Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus
We examined the effects of fluoxetine, a selective serotonin re-uptake inhibitor, of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, and of combined administration of these agents on morphometric characteristics of principal cells of the murine hippocampus. Fluoxetine (5 mg/kg), sildenafil (2...
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Інститут фізіології ім. О.О. Богомольця НАН України
2013
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irk-123456789-1481332019-02-18T01:24:26Z Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus Mahmoodi, M. Shahidi, S. Hashemi-Firouzi, N. Komaki, A. We examined the effects of fluoxetine, a selective serotonin re-uptake inhibitor, of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, and of combined administration of these agents on morphometric characteristics of principal cells of the murine hippocampus. Fluoxetine (5 mg/kg), sildenafil (2 mg/kg), or a combination of these drugs in the above doses were administered i.p. daily for 2 weeks to male mice. Hippocampal sections (5 mm thick) were stained with hematoxylin/eosin. Both drugs and their combination evoked no considerable changes in the dimensions of pyramidal cells in the CA1 and CA2 areas and in the dentate gyrus (DG), except for a trend toward some decrease of this parameter after fluoxetine injections in the CA1 area. Combined administration of fluoxetine and sildenafil provided significant decreases in the density of pyramidal neurons (their mean number per 10 mm of the slice) in the CA1 area and DG. Isolated administration of fluoxetine resulted in significant but less intense decreases in the density of principal cells in the CA2 area and DG. Possible mechanisms of the effects of the mentioned drugs are discussed. Further studies of interaction between fluoxetine and sildenafil in their effects on morphological and physiological properties of cells in different subregions of the hippocampus are recommended. Ми досліджували вплив флуоксетину (селективного інгібітора зворотного захвату серотоніну), силденафілу (інгібітора фосфодіестерази-5, PDE5) та їх сукупного введення на морфометричні характеристики основних (пірамідних) клітин гіпокампа мишей. Флуоксетин (5 мг/кг), силденафіл (2 мг/кг) або комбінація цих агентів у зазначених дозах уводилися самцям мишей внутрішньоочеревинно щоденно протягом двох тижнів. Зрізи гіпокампа завтовшки 5 мкм забарвлювали гематоксиліном та еозином. Обидві речовини та їх комбінація не викликали значних змін розмірів пірамідний нейронів у зонах CA1, CA2 та зубчастої звивини (ЗЗ), певна тенденція до зменшення зазначеного параметра спостерігалася після ін’єкцій флуоксетину в зоні CA1. Сукупна дія флуоксетину та силденафілу призводила до істотного зменшення щільності пірамідних нейронів (їх середньої кількості з розрахунку на 10 мкм зрізу) у зоні CA1 та ЗЗ. Обговорюються можливі механізми ефектів згаданих агентів. Доцільними є подальші дослідження особливостей взаємодії флуоксетину та силденафілу на морфологічні та фізіологічні характеристики клітин у різних підрозділах гіпокампа. 2013 Article Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus / M. Mahmoodi, S. Shahidi, N. Hashemi-Firouzi, A. Komaki // Нейрофизиология. — 2013. — Т. 45, № 5. — С. 332-337. — Бібліогр.: 22 назв. — англ. 0028-2561 http://dspace.nbuv.gov.ua/handle/123456789/148133 611.81:612.823 en Нейрофизиология Інститут фізіології ім. О.О. Богомольця НАН України |
| institution |
Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| language |
English |
| description |
We examined the effects of fluoxetine, a selective serotonin re-uptake inhibitor, of sildenafil,
a phosphodiesterase-5 (PDE5) inhibitor, and of combined administration of these agents
on morphometric characteristics of principal cells of the murine hippocampus. Fluoxetine
(5 mg/kg), sildenafil (2 mg/kg), or a combination of these drugs in the above doses were
administered i.p. daily for 2 weeks to male mice. Hippocampal sections (5 mm thick) were
stained with hematoxylin/eosin. Both drugs and their combination evoked no considerable
changes in the dimensions of pyramidal cells in the CA1 and CA2 areas and in the dentate
gyrus (DG), except for a trend toward some decrease of this parameter after fluoxetine
injections in the CA1 area. Combined administration of fluoxetine and sildenafil provided
