European Journal of Pharmacology 779 (2016) 59–65

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Neuropharmacology and analgesia

Piracetam prevents memory deficit induced by postnatal propofol

exposure in mice
Yuan-Lin Wang a,1, Feng Li b,1, Xin Chen a,n
a
Department of Anesthesiology, Huai’an First People's Hospital, Nanjing Medical University, Huai’an 223300, China
b
Department of Anesthesiology, the First People's Hospital of Yancheng, Yancheng 224006, China

art ic l e i nf o a b s t r a c t

Article history: Postnatal propofol exposure impairs hippocampal synaptic development and memory. However, the
Received 8 November 2015 effective agent to alleviate the impairments was not verified. In this study, piracetam, a positive allosteric
Received in revised form modulator of AMPA receptor was administered following a seven-day propofol regime. Two months after
22 February 2016
propofol administration, hippocampal long-term potentiation (LTP) and long-term memory decreased,
Accepted 4 March 2016
while intraperitoneal injection of piracetam at doses of 100 mg/kg and 50 mg/kg following last propofol
Available online 5 March 2016
exposure reversed the impairments of memory and LTP. Mechanically, piracetam reversed propofol ex-
Keywords: posure-induced decrease of BDNF and phosphorylation of mTor. Similar as piracetam, BDNF supple-
Propofol mentary also ameliorated propofol-induced abnormalities of synaptic plasticity-related protein expres-
Piracetam
sions, hippocampal LTP and long-term memory. These results suggest that piracetam prevents detri-
BDNF
mental effects of propofol, likely via activating BDNF synthesis.
Memory
Long-term Potentiation & 2016 Elsevier B.V. All rights reserved.

1. Introduction effectively reverse the impairments of hippocampal LTP and

Propofol is thought to be a safe general anesthetic in young
population. However, adverse effects after propofol administration
in central nervous system were still reported (Quan et al., 2013;
Veselis et al., 2004). As an allosteric potentiator and agonist of γ-
aminobutyric acid receptors α (GABARα) (Davies et al., 1998),
propofol is conceivable to induce acute effect on memory. Like-
wise, long-term effect after propofol administration in postnatal
animals also attracts wide attention. Previously, we and others
reported that repeated postnatal propofol exposure effects on
dendritic spine formation and synaptic plasticity-related proteins,
but not affects pyramidal neuronal death to impair hippocampal
long-term potentiation (LTP) and memory (Gao et al., 2014; Wang
et al., 2015a, 2015b). It is of potential interest to find effective
compound which has capacity to reduce the adverse effect in-
duced by propofol anesthesia.
As evidenced by our studies and others, propofol challenge at
early postnatal phase impaired hippocampal LTP (Gao et al., 2014;
Wang et al., 2015a, 2015b). Phosphatase and tensin homolog de-
leted on chromosome ten (PTEN) level was elevated after propofol
application and PTEN inhibitor-bisperoxovanadium (bpV) could
n
Correspondence to: Department of Anesthesiology, Huai’an First People’s
Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, Jiangsu 223300,
China.
E-mail address: xin_chen12@163.com (X. Chen).
1
Equal contribution.
memory (Wang et al., 2015b). However, bpV was applied before
propofol and possibly attenuated the anesthesia effects. The ef-
fective agent, with the potential to rescue propofol-induced da-
mages was more attractive.
Piracetam is a positive allosteric modulator of α-Amino-3-hy-
droxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs)
and hypothesized to act on ion channels or ion carriers, leading to
increase of neuronal excitability. Moreover, AMPAR stimulation is
supposed to be a useful method to repair deficits of hippocampal
synaptic plasticity and memory (Baudry et al., 2012). Although it
was still in debate regarding the use of piracetam in dementia or
cognitive impairment (Croisile et al., 1993), potential memory
enhancing effects of piracetam should take reconsideration (Fang
et al., 2014; Grossman et al., 2011; Kosta et al., 2013; Muley et al.,
2013).
In this study, we administered piracetam following a seven-day
propofol regime to explore the memory rescuing effect and its
mechanisms. We found that piracetam treatment following pro-
pofol exposure reversed propofol-induced decrease of brain de-
rived neurotrophic factor (BDNF) expression. Moreover, exogenous
BDNF following propofol administration has the similar activities
as piracetam to rescue the impairments of LTP and memory deficit.

