International journal
of of
Research
and
Review in in
Health
Sciences, July -2014
International
Journal
Recent
Advances
Multidisciplinary
Research, September -2014
sZ
International Journal of Recent Advances in Multidisciplinary Research
Vol. 01, Issue 03, pp.056-061, September, 2014
Full Length Research Article
VALERIANA OFFICINALIS ADMINISTRATION ON PREGNANT RATS AND POSTNATAL
DEVELOPMENT OF THE FEMALE OFFSPRING
*1Mara
Lúcia de Campos 2Carlos Alberto Mourao-Junior 3Marcos Antônio Fernandes Brandão
4 Rita de Cássia da Silveira e Sá, 5Lorena Ribeiro Silva 5Martha Oliveira Guerra
*1Programa
de Pós-graduação (Mestrado) em Ciências Biológicas do Programa Comportamento e Biologia
Animal da Universidade Federal de Juiz de fora – UFJF – Juiz de Fora (MG), Brasil
2Instituto de Ciências Biológicas, Departamento de Fisiologia, Universidade Federal de Juiz de Fora-UFJF- Juiz de
fora (MG), Brasil
3Faculdade de Farmácia e Bioquímica, Laboratório de Química Farmacêutica, Universidade Federal de Juiz de
Fora-UFJF- Juiz de fora (MG), Brasil
4Departamento de Fisiologia e Patologia, Centro de Ciências da Saúde, Universidade Federal da Paraíba-UFPBJoão Pessoa (PB), Brasil
5Centro de Biologia da Reprodução da Universidade Federal de Juiz de Fora – UFJF – Juiz de Fora (MG), Brasil
ARTICLE INFO
Article History:
Received 06th June, 2014
Received in revised form
03rd July, 2014
Accepted 10th August, 2014
Published online 30th September, 2014
Keywords:
Post-natal development,
Rats, pregnancy,
Valeriana officinalis.
ABSTRACT
Valeriana officinalis is used as a mild sedative but should be avoided during pregnancy due to scarce
data available about potential effects on the offspring. This paper evaluates physical development and
anxiety in female rats whose mothers were exposed to valerian during gestation. Twenty four pregnant
rats were distributed into four groups (n=6) and treated orally from the 12th to 19th day of gestation:
Control (1 ml of distilled water), and three valerian-treated groups with 500, 1000 and 2000
mg/Kg/day. Four females from each mother were selected to analyzed: time of eye opening, ear
unfolding, appearance of lanugo, hair, superior and inferior incisor eruption, vaginal opening; first date
of righting reflex, grasping reflex, cliff avoidance, and negative geotaxis. Anxiety was evaluated by the
elevated plus-maze test in offspring at age 90 days. Eruption of the inferior incisors (1000 and
2000mg/kg); appearance of lanugo and hair, and eye opening (500 mg/kg) were significantly altered in
the offspring. The neuromotor reflexes and the anxiety did not differ between the groups. The physical
development in the adult stage was not altered. These findings suggest that maternal treatment with
valerian during gestation did not alter physical, neuromotor and anxiety of the offspring.