significant decreases in the density of pyramidal neurons (their mean number per 10 mm of
the slice) in the CA1 area and DG. Isolated administration of fluoxetine resulted in significant
but less intense decreases in the density of principal cells in the CA2 area and DG. Possible
mechanisms of the effects of the mentioned drugs are discussed. Further studies of interaction
between fluoxetine and sildenafil in their effects on morphological and physiological
properties of cells in different subregions of the hippocampus are recommended. |
| format |
Article |
| author |
Mahmoodi, M. Shahidi, S. Hashemi-Firouzi, N. Komaki, A. |
| spellingShingle |
Mahmoodi, M. Shahidi, S. Hashemi-Firouzi, N. Komaki, A. Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus Нейрофизиология |
| author_facet |
Mahmoodi, M. Shahidi, S. Hashemi-Firouzi, N. Komaki, A. |
| author_sort |
Mahmoodi, M. |
| title |
Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus |
| title_short |
Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus |
| title_full |
Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus |
| title_fullStr |
Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus |
| title_full_unstemmed |
Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus |
| title_sort |
morphological effects of combined systemic administration of fluoxetine and sildenafil in the murine hippocampus |
| publisher |
Інститут фізіології ім. О.О. Богомольця НАН України |
| publishDate |
2013 |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/148133 |
| citation_txt |
Morphological Effects of Combined Systemic Administration of Fluoxetine and Sildenafil in the Murine Hippocampus / M. Mahmoodi, S. Shahidi, N. Hashemi-Firouzi, A. Komaki // Нейрофизиология. — 2013. — Т. 45, № 5. — С. 332-337. — Бібліогр.: 22 назв. — англ. |
| series |
Нейрофизиология |
| work_keys_str_mv |
AT mahmoodim morphologicaleffectsofcombinedsystemicadministrationoffluoxetineandsildenafilinthemurinehippocampus AT shahidis morphologicaleffectsofcombinedsystemicadministrationoffluoxetineandsildenafilinthemurinehippocampus AT hashemifirouzin morphologicaleffectsofcombinedsystemicadministrationoffluoxetineandsildenafilinthemurinehippocampus AT komakia morphologicaleffectsofcombinedsystemicadministrationoffluoxetineandsildenafilinthemurinehippocampus |
| first_indexed |
2025-07-12T18:25:10Z |
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2025-07-12T18:25:10Z |
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| fulltext |
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 4332
UDC 611.81:612.823
M. MAHMOODI1, S. SHAHIDI2, N. HASHEMI-FIROUZI1, and A. KOMAKI2
MORPHOLOGICAL EFFECTS OF COMBINED SYSTEMIC ADMINISTRATION
OF FLUOXETINE AND SILDENAFIL IN THE MURINE HIPPOCAMPUS
Received July 20, 2012.
We examined the effects of fluoxetine, a selective serotonin re-uptake inhibitor, of sildenafil,
a phosphodiesterase-5 (PDE5) inhibitor, and of combined administration of these agents
on morphometric characteristics of principal cells of the murine hippocampus. Fluoxetine
(5 mg/kg), sildenafil (2 mg/kg), or a combination of these drugs in the above doses were
administered i.p. daily for 2 weeks to male mice. Hippocampal sections (5 mm thick) were
stained with hematoxylin/eosin. Both drugs and their combination evoked no considerable
changes in the dimensions of pyramidal cells in the CA1 and CA2 areas and in the dentate
gyrus (DG), except for a trend toward some decrease of this parameter after fluoxetine
injections in the CA1 area. Combined administration of fluoxetine and sildenafil provided
significant decreases in the density of pyramidal neurons (their mean number per 10 mm of
the slice) in the CA1 area and DG. Isolated administration of fluoxetine resulted in significant
but less intense decreases in the density of principal cells in the CA2 area and DG. Possible
mechanisms of the effects of the mentioned drugs are discussed. Further studies of interaction
between fluoxetine and sildenafil in their effects on morphological and physiological
properties of cells in different subregions of the hippocampus are recommended.
Keywords: hippocampus, principal cells, fluoxetine, sildenafil, mice.
1 Department of Biology, School of Basic Sciences, Islamic Azad University,
Hamedan Branch, Hamedan, Iran.
2 Neurophysiology Research Center, Hamadan University of Medical
Sciences, Hamadan, Iran.
Correspondence should be addressed to N. Hashemi-Firouzi
(e-mail: nhashemifirozi@yahoo.com).
