased the time spent in the
former platform quadrant [F(3, 78) = 2.826, P = 0.045] in
the old rats relative to old controls (Fig. 2A).
In the visible-platform task, the time it took the old
vehicle-injected animals to escape onto the platform was
significantly increased compared with young adult controls
(factor age: F(1, 79) = 16.392, P < 0.001); pretreatment with NADH had no impact on the escape latencies
[F(3, 79) = 1.873, P = 0.159] when the platform was
visible (Fig. 2B).
Fig. 1. Performance of young adult (A, hollow symbols) and old (B,
filled symbols). Wistar rats treated with NADH (10 mg/kg (䊏) 50 mg/kg
(䉱) 100 mg/kg (䉬)) or vehicle (䊉) 20 min before the daily sessions
in the hidden-platform version of the water maze shown by the mean
time in seconds it took the rats to find the platform (∗ P < 0.05 vs. old
controls, two-way ANOVA followed by the Holm–Sidak method). Data
are presented as mean ± S.E.M (n = 10–12). For better comparison the
young adult controls (䊊) are also included in graph B.
controls, as indicated by increased time to find the hidden platform over days [factor age: F(1, 78) = 54.523,
P < 0.001]. There was also a significant interaction between age and day [F(1, 78) = 51.2, P < 0.001], since the
performance of the young adult, but not of the old animals,
improved across daily sessions. Significant differences between the two groups were evident from the second day
onward (Fig. 1B).
The repeated treatment with NADH improved the navigation performance of the old animals in the hidden-platform
task [F(3, 279) = 3.347, P = 0.020].
Old rats treated with 100 mg/kg NADH showed a faster
acquisition of the navigation task [t = 3.110, P = 0.002].
Within-group comparisons revealed significantly shorter es-
3.2. Rota-rod test
In the rota-rod test the vehicle-injected old animals
showed a shorter latency to fall off the revolving drum
Table 1
Effect of motor abilities on the rota-rod performance and the maze performance of young adult and old Wistar rats treated with NADH or vehicle 20 min
before the daily sessions in the hidden-platform version of the water maze shown by the swim speed (cm/s; ∗ P < 0.05 vs. day 2; # P < 0.05 old vs.
young adult) and the time spent on the rota-rod (s; ∗ P < 0.05 vs. vehicle; # P < 0.05 old vs. young adult) analysed with a two-way ANOVA followed
by the Holm–Sidak method or the t-test
Day of
testing
Morris
Day
Day
Day
Day
Day
Day
Day
Young adult rats
Vehicle
Old rats
NADH
(10 mg/kg)
water maze: swimming speed (cm/s)
2
23.9 ± 1.9
24.7 ± 3.1
3
23.5 ± 1.5
24.0 ± 0.8
4
20.2 ± 1.6
21.6 ± 1.4
5
21.3 ± 1.3
20.9 ± 1.3
18.6 ± 1.1∗
6
18.4 ± 1.2∗
18.1 ± 1.0∗
7
19.7 ± 1.9∗
∗
17.9 ± 1.2∗
8
16.9 ± 0.9
Rota-rod: time spent on the rod (s)
Day 10
169 ± 24
160 ± 19
Data are presented as mean ± S.E.M (n = 10–12).
NADH
(50 mg/kg)
23.7
20.9
18.3
20.9
18.8
17.8
17.6
±
±
±
±
±
±
±
1.1
1.9
1.3
2.5
1.4
1.2
1.1
171 ± 13
NADH
(100 mg/kg)
28.3
21.4
21.0
21.1
19.0
17.6
16.4
±
±
±
±
±
±
±
2.4
2.3
1.5
1.7
1.6∗
1.2∗
1.4∗
127 ± 6∗
Vehicle
14.7
15.0
15.6
14.1
14.4
14.0
13.9
±
±
±
±
±
±
±
NADH
(10 mg/kg)
0.8#
0.8
0.7
0.8
0.6
0.7
0.9
103 ± 17#
13.0
14.1
14.7
14.5
13.4
13.4
13.7
±
±
±
±
±
±
±
0.8
0.7
0.8
0.6
0.6
0.9
0.8
99 ± 12
NADH
(50 mg/kg)
13.7
14.1
13.8
13.6
12.8
12.7
12.0
±
±
±
±
±
±
±
0.4
0.8
0.5
0.2
0.4
0.5
0.7
103 ± 16
NADH
(100 mg/kg)
13.5
14.6
13.5
12.6
12.5
11.7
11.2
±
±
±
±
±
±
±
0.5
0.6
0.6
0.7
0.9
1.0
0.8
92 ± 10
152
A. Rex et al. / Behavioural Brain Research 154 (2004) 149–153
Fig. 2. Mean time spent in the former target quadrant during the spatial
probe (A) in young adult (white bars) and old (striped bars) Wistar rats
treated with different doses of NADH or vehicle 20 min before the session
on the ninth day and the performance of young adult and old Wistar rats
in the Morris water maze cued version using a visible platform (∗ P < 0.05
young adult vs. old, # P < 0.05 vs. vehicle, two-way ANOVA followed by
Holm–Sidak method). Data are presented as mean ± S.E.M (n = 10–12).
relative to young adult controls [F(1, 78) = 14.266, P <
0.001], indicating a decline in motor coordination (Table 1).