INTRODUCTION
Valeriana officinalis L. (Valerianaceae), or simply valerian, is a
perennial flowering plant native to Europe and parts of Asia. Its
use as a medicinal herb dates back to the time of ancient Greece
and Rome (Hobbs, 1989) and valerian was particularly known
as a sedative, anticonvulsant, migraine treatment and pain
reliever (Boullata and Nace, 2000). Valerian is most commonly
used to treat insominia (Tesche, 2002) and has been
recommended as an alternative for hypnotic drugs (Hadley and
Petry, 2003). In addition to being used for the treatment of
*Corresponding author: Mara Lúcia de Campos, Programa de Pósgraduação (Mestrado) em Ciências Biológicas do Programa
Comportamento e Biologia Animal da Universidade Federal de Juiz
de Fora – UFJF – Juiz de Fora (MG), Brasil
sleep disorders (Miyasaka et al., 2006), valerian has also been
used to treat anxiety (Miyasaka et al., 2006), gastrointestinal
problems (to control muscle spasms and cramps), and symptons
such as stress, excitability, and nervous tension (Hadley and
Petry, 2003). Because there is limited information on animal
and human effects, valerian is not recommended for use during
gestation and lactation. The lack of long-term studies and the
potential for cytotoxicity in the fetus and hepatotoxicity in the
mother strengthen this concern, and do not allow a conclusion
as to the safe use of valerian during pregnancy (Tesche, 2002,
Taylor et al., 2002; Yao et al., 2007). Prenatal exposure to
valerian has been implicated in delayed ossification in the
offspring, suggesting its transit through the placenta (Tuffik et
al., 1994); however compelling evidence for the passage of
valerian through the placenta is still wanting. In contrast, an in
vivo study showed that the administration of valerian ethanolic
International Journal of Recent Advances in Multidisciplinary Research
extract (2.79 g/Kg/day, p.o.) to pregnant rats between days 1-8
or 8-15 of gestation did not increase the incidence of internal
and external malformation of the fetuses and did not exert any
adverse effects related to fertility (Yao et al., 2007).The
mechanism of action of valerian in general and as a mild
sedative in particular has not been fully elucidated. The
pharmacological effect of the valerian extract and one of its
main constituents, namely valerenic acid, is believed to be
mediates by modulation of the neurotransmitter gammaaminobutyric acid (GABA) A receptor, a class of receptors on
which benzodiazepines are known to act (Holzl and Godau
1989; Mennini et al., 1993; Benke et al,. 2009). It is
noteworthy that alterations in juveniles in the GABA receptor
may persist into adulthood. For instance, it has been
demonstrated that neonatal exposure to benzodiazepines
reduced the level of anxiety in adult animals (Schroeder et al.,
1997).
During gestation, the hematoencephalic barrier is not fully
developed (Jonhson 1980), therefore drugs that pass through
the placenta could be interfering with the receptors in the brain.
Although it has been reported that intrauterine exposure to
drugs in general may not interfere with the embryo-fetal and
newborn development, the exposure may have later effects seen
as health disorders in adulthood. Such concerns led to the
evaluation of drug effects on animals exposed during puberty,
and now special attention is being given to their effects on the
offspring and their consequences in adulthood (Goodman et al.,
2011). In a study developed by Vieira and collaborators (2013),
evaluation of the behavior of Wistar rat offspring, born from
mothers treated during gestation with Hyperic perforatum
extract showed significant reduction of depression and anxiety
in the offspring at 10 and 60 days postpartum, suggesting
placental transit and long-term effects of hyperic extract.
Previous study of our group demonstrated no alterations in the
neonatal and neurobehavioral development of male rats
exposed to valerian during intrauterine life (Campos et al.,
2014). Because male and female has difference in the neuronal
and behavioural process (Kelly et al., 1999) the objective of
this study was to evaluate neonatal development and anxiety in
female rats whose mothers were exposed to valerian during
gestation.
MATERIALS AND METHODS
The experimental protocol followed the international guidelines
outlined in the Guide for care and use of laboratory animals
(NATIONAL RESEARCH COUNCIL 2003) and was
approved by the Ethics Committee on Animal Experimentation
of the Federal University of Juiz de Fora (protocol number
019/2011).
Valerian Extract
The dry extract of Valerian was imported by QUIMER®
company (Juiz de Fora. Brazil) (registration no 002/2009) and
supplied by ORTOFARMA® Company (Juiz de Fora. Brazil),
where the physicochemical quality analysis was carried out.
The dry extract was suspended in deionized water and later
preserved in a vacuum desiccator to avoid humidity. The dry
extract was selected as the test material because it is
traditionaly used by people in this form. In addition, valerian
has around 150 – 200 chemical components, including
057
alkaloids, sesquiterpenes and flavones (Carol and Linda, 1996;
Marder et al., 2003; Shahidi; Naczk, 2004). Individual testing
of components will be carried out in a future study.