INTRODUCTION
The hippocampus is an important brain structure that
is a target for a number of drugs [1]. Hippocampal
neuronal systems are involved in various physiological
functions, such as anxiety, depression [2], cognition,
learning, and memory [3, 4]. It is well known that the
hippocampus is one of the crucial cerebral regions
related to behavior, and its behavior-controlling
functions are affected by many neuroactive drugs [1,
2, 4-6]. In the CNS of mammals, the hippocampus is
one of the oldest brain regions from the phylogenetic
aspect. It consists of two major parts, the hippocampus
per se (Ammon’s horn, or cornu ammonis, CA) and the
dentate gyrus (DG) [2, 7-9]. The hippocampus proper
includes three subregions, areas CA1-CA3 [8, 9].
Fluoxetine, a selective serotonin re-uptake inhibitor
(SSRI) and a known antidepressant, is commonly used
in psychiatry [2]. It was found that this agent improves
cell proliferation and neurogenesis in the hippocampus
[1, 6]. The effects of fluoxetine have been reported
with respect to such activities as synaptogenesis
of pyramidal cells [2], plasticity of astrocytes [7],
expression of synaptic proteins [10], and elevation
of the spine density in the CA1 area and DG of the
hippocampus [8].
On the other hand, sildenafil, a phosphodiesterase-5
(PDE5) inhibitor, that easily penetrates the CNS,
increases the cGMP level [3, 11]. Sildenafil intensifies
neurogenesis and promotes functional recovery
after ischemia [12, 13], induces angiogenesis [12],
and increases the number of varicosities in the CA3
region of the hippocampus [4]. In addition, sildenafil
is useful for reversing sexual dysfunction resulting
from SSRI actions, including fluoxetine [14, 15].
The efficacy of combined treatment by fluoxetine
and sildenafil in anxiety, depression, and fertility
disorders has been reported [11, 14-16]; recent studies
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 4 333
MORPHOLOGICAL EFFECTS OF COMBINED SYSTEMIC ADMINISTRATION
indicated that nitric oxide synthase (NOS) activity in
the hippocampus mediates the effect of fluoxetine in
mice [17].
Considering the beneficial functional effects of
fluoxetine and sildenafil mentioned above, our study
was undertaken to examine the effects of systemic
administration of fluoxetine and sildenafil and their
co-administration on morphological characteristics
of principal neuronal components of the murine
hippocampus.
METHODS
Animals. Experimental N-MARI male mice (30 to 35 g;
n = 20) were obtained from the breeding colony of
the Iran Pasteur Institute (Tehran) and randomly
distributed into four groups (five animals in each).
Mice were housed at a constant temperature of 20 ± 2°C
with a 12:12 h light/dark cycle (lights on at 7:00 a.m)
with free access to food and water ad libitum.
Drug Treatment. One week after acclimatization,
experimental mice were i.p. treated with fluoxetine
(5 mg/kg; Tocris, Great Britain), sildenafil (2 mg/kg;
Vorin, India), or a combination of these drugs in the
above doses once a day for 15 consecutive days [2].
Control animals received a vehicle. The drugs were
freshly prepared each day in physiological saline.
The doses of drugs were calculated according to the
baseline weight of each animal.
Experimental Procedure. The mice were
anesthetized by a mixture of xylasine/ketamine
3 h after the last drug or vehicle injection [2],
transcardially perfused with 0.9% saline followed
by formalin, and decapitated. The brains were
immediately removed, post-fixed in fresh Bouin
solution for at least 7 days, and embedded in paraffin.
Using a rotatory microtome, serial coronal sections
of the brain (5 µm thick) were cut through the entire
hippocampus. A stereotaxic brain atlas [9] was used for
reference during sectioning procedures. After standard
dehydration, fixation, embedding into paraffin, and
deparaffinization procedures, the sections were
stained using a standard hematoxylin/eosin technique.
Slices were examined at a 400× magnification under
a BA 400 microscope (Motic, Spain) equipped with a
camera output to a computer monitor. The images were
stored using the respective software and assembled
using brightness at a level of +50. In the coronal
sections of the hippocampus, the number (density) of
principal neurons, their dimension, and thickness of
the pyramidal layer were measured in the CA1, CA2,
and CA3 regions and also in the DG. The alteration of
the neurons was estimated with the optical dissector
following a fractionator principle [7].