http://dx.doi.org/10.1016/j.ejphar.2016.03.013
0014-2999/& 2016 Elsevier B.V. All rights reserved.
60 Y.-L. Wang et al. / European Journal of Pharmacology 779 (2016) 59–65
2. Materials and methods
2.1. Animal and treatments
Postnatal male C57 mice (day 7) were housed in a pathogen-
free colony under a 12
h dark/light cycle at 24 °C. All protocols
and procedures used were approved by the Institutional Animal
Care and Utilization Committee of Nanjing Medical University. The
mice were administrated with propofol (75 mg/kg, 100 μl, i.p.)
once per day for consecutive 7 days as previously demonstrated
(Gao et al., 2014). Control mice received the same volume of saline.
Three h after last propofol challenge, the mice were in-
traperitoneally (i.p.) injected with piracetam (Purity 498%, Sigma,
USA) at doses of 100 mg/kg, 50 mg/kg and 25 mg/kg one time as
previously described (Abdel-Salam et al., 2011). Piracetam was
dissolved in DMSO and diluted in saline (final concentration of
DMSO was less than 0.1%). Control mice received the same volume
of vehicle (DMSO in saline). 3 h after last propofol application,
some of the mice received one time of intracerebroventricular
injection of BDNF (5 μg/animal in 5 μl of PBS) through stereotactic
injection (Han and Holtzman, 2000) (2.0 mm rostral, 1.5 mm lat-
eral, and 2.0 mm deep). Two months after treatments, the mice
received electrophysiological and behavioral tests.
2.2. Fear conditioning test
Fear conditioning task was applied to test the long-term
memory. Two months after treatment, behavioral task was carried
out as previously demonstrated (Wang et al., 2015a, 2015b).
Briefly, mice were placed in a fear-conditioning chamber to get a
5-min exploration (Stoelting Instruments). Three tone-footshock
pairings separated by 1 min interval were delivered on the train-
ing day. The 80 dB tone (2 kHz) lasted for 30 s, and the footshocks
(0.70 mA) lasted for 2 s. Context memory was completed one day
after training. Animals were subjected to tone test on day three.
The Freeze Frame Software was applied to record the freezing
time. Motionless lasting more than 1 s was considered as freezing.
The percent of time of freezing was calculated blindly by an
experimenter.
2.3. Hippocampal slice preparation and electrophysiology
After decapitation, brains were quickly removed and then
transferred to oxygenated, ice-cold cutting medium with a recipe
as previously described (Zhu et al., 2015b). Transversal hippo-
campal slices (300-μm thick) were prepared using a vibration
microtome (Leica, German) and transferred to an interface re-
cording chamber (Warning, USA). The slices were incubated in
aCSF for at least 1 h for recovery. For field excitatory postsynaptic
potential (fEPSP) recording, a single glass pipette filled with 4 M
NaCl was used. Twisted nichrome wires placed in CA1 stratum
radiatum were used to stimulate excitatory response at Schaffer
collateral–CA1 synapses. The data were acquired by a digitizer
1550A (Axon, USA) and amplified by differential amplifier (DAM
50, World Precision Instruments, USA) (10 kHz high-pass and
0.1 Hz low-pass filter). pCLAMP 10 software (Axon, USA) was used
to analyze the slope of fEPSP. LTP was induced by a protocol of
theta-burst stimulation (TBS, 10 bursts of 4 pulses at 100 Hz de-
livered at 5 Hz).
2.4. Western blots
24 h after piracetam or BDNF treatment, dorsal hippocampus