Experimental Assay
Twenty four female Wistar rats (Rattus norvegicus
Berckenhout, 1769), 90 days old and with regular estrous
cycles, were obtained from the vivarirum (Registro CIAEP
01.0048.2013) of the Reproductive Biology Center at the
Federal University of Juiz de Fora. Rats were housed in
individually ventilated polypropylene cages (ALESCO® São
Paulo. Brazil)), with hardwood chip bedding, at controlled
temperature (22 ± 2º C), with a 12-hour light/dark photoperiod.
The animals were fed ad libitum rat chow pellets NUVILAB
CR1® (Nuvital Nutrients Ltda., Colombo/PR) and received
water ad libitum. Females were placed in cages with male rats
in a ratio of 2:1 for natural mating. The presence of
spermatozoa in a vaginal smear indicated successful mating and
was considered as day one of gestation (Beaudoin, 1985). The
inseminated rats were housed individually in cages and
randomly divided into four groups (n = 6): three treated and one
control that received orally once daily 500 mg/Kg/day (T-500),
1000 mg/Kg/day (T-1000), 2000 mg/Kg/day (T–2000) of
valerian, and distilled water, respectively. The choice of the
lowest dose (500 mg/Kg) calculated for the rat was based on
the dose recommended for humans while the two other doses
were two and four times higher than the lowest dose (Al-majed
et al., 2006). Treatment began on the 12th day of gestation and
ended on the 19th day, corresponding to the most vulnerable
period for brain development (Vorhees and Rindler, 1990).
Neonatal Development
The day of birth was considered the first postnatal day. The
number of pups and the number of males and females born to
each litter were registered. Afterwards, the number of animals
per litter was reduced to eight animals in order to homogenize
nutritional status. The litter was observed daily for detection of
deaths and cannibalism. For each experimental group, four
females obtained from five litters were used to evaluate the
physical and reflex development of the pups. The animals were
identified by specific marking criteria (ear notches) established
by the vivarium of the Reproductive Biology Center. Only
females were chosen as there are gender differences in the
neuronal and behavioral processes (Kelly et al., 1999). The
male rats were studied separately and the results will be
presented elsewhere (Campos et al., 2014 article). Physical
development was observed in all pups from postnatal day one.
The following parameters were analyzed: date of eye opening,
ear unfolding, appearance of lanugo and hair, superior and
inferior incisor eruption, and vaginal opening. The day of first
appearance of these features was registered and for paired
structures, it was registered as the first day of appearance of
both structures (Chiavegatto et al., 1997; Dorce et al., 2009;
Oliveira et al., 2011). Data were expressed in animal frequency
per day of appearance of each physical development feature. To
evaluate the reflex development, the following tests were
carried out: grasping reflex (holding of a paper clip with the
forelimbs), righting reflex (return to normal ventral position
after lying on its back), cliff avoidance (animal movement
away from the cliff), and negative geotaxis (turning 180º after
being placed face-down on an inclined surface). The tests were
performed daily from postnatal day one until the day of
International Journal of Recent Advances in Multidisciplinary Research
058
appearance, with duration of 15 sec each (Chiavegatto et al.,
1997; Dorce et al., 2009; Oliveira et al., 2011). A positive
result was considered the day the animal first showed the reflex
being tested.
(Table 1). The date of appearance of the reflexes did not differ
among the groups (Table 2).
Anxiety Test
The percentage of time spent in the open arms was not
statistically different between the groups (H=2.47; p=0.48). The
descriptive statistical data for all groups are shown in table 3.