Statistical Analyses. All numerical data are shown
as means ± s.e.m. The significance of intergroup
differences was calculated by one-way ANOVA
followed by the post-hoc Tukey test for multiple
comparisons. The statistical significance was defined
at P < 0.05.
RESULTS
Figure 1 illustrates the effects of fluoxetine, sildenafil,
or a combination of these agents on the dimension of
principal cells in the CA1, CA2, and DG subfields of the
hippocampus. As can be seen, isolated introductions
of fluoxetine led to some trend to toward a decrease in
this parameter in the CA1 area (Fig. 1A). Nonetheless,
one-way ANOVA showed that differences between the
mean dimensions of principal cells in the mentioned
hippocampal regions related to both isolated and
combined treatment with the above agents did not
reach the level of significance.
Figure 2 illustrates the effects of drug treatment
on the density of principal cells in three regions of
the hippocampus under study. One-way ANOVA
revealed significant differences between the effects
in the groups. The Tukey-Kramer test showed that
a combination of fluoxetine and sildenafil provided
significant decreases in the density of principal cells
(their mean number per 10 mm of the slice) in the CA1
area and DG (P < 0.01, A, C). It should be mentioned
that isolated introductions of fluoxetine induced
considerable decreases in the cell density in the CA2
area and DG (P < 0.05 and P < 0.01, respectively,
B, C). At the same time, isolated action of sildenafil
did not evoke significant changes in the density of
principal cells in all the regions examined (only
mild insignificant trends toward decrease could be
noticed; A-C). Upon the combined action of the above-
mentioned agents, the cell density in the CA2 area was
practically similar to that in the control (B).
In Fig. 3, photomicrographs of slices of the CA1,
CA2, and DG regions of the hippocampus of mice
treated for 2 weeks with fluoxetine, sildenafil, and a
combination of fluoxetine and sildenafil or vehicle are
shown.
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 4334
M. MAHMOODI, S. SHAHIDI, N. HASHEMI-FIROUZI, and A. KOMAKI
1
2
2
2
1
2
0 0
Contr. Contr.Fluox FluoxSild SildFluox+Sild Fluox+Sild
0
00
0
2
4
4
4
2
4
3
6
6
6
3
6
4
8
8
8
4
8
5
10
10
10
5
10
6
12
14
16
18
20
µm
µm
µm
12
14
12
12
16
14
A A
C
BB
C
F i g. 1. Mean dimensions (diameters, mm) of principal (pyramidal)
cells in the CA1 area, CA2 area, and dentate gyrus (DG) of the
hippocampus (A-C, respectively) of mice treated for 2 weeks with
fluoxetine (Fluox), sildenafil (Sild), and their combination. Contr. is
the control group. Means ± s.e.m. are shown.
Р и с. 1. Середні розміри (діаметр, мкм) головних (пірамідних)
клітин у зонах СА1 та СА2 і в зубчастій звивині гіпокампа (А–C
відповідно) мишей, яким уводили флуоксетин, силденафіл або
їх комбінацію.
**
****
*
##
##
#
×
F i g. 2. Mean densities (numbers per 10 mm of the slice) of
pyramidal cells in the CA1 area, CA2 area, and dentate gyrus
of the hippocampus (A-C, respectively) of mice treated with
fluoxetine (Fluox), sildenafil (Sild), and their combination. **P <
0.01 compared to the control group, ##P < 0.01 compared to the
Fluox group, and × P < 0.05 compared to the Sild group. Other
designations are similar to those in Fig. 1.
Р и с. 2. Середні щільності (кількість на 10 мкм зрізу) піра-
мідних нейронів у зонах СА1 та СА2 і в зубчастій звивині
гіпокампа (А–С відповідно) мишей, яким уводили флуоксетин,
силденафіл або їх комбінацію.
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 4 335
MORPHOLOGICAL EFFECTS OF COMBINED SYSTEMIC ADMINISTRATION
CA1
CA2
DG
Contr. Fluox Sild
10 µm
Fluox+Sild
CA1
CA2
CA3
CA4
DG
F i g. 3. Photomicrographs of hematoxylin/
eosin-stained slices of the hippocampus. A) At
a low magnification, B) at a high magnification.
Regions of the hippocampus are shown at the
left; designations of the groups similar to those
in Figs. 1 and 2 are shown above.
