Short communication
Influence of the phosphodiesterase type 5inhibitor, sildenafil, on antidepressant-likeactivity of magnesium in the forced swim testin mice
Katarzyna Soca³a1, Dorota Nieoczym1, Ewa Poleszak2, Piotr WlaŸ1
Department of Animal Physiology, Institute of Biology and Biochemistry, Maria Curie-Sk³odowska University,Akademicka 19,PL 20-033 Lublin, Poland
Chair and Department of Applied Pharmacy, Medical University of Lublin, ChodŸki 1, PL 20-093 Lublin, Poland
Correspondence: Piotr WlaŸ, e-mail: [email protected] Abstract: Magnesium, which acts as an antagonist of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, exerts antidepressant- like activity in animal models of depression. The present study was undertaken to elucidate the influence of sildenafil, a phosphodi- esterase type 5 inhibitor, on the anti-immobility action of magnesium in the forced swim test in mice. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. Serum and brain magnesium levels were as- sayed spectrophotometrically. Magnesium at a dose of 30 mg/kg, ip significantly decreased the immobility time while sildenafil (5, 10 and 20 mg/kg, ip) in a dose-dependent manner reduced the antidepressant-like activity of magnesium. The co-administration of magnesium with sildenafil at the highest dose entirely abolished the antidepressant-like effect of magnesium and caused a statisti- cally significant increase in immobility duration as compared to the control group. Combination of magnesium with sildenafil re- sulted in a potent reduction (80%) of locomotor activity and pharmacokinetic studies showed a significant increase of magnesium concentration in serum (as compared to magnesium treatment alone) without changes within brain tissue in mice treated with mag- nesium and sildenafil. When given alone, sildenafil caused a significant increase in magnesium levels in both serum and brain. Our results indicate that a simultaneous treatment with magnesium and sildenafil results in hypermagnesemia in laboratory animals. However, the mechanism underlying this effect remains elusive. Key words: phosphodiesterase 5, sildenafil, magnesium, depression, erectile dysfunction, antidepressant, forced swim test, mice Introduction
PDE5) cell signaling pathway [6]. During sexual
Sildenafil, an active compound of Viagra, is the first-
stimulation, corpus cavernosum nerves and endothe-
line oral treatment for erectile dysfunction of multiple
lial cells release NO, which via guanylate cyclase ac-
etiologies. The mechanism of action of sildenafil in-
tivation promotes cyclic guanosine 3´,5´-monopho-
volves the nitric oxide/cyclic guanosine 3´,5´-mono-
sphate (cGMP) production. Cyclic GMP, in turn, al-
Pharmacological Reports, 2012, 64, 205211
lows corporal smooth muscle cells relaxation and
zures [2, 14]. Magnesium deficiency is quite com-
leads to an erection. The intracellular level of cGMP
mon. In general population, hypomagnesemia is
is regulated by PDE5 – an enzyme which hydrolyzes
estimated at 6.9% but it varies greatly depending on
cyclic nucleotides. Sildenafil works as a selective in-
patients’ general condition [14]. Numerous magne-
hibitor of PDE5. By inhibiting cGMP degradation, it
sium dietary supplements are available on the market
improves the relaxation of smooth muscles in the cor-
and magnesium supplementation is an important issue
pus cavernosum and thus resulting in erection [16,
in contemporary medicine. Moreover, it is one of the
44]. Sildenafil exerts various effects on the central
new emerging approaches in the treatment of depres-
nervous system. The recent data show that it pos-
sesses neuroprotective properties, enhances neuro-
Since both magnesium and sildenafil may alter glu-
tamatergic neurotransmission and magnesium supple-
The NO/cGMP pathway has also been implicated
mentation is of high probability in men taking silde-
in the neurobiology of depression. A number of ex-
nafil, the aim of the present study was to investigate
periments indicate that inhibitors of this pathway ex-
the effect of sildenafil on the antidepressant-like ac-
hibit antidepressant effects and enhance the efficacy
tivity of magnesium in the forced swim test in mice.
of serotonin reuptake inhibitors [17, 18, 20]. Nitric
In order to evaluate the potential pharmacokinetic in-
oxide plays an extremely important role in the central
teractions between sildenafil and magnesium, total
nervous system where it acts as a neuronal messenger.
