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Abstract: The effect of chronic administration of phenobarbitone on uterotrophic potency, estrous cycle, and their gravimetrical, histological and
biochemical changes has been studied. Three groups of healthy adult female albino rats having six rats in each group were taken. The rats of groups
II and III were administered Phenobarbitone at the dose level 5.00mg and 7.5mg/100g body weight respectively intraperitoneally/daily for 30 days.
However, the rats of group I (Control) were given saline alone. Completions of the experimental periods, the rats were sacrificed and the histological
study of uterus was performed. The estrous cycles of these rats were irregular with prolonged diestrus and reduced oestrus, estrus and metaestrus
phases also support the decreased estrogen synthesis. Responsible for cornification of vaginal smear in phenobarbitone treated rats and
histometrical changes of uterine parameters like diameter, thickness of myometrium and endometrium and surface epithelial cell height were
decreased significantly. Biochemical changes of endocrine glands are parallel to the gravimetrical changes, the protein and glycogen contents are
decreased significantly and increased cholesterol content significantly due to the phenobarbitone administration.
Keywords: Phenobarbitone, Uterotrophic activity, Endocrine, Estrous cycle, Rat
INTRODUCTION
Reproduction is a complex and continuous process that starts before
birth and continues through puberty and a series of endocrine and
behavioral events that include estrous cycles, ovulation, breeding,
conception, gestation, parturition and lactation. Phenobarbitone is a
commonly used antiepileptic belonging to barbiturate group. The
exact mechanism of action of phenobarbitone is not known, but
enhancement of inhibitory processes and diminution of excitatory
transmission are known to contribute for the antiepileptic activity
[1]. The most common adverse effect following administration of
phenobarbitone includes sedation, depression, nystagmus, ataxia,
paradoxical
excitement,
restlessness,
and
confusion.
Hypersensitivity reactions occur in a small proportion of patients.
Phenobarbitone is also known to cause skin reactions in 1 to 3% of
patients, the common ones being maculopapular, morbilliform, or
scarlatiniform rashes [2]. Prolonged treatment of barbiturates to
immature or pregnant rats decreases the uterotrophic potency to
synthetic estrogens or cause foetal resorption or abortion
respectively [3-4]. Besides, these sedatives may interfere in the
conversion of pregnenolone to progesterone, thus altering the
steroidal environment essential for ovulation [5]. Secretion of
pituitary gonadotrophins are regulated by brain and neurons
situated in the anterior part of the hypothalamus which synthesize
the gonadotrophin releasing hormones (GnRH) [6]. Therefore, it is
aimed to study the chronic effects of phenobarbitone on female
reproductive activities like uterotrophic potency and estrous cycle
in adult female rats. The gravimetric, histological, micrometric and
biochemical methods are employed to analysis the uterotrophic
potency.
Phenobarbitone:
Phenobarbitone is a barbiturate, marketed between 1934-1945
under the brand name Luminal by Friedr Bayer et al., the first
barbiturate drug, barbital, was synthesized in 1902 by German
chemists Emil Fischer and Joseph Von Mering at Bayer. By 1904
several related drugs, including phenobarbitone, had been
synthesized by Fischer. Phenobarbitone was brought to market in
1912 by the drug company Bayer using the brand Luminal. It
HN
3d-Structure of Phenobarbitone
Materials Methods
Rat is used as experimental animal model since 1856. Since its
domestication, the rat has probably contributed more substantially
to the advancement of the biological sciences than any other
laboratory species. Therefore, in the present study the rat in used as
experimental model.
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Sl. No.
1
2
3
Sl. No.
Treatment
Control
(0.2ml Saline)
Phenobarbitone
(5.00mg)
Phenobarbitone
(7.5mg)
2
3
Proestrus
4.41 0.31
4.02 0.25
3.98 0.42
Table 3: Effect of Phenobarbitone on Uterine Gravimetric and Biochemical Parameters in Albino Rats
Sl. No.
Treatment
1
2
Control
(0.2ml Saline)
Phenobarbitone (5.00mg)
Phenobarbitone (7.5mg)
Uterus Wt.
mg/100g body
wt.
205.91 8.59
Cholesterol
g/mg
Protein g/mg
Glycogen
g/mg
4.18 0.09
8.18 0.2
1.98 0.05
167.04** 3.84
5.89** 0.07
6.89*** 0.05
1.60* 0.05
148.47***
4.50
6.96*** 0.06
5.89*** 0.07
1.56* 0.08
Treatment
Uterus diameter
(
m)
Thickness of
Myometrium (
m)
Thickness of
Endometrium (
m)
Height of epithelial
cell (
m)
Control
(0.2ml Saline)
Phenobarbitone
(5.00mg)
Phenobarbitone (7.5mg)
631.96 22.16
169.61 8.04
390.78 7.56
32.33 1.40
462.23*** 17.03
105*** 1.88
310.82*** 2.26
26.22* 1.55
305.12*** 11.62
88.06*** 0.97
285.06*** 0.14
20.65*** 1.02
2
3
Animals
Healthy, sexually matured, regularly cycling, colony bred virgin
female rats of Wistar strain (Rattus norvegicus) aged three months
and weighing 150 -200 gm were purchased from National Institute
of Nutrition, Hyderabad. The rats were housed in polypropylene
cages measuring 12x108, under well ventilated animal house
conditions (temperature: 28-31C, photoperiod: 12 hours natural
light and 12 hours natural dark, humidity: 50-55%). The rats were
fed with balanced diet as per CFTRI formula and tap water ad
libitum. They were maintained as per the principles of laboratory
animals care (NIH Publication No. 85-88, 1985).
The animals were divided into three groups, each consisting of six
rats in each group and treated as follows.
Group-I: Control, received 0.2 ml saline/ 100gm body weight.
Group-II: Received 5.0 mg phenobarbitone / 100gm body weight
Group- III: Received 7.5 mg phenobarbitone / 100gm body weight.
The body weight of each rat was recorded every day before the
treatment. The treatment for each rat was started at estrous phase.
Vaginal smears from each rats were monitored daily, only rats with
normal estrous cycles [7-8] were selected for the experiment, to study
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RESULTS
Genaral Observations
Behavior
The rats which received the chronic treatment of phenobarbitone
were as active as the control rats. The phenobarbitone treatment
caused sedation for 3 to 6 hours. This sedation caused is dose
dependent. After period of sedation the animals show normal
activities. However, the total intake of feed/day is not much altered
due to drug administration.
Mortality
No mortality is observed in either control group or in the
experimental group that received phenobarbitone.
DISCUSSION
The principle of CNS influencing drugs is the anticonvulsants,
antiparkinsonism drugs, opioid and non-opioid analgesics, appetite
suppressants, antiemetics, analgesics, antipyretics, certain
stimulants, neutolectics, transquilizers sedatives and hypnotics.
These drugs are known to interfere with the functions of CNS
including hypothalamus there by modify the activity of hypophysis
and gonads. The secretion and release of pituitary follicle
stimulating hormone (FSH), luteinizing hormone (LH) and prolactin
(PRL) are directly dependent on hypothalamic releasing hormonesGnRH. Therefore, the drugs which modify the functions of CNS may
also affect the pituitary functions.
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