Р и с. 3. Мікрофотографії зрізів гіпокампа
(забарвлення гема токсиліном/еозином).
DISCUSSION
In this study, we evaluated counts and dimensions of
principal neurons in the CA1, CA2, and DG regions
of the hippocampus after two weeks of treatment with
fluoxetine, sildenafil, or a combination of these agents.
Fluoxetine inhibits SERT activity and increases
extracellular levels of serotonin [2]. Serotonin is
known to regulate neurogenesis and cell proliferation
and to facilitate the growth of neurons [1, 2, 6, 7].
An increasing serotonin level resulting from chronic
administration of fluoxetine considerably affects the
hippocampus [1, 6, 7]. Possible mechanisms of the
effect of fluoxetine (an SSRI antidepressant) might
A
B
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 4336
M. MAHMOODI, S. SHAHIDI, N. HASHEMI-FIROUZI, and A. KOMAKI
be attributed to changes in the level of neurotropic
factors, neural growth, and synaptic plasticity [7]. In
addition, previous studies demonstrated that treatment
with fluoxetine promotes cell proliferation in the
case of stress [1, 7] and increases neurogenesis and
cell proliferation in the hippocampus [1, 6]. Chronic
administration of fluoxetine was reported to influence
expression of several synaptic proteins [10], to
intensify the process of synaptogenesis, and to restore
the synaptic density in the hippocampus [2].
Sildenafil, which successfully crosses the blood-
brain barrier [18], inhibits PDE5 in the CNS [4]. The
activity of guanylyl cyclase (GC), the enzyme that
mediates production of cGMP, is known to be initiated
by activation of NOS and increase in nitric oxide
(NO) production [18]. A few experiments showed that
sildenafil, as a selective PDE5 inhibitor, increases
cGMP accumulation in the hippocampus [4]. The
NO/cGMP pathway mediates protein modifications
[19]. In vitro studies demonstrated that high levels
of cGMP modulate differentiation of stem cells into
neurons [5]. Sildenafil, at the same time, exerts a
protective effect against neurodegeneration, increases
cell survival [5], induces an increase in the contents
of a few proteins, and mediates a long-lasting
neuroprotective effect of the hippocampus [12].
This PDE5 inhibitor enhances the cGMP levels in
varicosities in the hippocampus [4]. Relatively mild
effects of sildenafil found in our study are, probably,
related to the duration of treatment, a relatively low
dose of sildenafil, and peculiarities of the histological
method used.
The hippocampus is rich with NOS and GC [20].
The NO–cGMP pathway has an important modulatory
effect on the serotonergic system [17, 21]. Systemic
administration of a NO inhibitor increases the efflux
of serotonin in the hippocampus [21]. In serotonergic
neurons, the serotonin re-uptake transporter (SERT)
is co-localized with NOS [22]. Interaction between
NOS and SERT negatively modulates SERT activity
and increases nNOS activity and cGMP accumulation,
thus enhancing serotonin re-uptake [20-22]. It seems
possible that interaction between fluoxetine and
sildenafil can provide the above effects.
Our results show that, in the case of relatively
long (2 weeks) systemic administration, fluoxetine,
sildenafil, and their combination exert certain effects
on morphometric characteristics of principal cells
in the murine hippocampus. With respect to the
dimensions of pyramidal cells, the effects of these
drugs, applied in any mode in the doses used, did
not reach the level of significance (a trend toward a
decrease in the mentioned parameter in the CA1 area
under the action on fluoxetine deserves, however,
certain attention). At the same time, there were clear
decreases in the number (density) of pyramidal cells
in the CA1 area and DG under conditions of combined
treatment with fluoxetine and sildenafil. Thus, it
seems that positive functional effects of a combination
of these drugs [11, 14-16] can be accompanied by
structural shifts in the hippocampus, which should
be interpreted as negative from a certain aspect. At
the same time, it should be mentioned that fluoxetine,
when applied in an isolated mode, also led to decreases
in the number of principal cells, but not in the same
hippocampal zones (this effect was obvious in the CA2
area and DG; Fig. 2B, C).
Thus, our study showed that chronic treatment
with fluoxetine influences the regular arrangement of
pyramidal neurons in some parts of the hippocampus.