brain and serum concentrations of magnesium were
It is involved in neurotransmission, synaptic plastic-
ity, perception of pain and learning [12]. The NO/cGMP pathway affects i.a., excitatory neurotransmis-sion mediated through the N-methyl-D-aspartate(NMDA) subtype of glutamate receptors [42]. Inter-
Materials and Methods
actions between NO/cGMP pathway and glutamater-gic neurotransmission are bidirectional. On the onehand, stimulation of NMDA receptor results in Ca2+
influx which leads to NO synthase activation and NOproduction. On the other hand, NO and cGMP modu-
The experiments were carried out on male Albino
late NMDA receptor activity and may regulate release
Swiss mice weighing 25–30 g, purchased from a li-
of glutamate by negative feedback mechanisms [18,
29, 42]. There is an increasing evidence for the in-
S³aboszów, Poland). The animals were housed in
volvement of NMDA-mediated neurotransmission in
groups of up to 10 mice in polycarbonate cages under
pathophysiology of depression and antidepressant-
standard laboratory conditions (temperature main-
like activity of NMDA receptor antagonists in animal
tained at 23–25°C, humidity 50–60% and 12 h
studies [19, 32, 33, 45]. Magnesium, which blocks the
light/dark cycle, lights on at 06:00 h) with free access
NMDA receptor channel in a voltage-dependent fash-
to food pellets (Murigran, Agropol S.J., Motycz, Po-
ion, also exhibits antidepressant activity in animal
land) and tap water. All experiments were performed
studies and clinical trials [7, 38, 40]. It is also active
following at least 7 days of acclimatization. The ex-
in an animal model of mania [1]. This second most
perimental protocols were approved by the Ethical
abundant intracellular cation plays a fundamental role
Committee of the Medical University in Lublin
in innumerable regulatory processes. It participates in
(license number 69/2009) and all procedures were in
over 325 different enzymatic reactions such as hy-
accordance with the European Communities Council
drolysis of high-energy phosphate groups or nucleic
Directive of 24 November 1986 (86/609/EEC).
acid and protein synthesis. It regulates conductivity ofion channels and is involved in hormone receptor
binding, muscle contraction and neurotransmitters re-lease [11, 13]. Therefore, magnesium depletion brings
Magnesium hydroaspartate (Farmapol, Poznañ, Poland)
about dramatic clinical implications ranging from hy-
and sildenafil citrate (Polpharma, Starogard Gdañski,
pertension, arrhythmias and neuromuscular hyperex-
Poland) were dissolved in saline and administered
citability to acute myocardial infarction or even sei-
intraperitoneally (ip) at a volume of 10 ml/kg, 30 min
Pharmacological Reports, 2012, 64, 205211
Sildenafil and antidepressant-like activity of magnesium
before the respective test. The dosage of magnesium
able reagent (Liquick Cor-Mg, Cormay, Lublin, Po-
refers to pure magnesium ions. Control animals re-
land) and reaction mixture absorbance was measured
ceived an ip injection of saline. The doses and pre-
at 520 nm employing a spectrophotometer (Hitachi
treatment schedules were selected on the basis of
U-3010, Tokyo, Japan). The magnesium concentra-
those reported in the literature and previous experi-
tions were expressed in mg/100 ml for serum and µg/g
ments from our laboratory [29–31, 35–38]. Forced swim test Statistical analysis
The test was conducted according to the method de-
All results are presented as the means ± standard error
scribed by Porsolt et al. [41]. Mice were placed indi-
of the mean (SEM) and evaluated by using one-way
vidually in glass cylinders (height 25 cm, diameter
analysis of variance (ANOVA) followed by Student-
10 cm). The cylinders contained 10 cm of water main-
Newman-Keuls post-hoc test for multiple comparison
tained at 23–25°C. Animals were allowed to swim for
or by unpaired Student’s t-test, where appropriate. A p
6 min. Total duration of immobility was recorded dur-
value less than or equal to 0.05 was considered to be
ing the last 4 min of the test. The duration of immobil-
ity was defined as the time when the mouse remainedfloating passively, made no attempts to escape andshowed only slow movements to keep its head abovethe water. Locomotor activity Forced swim test
Locomotor activity of mice was determined by using
The effect of magnesium, alone and in combination
actimeters (30 cm diameter, 12 cm high, MultiServ,
with sildenafil, on immobility time in the forced swim
Lublin, Poland) equipped with two perpendicular in-
test in mice is shown in Figure 1 (one-way ANOVA:
frared light beams located 1.5 cm above the floor.