At 90 days old, one female from each litter was randomly
chosen and used in the elevated plus maze test, totaling six
females for each treatment. The elevated plus maze apparatus
consisted of two open arms and two closed arms (50 cm long
and 10 cm wide) with walls 30 cm high, elevated 60 cm above
the floor. Each arm was positioned at 90º relative to the
adjacent arms and all arms were connected through a central
area (10 x 10 cm), forming a plus sign. To investigate anxiety,
each rat was placed at the center of the maze facing one of the
open arms. The time spent (in seconds) in the open and closed
arms were recorded for 5 min (Pellow et al, 1985). After each
trial, the plus maze was carefully cleaned with 70% isopropyl
alcohol. The variable used as an indicator of anxiety was the
time percentage the animal spent in the open arms (% tOP):
(time spent in the open arms divided by time spent in the open
and closed arms) x 100. The use of % tOP instead of the
measurement of time spent in the open arms alone has the
advantage of taking into account an important intervening
variable which is the locomotor activity of the animal (Rodgers
and Dalvi, 1997).
Statistical Analysis
The data obtained from the physical and reflex tests were
presented according to the frequency of pups that exhibited
developmental signs in each day. The frequency was grouped
in three categories, taking into account the day in which the
control group showed a higher frequency of individuals
displaying physical or reflex signs:
Category 1: Frequency similar to control group.
Category 2: Frequency prior to that exhibited by control group.
Category 3: Frequency posterior to (after) that exhibited by
control group.
The results were analyzed using the Fisher exact test (α = 0.05)
for comparison of the control group with each treated group.
Differences were considered significant when p ≤ 0.01 (to
avoid the effect of multiple comparisons on the alpha risk). The
results of the elevated plus-maze test were evaluated by use of
descriptive analysis presented as mean ± standard mean error.
The mean values of the groups were compared using the nonparametric Kruskal-Wallis test. The level of significance
considered was α = 0.05. The tests were performed using SPSS
program version 19.
RESULTS
In females, the date of appearance of the physical parameters
such as vaginal opening, ear unfolding, appearance of lanugo,
and eruption of the superior incisors was similar to that of the
control group. However, the eruption of the inferior incisors
was markedly delayed between the control group and the
treated groups T-1000 (2=9.91; gl=2; p=0.007) and T-2000
(2=11.518; gl=2; p=0.003) (Table 1). Significant delay was
also observed in the appearance of hair between T-500
(2=15.99; gl=2; p < 0,001) and control animals, and in the eye
opening between control and T-500 (2=9.09; gl=2; p=0.01)
Elevated Plus Maze
DISCUSSION
The CNS is protected from entry of potential toxins through the
blood-brain barrier, which is not fully developed at birth. For
this reason, a given agent can be selectively toxic in that it may
have no effect on the mother while being harmful to the fetus,
resulting in abnormalities that affect, for instance, the
development of neuronal processes (Johnson, 1980). Hence,
exposure to psychopharmacs during gestation may produce
alterations in development of the nervous system that could be
involved in physiologic changes later in life (Kellog et al.,
1992; Kellog et al., 2000; Nicosia et al., 2003). The evaluation
of the physical development of the offspring is a relevant tool
for the investigation of the toxic potential of agents
administered to mothers during gestation. Despite the delay
observed in the developmental parameters analyzed in this
study (appearance of lanugo and hair, and eruption of the
inferior incisors), none of the animals from control or treated
groups exhibited morphological changes in these parameters in
the adult life, indicating that valerian exerted transient adverse
effects on the female offspring.
The reflex development is considered another relevant
paramenter in toxicological assays as it can indicate the
occurrence of deleterious effects on brain maturation (Fox,
1965). Therefore, delayed reflex responses suggest
developmental alterations in the CNS which can represent a
predictive factor for behavioral modifications in adulthood. The
exposure to psychopharmacs that act on GABA receptors
during brain develoment can induce reflex alterations such as
delayed geotaxis response (Nicosia et al., 2003). It has been
shown that the pharmacological effect of valerian extract is
mediated by modulation of GABA A receptor (Benke et al.,
2009); however the results obtained in this study do not
corroborate this information as exposure to valerian at the
tested doses did not alter any of the reflex responses tested
when compared to control values.