The effect of co-administration of fluoxetine and
sildenafil with respect to the number (density) of these
principal cells differs from that of fluoxetine applied
in an isolated manner. The effects of fluoxetine
and sildenafil on morphometric characteristics of
pyramidal hippocampal neurons are not additive.
These facts show that further research of the effects
of systemic administration of these drugs in different
subfields of hippocampus using morphological
(morphometric), pharmacological, and physiological
approaches is needed.
All experimental procedures and examination conditions
were approved by the Committee of Islamic Azad University
of Hamadan Branch and performed according to the Guide for
Care and Use of Laboratory Animals published by the United
States National Institutes of Health (NIH Publication No. 85-23,
revised 1985).
There is no conflict of interest for any of the authors
(M. Mahmoodi, S. Shahidi, N. Hashemi-Firouzi, and
A. Komaki).
M. Maхмуді1, С. Шахіді2, Н. Хашемі-Фіроузі1, A. Koмакi2
ВПЛИВ СУКУПНИХ УВЕДЕНЬ ФЛУОКСЕТИНУ ТА
СИЛДЕНАФІЛУ НА МОРФОЛОГІЧНІ ХАРАКТЕРИСТИ-
КИ ГІПОКАМПА МИШЕЙ
1 Відділ біології, факультет фундаментальних наук,
Ісламський університет Азад, Хамадан (Іран).
2 Нейрофізіологічний дослідницький центр, Хамаданський
медичний університет, Хамадан (Іран).
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2013.—T. 45, № 4 337
MORPHOLOGICAL EFFECTS OF COMBINED SYSTEMIC ADMINISTRATION
Р е з ю м е
Ми досліджували вплив флуоксетину (селективного інгі-
бітора зворотного захвату серотоніну), силденафілу (інгі-
бітора фосфодіестерази-5, PDE5) та їх сукупного введення
на морфометричні характеристики основних (пірамідних)
клітин гіпокампа мишей. Флуоксетин (5 мг/кг), силденафіл
(2 мг/кг) або комбінація цих агентів у зазначених дозах уво-
дилися самцям мишей внутрішньоочеревинно щоденно про-
тягом двох тижнів. Зрізи гіпокампа завтовшки 5 мкм забарв-
лювали гематоксиліном та еозином. Обидві речовини та їх
комбінація не викликали значних змін розмірів пірамідний
нейронів у зонах CA1, CA2 та зубчастої звивини (ЗЗ), пев-
на тенденція до зменшення зазначеного параметра спосте-
рігалася після ін’єкцій флуоксетину в зоні CA1. Сукупна дія
флуоксетину та силденафілу призводила до істотного змен-
шення щільності пірамідних нейронів (їх середньої кіль-
кості з розрахунку на 10 мкм зрізу) у зоні CA1 та ЗЗ. Об-
говорюються можливі механізми ефектів згаданих агентів.
Доцільними є подальші дослідження особливостей взаємо-
дії флуоксетину та силденафілу на морфологічні та фізіоло-
гічні характеристики клітин у різних підрозділах гіпокампа.
REFERENCES
1. J. E. Malberg and R. S. Duman, “Cell proliferation in adult
hippocampus is decreased by inescapable stress: reversal by
fluoxetine treatment,” Neuropsychopharmacology, 28, No. 9,
1262-1271 (2003).
2. T. Hajszan, N. J. MacLusky, and C. Leranth, “Short-term
treatment with the antidepressant fluoxetine triggers pyramidal
dendritic spine synapse formation in rat hippocampus,” Eur.
J. Neurosci., 21, No. 5, 1299-1303 (2005).
3. J. Prickaerts, W. C. van Staveren, A. Sik, et al., “Effects of
two selective phosphodiesterase type 5 inhibitors, sildenafil
and vardenafil, on object recognition memory and hippocampal
cyclic GMP levels in the rat,” Neuroscience, 113, No. 2, 351-
361 (2002).
4. K. Rutten, J. D.Vente, A. Sik, et al., “The selective PDE5
inhibitor, sildenafil, improves object memory in Swiss mice
and increases cGMP levels in hippocampal slices,” Behav.
Brain Res., 164, No. 1, 11-16 (2005).
5. U. Gómez-Pinedo, R. Rodrigo, O. Cauli, et al., “cGMP
modulates stem cells differentiation to neurons in brain in
vivo,” Neuroscience, 165, No. 4, 12756-12786 (2010).