F (4, 51) = 35.080; p < 0.001). Magnesium at a dose
Mice were placed individually in an actimeter for
of 30 mg/kg significantly decreased immobility time
5 min. After acclimatization, locomotor activity was
from 193.80 ± 4.38 s in the control group to 132.00
recorded as the number of interruptions of light beams
± 5.69 s (p < 0.001). Sildenafil in a dose-dependent
Determination of serum and brain magnesium concentration
After drug pretreatment, mice were sacrificed by de-capitation and the trunk blood was collected in poly-ethylene tubes. Serum was isolated 1 h after blood co-agulation by centrifugation at 5,000 × g for 10 min at4°C and frozen at –30°C. The brains were rapidly re-moved after decapitation, washed in saline and ho-mogenized (PRP 200, PRO Scientific Inc., Connecti-cut, USA) in 0.1 M phosphate buffered saline (pH7.4) at 26,000 rpm for 3 min at 4°C. The homogenateswere centrifuged at 21,000 × g for 30 min at 4°C andthe supernatant was frozen at –30°C. Fig. 1. The effect of sildenafil on the antidepressant-like activity of
Total magnesium concentration in serum and brain
magnesium in the forced swim test in mice. Magnesium and sildenafilwere administered ip 30 min before the test. Each experimental
homogenates was determined by using xylidyl blue
group consisted of 10–12 animals. Data are presented as the means
method. Ten microliters of thawed serum or brain su-
± SEM. ** p < 0.01, *** p < 0.001 vs. saline-treated group; p < 0.05,
p < 0.001 vs. magnesium-treated group (one-way ANOVA with
pernatant was mixed with 1 ml of commercially avail-
Student-Newman-Keuls post-hoc test)
Pharmacological Reports, 2012, 64, 205211
manner reduced the antidepressant-like activity of
mice is shown in Table 1 (one-way ANOVA: F (5, 53)
magnesium. The combination of magnesium with
= 7.710; p < 0.001). Sildenafil, at any dose tested, as
sildenafil at the highest dose of 20 mg/kg entirely
well as magnesium administered alone did not affect
abolished the antidepressant-like effect of magnesium
locomotor activity in mice. The combined administra-
and caused a statistically significant increase in total
tion of magnesium with sildenafil at the highest dose
duration of immobility as compared to saline-treated
of 20 mg/kg significantly reduced the activity counts
(p < 0.001 vs. the control group and magnesium-treated group). Locomotor activity Effect of sildenafil on serum and brain
The effect of sildenafil and combined administration
magnesium concentration
of sildenafil and magnesium on locomotor activity in
The effects of combined administration of magnesiumand sildenafil on serum (one-way ANOVA: F (2, 30)
Tab. 1. Effect of sildenafil and magnesium administered separately
= 118.92; p < 0.001) and brain (one-way ANOVA:
or jointly on spontaneous locomotor activity in mice
F (2, 30) = 4.169; p = 0.025) magnesium concentra-tions in mice are shown in Table 2. The administration
of magnesium at a dose of 30 mg/kg significantly in-
creased the concentration of magnesium in serum
(p < 0.001) as well as in the brain (p < 0.05) as com-pared to saline-treated group. Co-administration of
magnesium with sildenafil (20 mg/kg) caused an
additional increase in serum magnesium levels with
no effect on magnesium concentration within the
Magnesium (30 mg/kg) + sildenafil (20 mg/kg)
brain (p < 0.001 and p > 0.05 as compared to magne-sium-treated group, respectively).
Magnesium and sildenafil were administered ip 30 min before thetest. Each experimental group consisted of 9–10 animals. Data are
The influence of sildenafil administered alone on
presented as the means ± SEM. = p < 0.001 vs. saline-treated group;
serum (t-test p < 0.001) and brain (t-test p < 0.001)
> p < 0.001 vs. magnesium-treated group (one-way ANOVA withStudent-Newman-Keuls post-hoc test)
magnesium level is shown in Table 2. Sildenafilcaused a statistically significant increase in magne-sium concentrations in both serum and brain. Tab. 2. Effect of magnesium and sildenafil administered separately or jointly on serum and brain magnesium concentrations in mice Discussion
In recent years, there has been an increased interest in
A. Saline + saline
the involvement of magnesium in the pathophysiology
and treatment of depression. Magnesium deficiency isbelieved to contribute to mood disorders in spite of the
fact that blood tests of depressed patients provide fre-quently contradictory results. Serum/plasma levels of
B. Saline
magnesium ions in depressives may be elevated, de-
creased or may remain unchanged [10, 11, 24]. Nu-merous studies indicate that magnesium possesses po-
Magnesium and sildenafil were administered ip 30 min before de-
tent antidepressant-like properties in the forced swim
capitation. Each experimental group consisted of 9–12 animals. Data are presented as the means ± SEM. A: = p < 0.05, > p < 0.001 vs.