During the brain development process, the interaction between
the neurotransmitters and their respective receptors can
influence the development of the CNS by modulating the
proliferation of non-differentiated cells (Lauder, 1986; Emerit
et al., 1992; Nguyen et al., 2001). GABA is a neurotransmitter
known to exert inhibitory effects on the mature brain; however,
during its development, GABA produces excitatory effects,
which can influence early neocortical development, such as
neurogenesis and synaptogenesis, that can result in futher
alterations later in life (Cherubini et al., 1991; Owens et al.,
1996). Benzodiazepines comprise a group of substances that
enhance the effect of GABA at the GABA A receptor, resulting
in sedative, hypnotic, anxiolytic, anticonvulsant and muscle
relaxant properties. A study carried out by Schroeder and
collaborators (1997) showed that exposure to diazepam during
the neonatal stage (period in which the brain is still developing)
International Journal of Recent Advances in Multidisciplinary Research
059
Table 1. Physical development in female offspring of mothers exposed to valerian aqueous extract (500, 1000, 2000 mg/Kg) or to
distilled water (control) during gestation
Physical parameters
Ear unfolding
Prior
Day 5
After
Eruption of inferior incisors
Prior
Day 11
After
Eruption of superior incisors
Prior
Day 9
After
Appearence of lanugo
Prior
Day 4
After
Appearance of hair
Prior
Day 8
After
Eye opening
Prior
Day 17
After
Vaginal opening
Prior
Day 33
After
Control
n=24
T-500
n=26
T-1000
n=18
T-2000
n=21
29.2% (7)
58.3% (14)
12.5% (3)
23.1% (6)
73.1% (19)
03.8% (1)
38.9% (7)
61.1% (11)
00.0% (0)
33.3% (7)
61.9% (13)
04.8% (1)
12.5% (3)
37.5% (9)
50.0% (12)
00.0% (0)
46.2% (12)
53.8% (14)
00.0% (0)
16.7% (3)
83.3% (15)*
33.3% (0)
04.8% (1)
95.2% (20)*
04.2% (1)
58.3% (14)
37.5% (9)
03.8% (1)
46.2% (12)
50.0% (13)
05.5% (1)
33.3%( 6)
61.2% (11)
0.00% (0)
66.7% (14)
22.3% (7)
16.6% (4)
66.7% (16)
16.7% (4)
11.5% (3)
34.6% (9)
53.9% (14)
33.3% (6)
38.9% (7)
27.7% (5)
23.8% (5)
61.9% (13)
14.3% (3)
29.1% (7)
66.8% (16)
04.1% (1)
11.5% (3)
34.6% (9)*
53.9% (14)
44.4% (8)
33.3% (6)
22.3% (4)
66.6% (14)
23.8% (5)
09.6% (2)
16.6% (4)
75.0% (18)
08.4% (2)
42.3% (11)
30.8% (8)*
26.9% (7)
05.6% (1)
66.6% (12)
27.8% (5)
23.8% (5)
47.6% (10)
28.6% (6)
0.00% (0)
42.8% (10)
57.2% (14)
17.4% (4)
08.7% (2)
73.9% (17)
27.8% (5)
44.4% (8)
27.8% (5)
04.8% (1)
57.1% (12)
38.1% (8)
The results are expressed in percentage followed by the corresponding number of females that presented physical development in the three categories: prior, similar day to
control, after. The asterisk indicates statistical difference between control group and the respective treatment group.