was isolated and homogenated for BDNF and mTor measurement.
In addition, as referred by our previous studies (Wang et al., 2015a,
2015b), p-CamKIIα, p-PKA and PSD-95 were evaluated two
months after propofol application. Dorsal hippocampus homo-
genates were lysed for protein isolation. BCA protein assay kit was
applied to analyze the protein concentrations (Thermo, USA). After
sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-
PAGE) and blots transferring, primary antibodies against BDNF
(1:2000, Cell Signaling Technology, Danvers, MA, USA), proBDNF
(1:2000, Cell Signaling Technology, Danvers, MA, USA), p-CamKIIα
(1:2000, Millipore, Bedford, MA, USA), CamKIIα (1:2000, Millipore,
Bedford, MA, USA), p-PKA (1:2000, Millipore, Bedford, MA, USA),
PKA (1:2000, Millipore, Bedford, MA, USA), PSD-95 (1:2000, Mil-
lipore, Bedford, MA, USA), mTor (1:1000, Santa Cruz, USA), p-mTor
(Ser 2448) (1:1000, Santa Cruz, USA) and Actin (1:3000, Cell Sig-
naling Technology, Danvers, MA, USA).
2.5. Real-time PCR
Total RNA was extracted using Trizol reagent kit (Invitrogen,
Carlsbad, USA) to analyze BDNF mRNA transcript. Reverse tran-
scription was carried out using random primer and Moloney-
murine leukemia virus reverse transcriptase (Promega, Madison,
USA). Real-time PCR was performed for the quantification of BDNF.
Relative expression values were calculated as the ratio of target
cDNA to Actin. The primers used in real-time PCR were presented
as following:
BDNF sense primer 5-GGGTCACAGCGGCAGATAAA-3; BDNF
antisense primer 5-GCCTTTGGATACCGGGACTT-3; Actin sense pri-
mer 5-ATGAGGTAGTCTGTCAGGT-3; Actin antisense primer
5-ATGGATGACGATATCGCT-3.
2.6. Statistical analyses
Data were presented as means 7S.E.M and analyzed by
Graphpad Prism software. Two-tail student t-test was used to
determine statistical significance between two groups. When
more than two groups were compared, one-way ANOVA followed
by a Newman–Keuls post hoc test was used to determine statis-
tical significance. Po0.05 were considered statistically significant.
3. Results
3.1. Piracetam promoted BDNF expression in propofol-challenged
mice
The food intake and weight of the mice were monitored every
day during the experiments. There was no obvious difference
among groups. We detected the BDNF expression by Western
blotting and real-time PCR. As shown in Fig.1A, propofol regime
significantly reduced hippocampal BDNF level 24 h after last pro-
pofol application. Piracetam at middle dose (50 mg/kg) or high
dose (100 mg/kg) significantly enhanced BDNF expression com-
pared with propofol model group. Results from RT-PCR showed
that BDNF at mRNA level was not affected by propofol or pir-
acetam (Fig.1B). These results suggested that BDNF maturation or
synthesis were inhibited by propofol challenge. That idea was
further supported by the altered expression of pro-BDNF level
(Fig.1C). In addition, we detected mTor activity, which is important
for protein synthesis. As shown in Fig.1D, p-mTor was significantly
decreased after propofol challenge. Consistent with BDNF ex-
pression, p-mTor level was also enhanced after middle or high
dose of piracetam treatment. Total mTor level was not affected by
either propofol or piracetam treatment (Fig.1D).
3.2. Piracetam rescues memory deficit challenged by propofol
As piracetam reversed propofol-induced decrease of BDNF
 Y.-L. Wang et al. / European Journal of Pharmacology 779 (2016) 59–65 61