test in rodents and anxiolytic-like activity in the ele-
saline-treated group; ? p < 0.001 vs. magnesium-treated group
vated plus maze test in mice. In addition, the anti-
(one-way ANOVA with Student-Newman-Keuls post-hoc test). B: = p < 0.01, > p < 0.001 vs. saline-treated group (Student’s t-test)
immobility action of imipramine, citalopram and tia-
Pharmacological Reports, 2012, 64, 205211
Sildenafil and antidepressant-like activity of magnesium
neptine as well as of NMDA receptor antagonists and
Magnesium also activates the activity of guanylate
glycine* receptor ligands is enhanced by joint admini-
cyclase which promotes cGMP formation [34]. Per-
stration of magnesium [7, 36, 37, 40]. Apart from data
haps the influence of sildenafil and magnesium, ad-
obtained in animal studies, magnesium supplementa-
ministered alone, on the GABAergic neurotransmis-
tion was reported to be effective in the treatment of
sion was too weak to impair locomotor activity in
major depressive disorder [10], rapid cycling bipolar
mice and only when administered jointly they cause
affective disorder [5] and mania [21]. The antidepres-
noticeable behavioral response. Data from pharma-
sant- and anxiolytic-like effects of magnesium are
cokinetic studies revealed, nevertheless, that a distinct
most likely related to its antagonist properties to the
mechanism could be responsible for the reduction of
spontaneous locomotor activity in mice after com-
The present study demonstrates that the anti-
bined treatment with sildenafil and magnesium. Co-
immobility action of magnesium in the forced swim
administration of these two substances resulted in
test in mice was reduced by sildenafil in a dose-
a significant increase in magnesium serum level (by
dependent manner. Interestingly, sildenafil, at the
78%), as compared with magnesium treatment alone,
highest dose used, not only entirely abolished the
without changes within brain tissue. Magnesium
magnesium-induced antidepressant effect but also
overload occurs rarely, mainly because of excessive
prolonged the duration of immobility as compared to
intake of magnesium or failure of its excretion. Hy-
the control group. These results could imply that com-
permagnesemia is manifested by hypotension, brady-
bined administration of magnesium and sildenafil
cardia, hyporeflexia, neuromuscular hypoexcitability
leads to depressogenic effects. As the combination of
and sedation [9, 46, 47]. Clinical symptoms of mag-
magnesium with sildenafil resulted in a potent reduc-
nesium overload may mimic central anesthetic effect.
tion (80%) of the locomotor activity, changes in the
But in fact, they are due to the peripheral action of
general motor function may have interfered with data
magnesium [9]. The brain magnesium concentration
is tightly regulated and the blood-brain barrier pro-
Locomotion and exploratory behavior are regulated
tects against acute changes in the magnesium concen-
and mediated by various types of neurotransmitter
tration. An acute increase in plasma magnesium con-
systems, in particular mesolimbic dopaminergic path-
centration is usually not associated with an increase in
ways [3, 8, 25, 27]. Sildenafil, which acts through the
brain intracellular magnesium concentration [11, 15,
NO/cGMP/PDE5 pathway, may affect both excitatory
40]. In most animals, serum magnesium level reaches
and inhibitory neurotransmission [42]. Likewise,
1.8–2.7 mg/100 ml and sedation becomes evident at
magnesium is involved in signal transmission within
serum magnesium level of 4–5 mg/100 ml [28]. It
the central nervous system. It acts as non-competitive
seems that sildenafil administered with magnesium
antagonist of NMDA receptors [39], modulates the
leads to hypermagnesemia, as in the present study
turnover of different neurotransmitters such as amino
sildenafil elevated serum magnesium levels up to
acids, neuropeptides, cytokines and nitric oxide [11]
6.5 mg/100 ml. Thus, sildenafil might have enhanced
and participates in binding of monoamines to their re-
magnesium absorption from the peritoneal cavity
ceptors [4]. A common site of action for sildenafil and
and/or it could have impaired magnesium renal excre-
magnesium may be the GABAA receptor. Increased
tion. To establish the mechanism accountable for this
GABAergic transmission causes sedation and may
effect, in a separate experiment we assayed serum and
lead to the reduction of locomotor activity [26].
brain magnesium levels after single administration of
Huang et al. [22] showed that increased cGMP con-
sildenafil without magnesium pre-treatment. The in-
centration evoked by sildenafil treatment enhances
creased serum magnesium concentration (by 13%)
the release of GABA, while Poleszak [35] suggests
after sildenafil treatment implies that hypermagne-
that anxiolytic-like effects of magnesium are related
semia, observed in former experiment, was rather due
to its ability to activate GABAA-gated chloride chan-
to the malfunctioning of magnesium transport in kid-
nels. In addition, synergistic interaction of magne-
neys than the excessive magnesium intake from the
sium with benzodiazepines (diazepam and chlordi-
azepoxide) in the elevated plus maze test in mice ar-
Mammalian magnesium transport across biological
gue for the involvement of benzodiazepine/GABAA
membranes is mediated by two main systems: Na+-
system in the anxiolytic activity of magnesium [35].