Table 2. Physical development in female offspring of mothers exposed to valerian aqueous extract (500, 1000, 2000 mg/Kg) or to
distilled water (control) during gestation
Reflexological parameters
Grasping reflex
Prior
Day 2
After
Postural response
Prior
Day 2
After
Cliff avoidance
Prior
Day 8
After
Negative geotaxis
Prior
Day 9
After
Control (n=24)
T-500 (n=26)
T-1000 (n=18)
T-2000 (n=21)
29.2% (7)
58.3% (14)
12.5% (3)
23.1% (6)
73.1% (19)
03.8% (1)
38.9% (7)
61.1% (11)
00.0% (0)
33.3% (7)
61.9% (13)
04.8% (1)
04.2% (1)
58.3% (14)
37.5% (9)
03.8% (1)
46.2% (12)
50.0% (13)
05.5% (1)
33.3% (6)
61.1% (11)
00.0% (0)
66.7% (14)
33.3% (7)
16.6% (4)
66.8% (16)
16.6% (4)
11.5% (3)
34.6% (9)
53.9% (14)
33.3% (6)
38.9% (7)
27.8% (5)
23.8% (5)
61.9% (13)
14.3% (3)
45.8% (9)
25.0%( 6)
29.2% (7)
73.1% (19)
07.0% (2)
19.9% (5)
61.1% (11)
11.1% (2)
27.8% (5)
57.2% (12)
19.0% (4)
23.8% (5)
The results are expressed in percentage followed by the corresponding number of animals that presented physical development in the three categories: prior, similar day to
control, after. None of the differences were statistically significant.
Table 3. Anxiety test carried out in female offspring of mothers
exposed to valerian aqueous extract (500, 1000, 2000 mg/Kg) or to
distilled water (control) during gestation
Groups
Control
T-500
T-1000
T-2000
n
6
6
6
6
% (tOP)
0.183±0.012
0.178±0.035
0.178±0.016
0.182±0020
Results expressed in mean ± standard error (median). Kruskal- Wallis test, p≥0.05.
None of the differences were statistically significant. % tOP - time percentage the
animal spent in the open arms
reduced the level of anxiety in the animal`s adulthood. Similar
results were obtained with hyperic, which reduced anxiety in
the adulthood of offspring born from mothers treated during the
gestational period (Vieira et al., 2013). In contrast, the data
obtained in this study showed that the prenatal exposure to
valerian did not alter the levels of anxiety in the offspring as
tested in the elevated plus maze. Considering that various
subtypes of GABA A receptor showing functional and
morphological differences have already been identified (Olsen
and Sierghat, 2009), the difference between the information
found in the literature regarding intrauterine exposure to
International Journal of Recent Advances in Multidisciplinary Research
benzodiazepines and the obtained results regarding intrauterine
exposure to valerian could be due to the binding of
benzodiazepines and valerian to distinct subtypes of GABA A
receptors. In conclusion, despite the significant alterations
observed during the postnatal period, the findings presented in
this study indicate that either valerian is not crossing the
placenta or the exposure to valerian during gestation does not
alter neonatal development and anxiety of the animals in
adulthood.
Acknowledgments
Financial support by FAPEMIG Rede Toxifar: Rede 26/11;
Rede Bioterismo: Rede 31/11. The authors are grateful to Dr.
Cynthia Pekow for reviewing the English version of the
manuscript.
REFERENCES
Al-Majed, A.A., Al-Yahya, A.A., Al-Bekairi, A.M., AlShabanah, O.A. and Qureshi, S. 2006. Studies on the
cytological and biochemical effects of valerian in somatic
and germ cells of Swiss albino mice. Food Chem Toxicol.
44:1830–1837.
Benke, D., Barberis, A., Kopp, S., Altmann, K., Schubiger, M.,
Vogt, K.E, Rudolph, U. and Möhler, H. 2009. GABA A
receptors as in vivo substrate for the anxiolytic action of
valerenic acid, a major constituent of valerian root extracts.
Neuropharmacol. 56:174-181.
Beudoin, A.R.1985. The embryotoxicity of gossypol. Teratol.
32:251-257.
Boullata, J.I. and Nace, A.M.2000 Safety issues with herbal
medicine. Pharmacotherapy. 20:257–269.