Fig. 1. Piracetam enhanced BDNF expression in propofol challenged mice. A) Propofol challenge decreased BDNF level, which was eliminated by middle dose and high dose
of piracetam treatment. Piracetam at high dose did not affect BDNF level in control mice; B) Propofol challenge and piracetam did not affect BDNF mRNA transcript; C)
Propofol challenge decreased proBDNF level, which was eliminated by high dose of piracetam treatment. Piracetam at high dose did not affect proBDNF level in control mice;
D) Propofol challenge decreased p-mTor level, which was eliminated by middle dose and high dose of piracetam treatment. Piracetam at high dose did not affect p-mTor
level in control mice. Data were presented as mean and S.E.M. The values were obtained from five animals in each group. *P o 0.05 compared with control, $P o 0.05
compared with propofol.

level, we asked whether piracetam reversed the memory deficit in
propofol-challenged mice. Two months after indicated drug
treatments, long-term memory was detected by a fear condition-
ing task. As shown in Fig. 2A, context memory after propofol ex-
posure significantly decreased compared with control group. By
contrast, piracetam at middle (50 mg/kg) and high dose (100 mg/
kg) effectively reversed propofol-induced memory impairment.
Piracetam administrated in the control mice did not further in-
crease the context memory. A consistent result was found in the
cue memory (Fig. 2B). By contrast, one time injection of high dose
of piracetam at adult phase did not affect both of context memory
and cue memory in control and propofol-challenged mice (Fig.2C,
D). By contrast, intracerebroventricular injection of BDNF 2 h after
postnatal propofol administration reversed the context and cue
memory (Figs. 2E,F), but did not further increase memory in
control mice.
3.3. Piracetam rescues hippocampal long-term potentiation
We induced LTP at Schaffer Collatera-CA1 synapses to confirm
the protective effect of piracetam. As shown in Fig.3A,B,C, post-
natal propofol exposure impaired the hippocampal LTP, which was
reversed by piracetam injection. As a positive control, exogenous
BDNF could also reverse the LTP deficit challenged by propofol
(Fig. 3B). By contrast, piracetam or BDNF alone did not affect the
LTP in control mice.
3.4. Piracetam activates PKA, CamKII and increases PSD-95 expres-
sion challenged by Propofol
We also detected hippocampal p-CamKII, PSD-95 and p-PKA
levels. As shown in Fig. 4, propofol application decreased the ex-
pressions of p-CamKII (Fig. 4A,B), p-PKA (Fig. 4A,C) and PSD-95
62 Y.-L. Wang et al. / European Journal of Pharmacology 779 (2016) 59–65

Fig. 2. Early treatment with Piracetam rescues memory deficit challenged by propofol. A) Propofol challenge decreased context memory, which was inhibited by early
middle dose and high dose of piracetam treatment. Piracetam at high dose did not affect context memory in control mice. The values were obtained from five animals in each
group; B) Propofol challenge decreased cue memory, which was revered by middle dose and high dose of piracetam treatment. Piracetam at high dose did not affect cue
memory in control mice; C, D) Piracetam treatment at adult phase did not rescue the deficits in both of context memory and tone memory. E) BDNF supplementary rescued
the context memory in mice challenged by propofol; F) BDNF supplementary rescued the cue memory in mice challenged by propofol; Data were presented as mean and S.E.
M. *P o 0.05 compared with control. $P o 0.05 compared with propofol group.

(Fig. 4A,D). However, the decreases of those proteins were re-
versed by piracetam injection. Similarly, exogenous BDNF injection
also enhanced expressions of p-CamKII, PSD-95 and p-PKA in
propofol challenged mice. At this time point, BDNF level was also
detected. However, BDNF in different groups were not altered
(Fig. 4E,F).
4. Discussion
Although PTEN inhibitor bpV prevented propofol-induced
memory deficit (Wang et al., 2015b), pre-propofol administration
might affect the anesthesia effect. The most attractive strategy is to
treat the propofol-challenged mice post anesthesia. In this study,
piracetam was applied three h after propofol exposure. Interest-
ingly, this treatment regime could rescue the memory deficit.
Potential mechanism was related to BDNF synthesis, as exogenous
BDNF could also ameliorate the memory deficit, hippocampal LTP
and expressions of synaptic plasticity-related proteins.
In our previous study, we demonstrated that PTEN level was
elevated after propofol exposure (Wang et al., 2015b). The accu-
mulation of PTEN is possibly due to the calpain inactivation, as
PTEN is a potential substrate of Calpain (Wang et al., 2014). In fact,
during propofol anesthesia, GABA receptor activation would lead
to inactivation of excitatory receptors. As reported, Calpain acti-
vation following NMDARs is critical for memory formation and
 Y.-L. Wang et al. / European Journal of Pharmacology 779 (2016) 59–65 63

Fig. 3. Piracetam rescues hippocampal long-term potentiation. A) Propofol challenge decreased hippocampal LTP, which was rescued by high dose of piracetam treatment;
B) The response traces for the baseline point (grey) and the 120th time point (black). Scar bar: 0.5 mV/5 ms; C) Quantification data of the LTP level at 120th minute in
different groups. Data were presented as mean and S.E.M. *P o 0.05 compared with control. $P o0.05 compared with propofol group.