6. B. Chanrion, C. Mannoury la Cour, F. Bertaso, et al., “Physical
interaction between the serotonin transporter and neuronal
nitric oxide synthase underlies reciprocal modulation of their
activity,” Proc. Natl. Acad. Sci. USA., 104, No. 19, 8119-8124
(2007).
7. J. E. Malberg, A. J. Eisch, E. J. Nestler, and R. S. Duman,
“Chronic antidepressant treatment increases neurogenesis in
adult rat hippocampus,” J. Neurosci., 20, No. 24, 9104-9110
(2000).
8. B. Czéh, M. Simon, B. Schmelting, et al., “Astroglial
plasticity in the hippocampus is affected by chronic
psychosocial stress and concomitant fluoxetine treatment,”
Neuropsychopharmacology, 31, No. 8, 1313-1326 (2006).
9. S. D. Norrholm and C. C. Ouimet, “Chronic fluoxetine
administration to juvenile rats prevents age-associated
dendritic spine proliferation in hippocampus,” Brain Res., 883,
No. 2, 205-215 (2000).
10. J. Tigges and T. R. Shantha, A Stereotaxic Brain Atlas of
the Tree Shrew (Tupaia glis), Waverly Press, Baltimore, MD
(1996).
11. O. F. O’Leary, X. Wu, and E. Castren, “Chronic fluoxetine
treatment increases expression of synaptic proteins in the
hippocampus of the ovariectomized rat: role of BDNF
signalling,” Psychoneuroendocrinology, 34, No. 3, 367-381
(2009).
12. N. Liebenberg, B. H. Harvey, L. Brand, and C. B. Brink,
“Antidepressant-like properties of phosphodiesterase type 5
inhibitors and cholinergic dependency in a genetic rat model
of depression,” Behav. Pharmacol., 21, 540-547 (2010).
13. C. V. Romanini, A. P. Schiavon, E. D. Ferreira, et al.,
“Sildenafil prevents mortality and reduces hippocampal
damage after permanent, stepwise, 4-vessel occlusion in rats,”
Brain Res. Bull., 81, No. 6, 631-640 (2010).
14. R. Zhang, Y. Wang, L. Zhang, et al., “Sildenafil (Viagra)
induces neurogenesis and promotes functional recovery after
stroke in rats,” Stroke, 33, No. 11, 2675-2680 (2002).
15. W. W. Shen, Z. Urosevich, and D. O. Clayton, “Sildenafil
in the treatment of female sexual dysfunction induced by
selective serotonin reuptake inhibitors,” J. Reprot. Med., 44,
No. 6, 535-542 (1999).
16. M. M. Hosseini and H. Yarmohammadi, “Effect of fluoxetine
alone and in combination with sildenafil in patients with
premature ejaculation,” Urol. Int., 79, No. 1, 28-32 (2007).
17. H. G. Nurnberg, P. L. Hensley, A. J. Gelenberg, et al.,
“Treatment of antidepressant-associated sexual dysfunction
with sildenafil: a randomized controlled trial,” J. Am. Med.
Ass., 289, 56-64 (2003).
18. J. Zhang, X. Y. Huang, M. L. Ye, et al., “Neuronal nitric oxide
synthase alteration accounts for the role of 5-HT1A receptor in
modulating anxiety-related behaviors,” J. Neurosci., 30, 2433-
2441 (2010).
19. S. Uthayathas, S. S. Karuppagounder, B. M. Thrash, et al.,
“Versatile effects of sildenafil: recent pharmacological
applications,” Pharmacol. Reports, 59. No. 2, 150-163 (2007).
20. A. J. Gow, C. R. Farkouh, D. A. Munson, et al., “Biological
significance of nitric oxide-mediated protein modifications,”
Am. J. Physiol. Lung Cell Mol. Physiol., 287, No. 2, 262-268
(2004).
21. C. B. Zhu, W. A. Hewlett, S. H. Francis, et al., “Stimulation
of serotonin transport by the cyclic GMP phosphodiesterase-5
inhibitor sildenafil,” Eur. J. Pharmacol., 504, Nos. 1/2, 1-6
(2004).
22. G. Wegener, V. Volke, and R. Rosenberg, “Endogenous nitric
oxide decreases hippocampal levels of serotonin and dopamine
in vivo,” Br. J. Pharmacol., 130, No. 3, 575-580 (2000).
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