Campos, M.L., Mourão-Juinior, C.A., Sá, R.C.S., Brandão,
M.A.F. and Guerra, M.O. 2014. Physical and
neurobehavioral development of rat offspring after maternal
exposure to Valeriana officinalis during gestation. Journal
of Medicinal Plant Research. 8(36): 928-935.
Carol, A.N., Linda, A.A. 1996. Herbal Medicines—A Guide
for Health-Care
Cherubini, E., Gaiarsa, J.L. and Ben-Ari, B. 1991. GABA: an
excitatory transmitter in early postnatal life. Trends
Neurosci. 14(12):515-519.
Chiavegatto, S., Oliveira, C.A. and Bernardi, M.M. 1997.
Prenatal exposure of rats to diphenhydramine: effects on
physical development, open field and gonadal hormone
levels in adults. Neurotoxicol and Teratol. 19:511–516.
Dorce, A.L.C., Bellot, R.G., Dorce, V.A.C. and Nencioni,
A.L.A. 2009. Effects of prenatal exposure to Tityus
bahiensis scorpion venom on rat offspring development.
Reprod Toxicol. 28:365–370.
Emerit, M.B., Riad, M., Hamon, M. 1992. Trophic effects of
neurotransmitters during brain maturation. Biol Neonate.
62(4):193–20.
Fox, M.W. 1965. Reflex ontogeny and behavioral development
of the mouse. Anim Behav. 13:234-245.
Goodman, A., Schorge, J. and Greene, M.F. 2001. The longTerm effects of in utero exposures- The DES Story. N Engl
J Med. 364:2083-2084.
Hadley, S. and Petry, J.J. 2003. "Valerian". American family
physician 67(8): 1755–1758.
Hobbs, C. 1989. Valerian Herbal Gram. 21:10-34 In:Yao, M.,
Ritchie, H.E. and Brown-Woodman, P.D. 2007. A
060
developmental toxicity-screening test of valerian. J
Ethnopharmacol. 113:204-209.
Holzl, J. and Godau, P. 1989. Receptor binding studies with
Valeriana officinalis on the benzodiazepine receptor. Planta
Med. 55:642.
Johnson, C.E. 1980. Permeability and vascularity of the
developing brain. Cerebellum vs cerebral cortex. Brain Res.
190:3-6.
Joseph, I. B and Angela M.N. 2000. Safety Issues with Herbal
Medicine: Common Herbal Medicine. Pharmacotherapy.
20(3): 257-269.
Kellogg, C.K., Taylor, M.K., Rodriguez-Zafra, M. and Pleger,
G.L. 1992. Altered stressor-induced changes in GABA
receptor function in the cerebral cortex of adult rats exposed
in utero to diazepam. Pharmacol Biochem Behav. 44:267–
273.
Kellogg, C.K., Yao, J. and Pleger, G.L. 2000. Sex-specific
effects of in utero manipulation of GABA receptors on preand postnatal expression of BDNF in rats. Dev Brain Res.
121:157–167.
Kelly, S.J., Ostrowski, N.L. and Wilson, M.A. 1999. Gender
differences in brain and behavior: hormonal and neural
bases. Pharmacol Biochem Behav. 64:655-664.
Lauder, J.M., Han, V.K.M., Henerson, P., Verdoon, T. and
Towle, A.C. 1986. Prenatal ontogeny of the GABAergic
system in the rat brains: an immunocytochemical
study. Neurosci. 19:465–493.
Marder, M., Viola, H., Wasowski, C., Fernández, S., Medina,
J.H. and Paladini, A.C. 2003. 6-methylapigenin and
hesperidin: new valeriana flavonoids with activity on the
CNS. Pharmacol Biochem Behav. 75 (3): 537–45
Mengue, S.S., Mentz, L.A. and Schenkel, E.P. 2001. Uso de
plantas medicinais na gravidez. Rev Bras Farmacogn.
11:21-35.
Mennini, T., Bernasconi, P., Bombardelli, E. and Morazzoni, P.