dependent and Na+-independent pathways. Although in-
Pharmacological Reports, 2012, 64, 205211
tracellular magnesium level is precisely regulated, the
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Pharmacological Reports, 2012, 64, 205211
16 Review ΠChemical structure of phenothiazines and their biological activity.
Agata Jaszczyszyn, Kazimierz G¹siorowski, Piotr „wi¹tek, Wies³aw Malinka, Katarzyna Cieœlik-Boczula, Joanna Petrus, Bogus³awa Czarnik-Matusewicz
24 Review Œ What™s the role of topiramate in the management of patients with hyperkinetic movement disorders?
Antonio Siniscalchi, Luca Gallelli, Chiara Giofrè, Giovambattista De Sarro
31 Review ΠAnimal models of acute renal failure.
Amrit Pal Singh, Arunachalam Muthuraman, Amteshwar Singh Jaggi, Nirmal Singh, Kuldeep Grover, Ravi Dhawan
45 Anxiogenic effect of CCK8s in the ventral hippocampus of rats: possible involvement
Akbar Hajizadeh Moghaddam, Robabeh Sadat Hosseini, Ali Roohbakhsh
54 Anxiolytic-like effect of losartan injected into amygdala of the acutely stressed rats.
Luis H. Llano López, Fernando Caif, Sebastián García, Miriam Fraile, Adriana I. Landa, Gustavo Baiardi, José V. Lafuente, Jan J. Braszko, Claudia Bregonzio, Pascual A. Gargiulo
64 Sub-chronic exposure to noise affects locomotor activity and produces anxiogenic and depressive like behavior in rats.
70 Repeated administration of caffeine induces either sensitization or tolerance of locomotor stimulation depending on the environmental context.
Roberta Zancheta, Ana P.M. Possi, Cleopatra S. Planeta,
78 Chronic ethanol tolerance as a result of free-choice drinking in alcohol-preferring rats of the WHP line.
84 Analgesia and serum assays of controlled-release dihydrocodeine and metabolites in cancer patients with pain.
Wojciech Leppert, Przemys³aw Miko³ajczak, Ewa Kamiñska, Micha³ Szulc
94 Central effect of crocin on penicillin-induced epileptiform activity in rats.
Esmaeal Tamaddonfard, Nasrin Hamzeh Gooshchi, Sona Seiednejad-Yamchi
102 Analgesic and anticonvulsant activity of new derivatives of 2-substituted 4-hydroxybutanamides in mice.
Kinga Sa³at, Katarzyna Kulig, Robert Sa³at, Barbara Filipek, Barbara Malawska
113 Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery.
Pawe³ Wiczling, Agnieszka Bienert, Pawe³ Sobczyñski, Roma Hartmann-Sobczyñska, Krzysztof Bieda, Aleksandra Marcinkowska, Maria Malatyñska, Roman Kaliszan, Edmund Grzeœkowiak
123 Influence of 825 C>T polymorphism of G protein b3 subunit gene (GNB3) on hemodynamic response during dobutamine stress echocardiography.
Anna Banaœ, Edyta P³oñska, Barbara Larysz, Mateusz Kurzawski, Marek Dro�dzik
129 Fructose-fed streptozotocin-injected rat: an alternative model for type 2 diabetes.
Rachel D. Wilson, Md. Shahidul Islam
140 Exendin-4 reduces glycemia by increasing liver glucokinase activity: an insulin independent effect.
217 New conjugates of muramyl dipeptide and nor-muramyl dipeptide linked to tuftsin and retro-tuftsin derivatives significantly influence their biological activity.
Krystyna Dzierzbicka, Anna Wardowska, Ma³gorzata Rogalska, Piotr Trzonkowski
Elementary Co-Principal Middle School Co-Principal Director of Special Education August 2013 Dear HCS Families, I would like to take this opportunity to introduce myself. My name is Allegra Miller and I am honored and so excited to be the interim Elementary Co-Principal at HCS this year. What a great school this is! HCS is certainly a busy place: summer school, EEE summer program, Part 2
Chalutzim Chadashim/The New Pioneers Six-Week Subsidized Summer Service Mission to Ayalim Village in Israel’s Negev Inaugural Program: July 10th to August 21st 2011 The Jewish Federation and Ayalim invite you to join us on an extraordinary six-week journey to Israel. Participants will experience life in Israel as modern pioneers and make a significant imprint in the lives of tho