The treatment with NADH had no effects on the age-related
motor deficits [F(3, 78) = 0.739, P = 0.532] (Table 1).
4. Discussion
The present study confirms earlier findings that old rats
show a definitive cognitive decline in the water maze and
have impaired motor functions [13,15,30]. It is well-known
that the performance in the Morris water maze is declining
with increasing age of the animals [11]. The inferior performance could be induced partly by changes in motor abilities,
but aged rats also show, like humans, alterations in cognitive performance [29]. Changes in the water maze behaviour
seem to occur at the same time as changes in brain regions
involved with cognition, e.g. the hippocampus [14].
In the present study a positive action of NADH on
age-related learning deficits in the Morris water maze could
be shown. While the repeated treatment with NADH had
no effect in young adult rats, it counteracted the age-related
navigation deficits of old rats, shown by the delayed learning of the escape response in the hidden-platform version
of the maze. Additionally, in the spatial probe session the
NADH-treated rats spent more time in the former platform
quadrant (target quadrant) than the vehicle-treated old rats,
indicating a higher spatial accuracy. The specificity of the
NADH-effect on processes related to spatial learning and
memory processes is supported by the lack of effect on
motor performance, as measured by the swimming speed,
and on visually guided behaviour, determined in the morris
water maze cued version using a visible platform. Compared to old vehicle-treated animals the swim speed of the
rats treated with NADH was similar and the escape latency
of old rats in the visible-platform task was not dependent
on the treatment.
Furthermore, the rats were also evaluated in the rota-rod
test to investigate possible alterations in motor activity
and/or performance, respectively. The rota-rod test is one of
the tests commonly used in the context of motor function,
endurance and balance [8,19]. In the rota-rod test, performance of the old rats was significantly impaired, compared
to the young rats. However, NADH did not alter the rat’s
performance in the rota-rod test.
The mechanisms underlying the actions of NADH in the
brain are not known precisely yet. Apparently, two possible
mechanisms of action might contribute to the mnemotropic
effect of NADH in the old rats.
One possible mechanism of action could include a stimulation of dopamine function [20], since an in vitro study
showed that NADH stimulates dopamine synthesis via an increased activity of the tyrosin hydroxylase [31]. It is widely
accepted that dopamine neurons play an important role in
the regulation of cognitive functions [21,24]. A clinical microdialysis study demonstrated a sustained activation of the
mesolimbic dopaminergic system with an increased release
of dopamine during performance of cognitive tasks [12].
More specifically, transgenic mice lacking dopamine-1A receptors, showed an impaired performance in the Morris water maze without swimming disabilities [28]. The dopamine
antagonist haloperidol impair also learning [25] while application of the dopamine D1 receptor agonists SKF 38393
and SKF 81297 enhanced performance in memory-impaired
aged rats [17].
Secondly, the functions of the central nervous system are
closely linked to the energy metabolism in the neurons [1].
Mitochondrial defects are described in a wide spectrum of
human illnesses, including degenerative diseases of the central nervous system and aging [32]. For example, the deficiency in cytochrome c oxidase is the most invariable defect
in mitochondrial electron transport enzymes in Alzheimers
disease [6].
NADH is an essential substrate for the energy transfer in
the mitochondrial respiratory chain [9]. Targets of NADH
include NAD+ /NADH dependent enzymes as the mitochondrial cytochrome c oxidase [34] or the NADH oxidoreductase, which is coupled to the mitochondrial respiratory chain
[18]. Additional supply could restore function of these mitochondrial enzymes.
In conclusion, our data indicate that NADH may counteract learning deficits occurring in the course of brain
aging, since a memory-enhancing effect of repeated NADH
treatment was evident in old, but not young adult rats.
A. Rex et al. / Behavioural Brain Research 154 (2004) 149–153
The difference was not only visible in the hidden-platform
version but also in the water maze spatial probe trial, indicating that NADH also improved retention of the learned
task. However, we have yet to address the underlying neurobiological mechanisms causing the enhanced cognitive
performance of the NADH-treated rats.
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