1993. In vitro study in the interaction of extracts and pure
compounds from Valerian officinalis roots with GABA,
benzodiazepine and barbiturate receptors. Fitoterapia.
64(4):291–300.
Miyasaka, L.S., Atallah, A.N. and Soares, B.G. 2006. Valerian
for anxiety disorders. Cochrane Database of Systematic
Reviews. 18, CD004515.
National Research Council. 2003. Manual sobre cuidado e uso
de animais delaboratório. Goiânia: National Academy Press.
Nguyen, L., Rigo, J.M., Rocher, V., Belacher, S., Malgrange,
B., Rogister, B., Leprince, P. and Moonen, G. 2001.
Neurotransmitters as early signals for central nervous
system development. Cell Tissue Res. 305:187–202.
Nicosia, A., Giardina, L., Di Leo, F., Medico, M., Mazzola, C.,
Genazzani, A.A. and Drago F. 2003. Long-lasting
behavioral changes induced by pre-or neonatal exposure to
diazepam in rats. Eur J Pharmacol.469:103–109.
Oliveira, C.D.R., Moreira, C.Q., Spinosa, H.S. and Yonamine,
M. 2011. Neurobehavioral, reflexological and physical
development of Wistar rat offspring exposed to ayahuasca
during pregnancy and lactation. Rev Bras Farmacogn.
26:1065-1076.
Olsen, R.W. and Sierghat, W. 2009. GABA A receptors:
Subtypes provide diversity of function and pharmacology.
Neuropharmacol. 56:141–148.
Owens, D.F., Boyce, L.H, Davis, M.B. and Kriegstein, A.
1996. Excitatory GABA responses in embryonic and
neonatal cortical slices demonstrated by gramicidin
International Journal of Recent Advances in Multidisciplinary Research
perforated-patch recordings and calcium imaging. J
Neurosci. 16:6414-6423.
Pellow, S., Chopin, P., File, S.E. and Briley, M. 1985.
Validation of open:closed arm entries in an elevated plusmaze as a measure of anxiety in the rat. J Neurosci
Methods. 14:149-167.
Professionals. The pharmaceutical Press, London. In: Yao, M.,
Ritchie, H.E. and Brown-Woodman, P.D. 2007. A
developmental toxicity-screening test of valerian. J
Ethnopharmacol. 113:204-209.
Rodgers, R.J., Dalvi, A. 1997. Anxiety, defence and the
elevated plus-maze. Neurosci Biobehav Rev. 21:801-810.
Schroeder, H., Humbert, A.C., Desor, D. and Nehlig, A.1997.
Long-term consequences of neonatal exposure to diazepam
on cerebral glucose utilization, learning, memory and
anxiety. Brain Res. 766:142–152.
Taylor, M. 2002. Alternative medicine and perimenopause. An
evidence-based review. Obstet Gynecol Clin N Am. 20:555573.
061
Tesche, B.J., 2002. Herbs commonly used by women: an
evidence-based review. Dis. Mon, 48:671-696.
Tuffik, S., Fujita, K., Seabra, M.L.V.K. and Lobo, L.L. 1994.
Effects of a prolonged administration of valepotriates in rats
on the mothers and their offspring. J Ethnopharmacol.
41:39-44.
Vieira, V.A., Campos, L.V., Silva, L.R., Guerra, M.O., Peters,
V.M. and Sá, R.C.S. 2013. Evaluation of postpartum
behaviour in rats treated with Hypericum perforatum during
gestation. Rev Bras Farmacogn. 23: 796-801.
Vorhees CV, Rindler JM. 1990. Effects of exposure period and
nutrition on the developmental neurotoxicity of
anticonvulsants in rats: short and long-term effects.
Neurotoxicol.11:273-283.
Yao, M., Ritchie, H.E. and Brown-Woodman, P.D. 2007. A
developmental toxicity-screening test of valerian. J
Ethnopharmacol. 113:204-209.
*******