hippocampal LTP (Briz et al., 2013; Zhu et al., 2015b). PTEN is a
negative regulator of Akt signaling pathway. The rising PTEN fol-
lowing propofol administration inactivates Akt. Although Akt sig-
naling pathway is critical for dendritic spine formation (Zhu et al.,
2015c), the downstream pathway was still not clear. In our present
study, following propofol administration, BDNF level decreased
transiently, accompanying by the decrease of mTor activity. In-
terestingly, BDNF at mRNA level was not affected, which indicated
that only translation level was affected by propofol. In fact, den-
drite mRNA was found to take part in the protein synthesis after
synaptic activation (Steward and Worley, 2001).
BDNF is an important regulator not only in synaptic activation
(Nagappan and Lu, 2005), but also in memory formation (Alonso
et al., 2005). In addition, BDNF is also critical for synaptic devel-
opment. BDNF supplementary increased synapse density in den-
drites of developing tectal neurons in vivo (Sanchez et al., 2006). In
addition, BDNF exerts a serial of functions in ameliorating the
memory deficit in pathological models (Lu et al., 2013; Zhu et al.,
2015a) through synaptic activation. In our recent study, we also
confirmed that piracetam could stimulate BDNF synthesis in pro-
pofol challenged mice.
Piracetam is a positive allosteric modulator of the AMPA re-
ceptors and it was suggested to activate NMDA receptors. Activa-
tion of excitatory receptors leads to BDNF synthesis and synaptic
activation (Obrietan et al., 2002; Perez-Gomez and Tasker, 2013).
Ampakine is a distinguished agent which could activate BDNF
release through activating AMPA receptors (Lauterborn et al.,
2009; Simmons et al., 2009). Synaptic activation, by blocking GABA
receptors or stimulating AMPA receptors or NMDA receptors could
also lead to BDNF synthesis (Verpelli et al., 2010). In our study,
BDNF level was selectively rescued by piracetam in propofol-
challenged mice in the early phase. While in control mice, BDNF
level was not stimulated by piracetam. Moreover, the BDNF level
in adult phase in propofol group was comparable to control group.
We concluded that piracetam could only depolarize pyramidal
neurons and promote BDNF synthesis in the propofol treated
newborn animals transiently.
Although the memory enhancing effect of piracetam was still in
debate and also the doses using in the memory facilitation were
pretty high in disease models (Bang et al., 2015), we found that
50 mg/kg piracetam was sufficient to reverse propofol-induced
decrease of BDNF synthesis in the newborn animals. Piracetam is a
cognition-enhancing drug with many beneficial properties. It im-
proves memory and learning ability. However, in our study, we did
not find obvious effect of piracetam in control mice. The dis-
crepancy might be caused by the relative low doses used in this
study. As referred by previous publication, 2-fold dose of pir-
acetam was applied in memory enhancing in adults (Bang et al.,
64 Y.-L. Wang et al. / European Journal of Pharmacology 779 (2016) 59–65

Fig. 4. Piracetam activates PKA, CamKII and increases PSD-95 level. A) Representative blots of p-CamKII, p-PKA and PSD-95; B) Quantification data of p-CamKII expression;
C) Quantification data of p-PKA expression; D) Quantification data of PSD-95 expression; E) BDNF level at adult phase in different groups were comparable; F) Quantification
data of BDNF expression. Data were presented as mean and S.E.M. The values were obtained from five animals in each group. *P o 0.05 compared with control. $P o 0.05
compared with propofol group.

2015). It is also possible that propofol-elicited hyperpolarization or
the signaling pathways could be reversed by piracetam-induced
synaptic activation in a limited time period. Consistently, a similar
dosage of piracetam (50 mg/kg) treatment at adult phase in pro-
pofol-challenged mice did not rescue the memory deficit.
CamkII and PKA are critical enzymes responsible for synaptic
plasticity and memory (Huang and Kandel, 1994; Impey et al.,
1998; Korte et al., 1995). The abnormalities of those signaling
pathways lead to impairment of synaptic plasticity, especially LTP.
In this and previous publications, the phosphorylation levels of
CamkII and PKA remarkably decreased in the mice challenged by
propofol (Wang et al., 2015b). These results were consistent with
the LTP and memory impairment. In addition, PSD-95, the post-
synaptic protein was also down-regulated after propofol challenge.
Piracetam treatment reversed the abnormalities of those proteins.
5. Conclusions
In this study, we found a novel role of piracetam in early
postnatal propofol model. Following propofol, piracetam could
 Y.-L. Wang et al. / European Journal of Pharmacology 779 (2016) 59–65
ameliorate the deficits of hippocampal LTP and memory due to
propofol challenge. We also evidenced that piracetam stimulated
mTor dependent BDNF synthesis to exert the functions.
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