Sodium valproate-induced menstrual disturbance in young women

Two young girls with epilepsy presented with menstrual disturbances whilst on treatment with sodium valproate. On withdrawing valproate therapy, period cyclicity returned to normal in both individuals. An exaggerated luteinising hormone response to parenterally administered gonadotropin-releasing hormone was present in both subjects. The temporal relationship between normalisatin of periods and stopping the sodium valproate suggests that this drug may possibly affect the control of the menstrual cycle through a GABAergic mechanism.     

丙戊酸钠抑制A549细胞生长

目的研究丙戊酸钠对肺癌A549细胞增殖和细胞周期的影响。方法MTT检测生长抑制,流式细胞仪检测细胞周期和凋亡,Western blot检测p21WAF1/CIP1蛋白表达。结果丙戊酸钠以剂量依赖性方式抑制A549细胞生长;丙戊酸钠上调G0/G1期比例,下调S期和G2/M期,不影响细胞凋亡;丙戊酸钠上调p21WAF1/CIP1蛋白表达。结论丙戊酸钠上调p21WAF1/CIP1表达,使细胞阻滞于G0/G1期,抑制A549细胞生长。     

Influences of the adrenal gland and photoperiod on the hamster oestrus cycle

The influence of the adrenal gland and photoperiod on the adult female hamster estrous cycle was investigated. Hamsters were exposed to 14 hours of light per day and estrous cycles were monitored. Normal cycles were characterized by a copious discharge every 4th day. Hamsters were then adrenalectomized, adrenalectomized and blinded, or blinded only. Adrenalectomized/blinded hamsters were given a .2% sodium saccharine-1%(w/v) sodium chloride solution to drink which promotes long-term survival in most adrenalectomized hamsters. With blinding alone, it took from 18 to 62 days for cessation of estrous cycles. Cycles ceased in a mean of 36.2 days in blinded/adrenalectomized hamsters. After adrenalectomy only, 3 hamsters continued to show 4-day estrous cycles for at least 9 weeks in response to the long days. 6 adrenalectomized animals died due to adrenal insufficiency but displayed several 4-day estrous cycles. It is suggested that in the hamster, adrenal hormones are nonessential for the long-term expression of estrous cyclicity. However, further research is needed to determine whether adrenal hormones are capable of modulating photoperiodic time measurement or ovarian regression.     

Methionine decreases the embryotoxicity of sodium valproate in the rat: in vivo and in vitro observations.

Methionine provided in the drinking water of pregnant rats injected with sodium valproate reduced the frequency of resorptions but did not improve embryo growth. Rats drinking methionine supplemented water had approximately twice the level of serum-free methionine and consumed only one-half the volume of water of controls. Using whole rat embryo cultures, the simultaneous addition of methionine and sodium valproate to the medium provided no protection from neural tube defects, nor did the addition of methionine to a medium of serum obtained from rats previously dosed with sodium valproate. However, protection from the teratogenic effects of sodium valproate was afforded by methionine when the culture medium was sera from rats consuming methionine and was particularly striking when embryos for culture were taken from pregnant rats that had been consuming methionine. These observations along with those of others indicated the importance of dietary and culture media methionine levels in evaluating experimental and regulatory teratology studies and suggested the possibility that methionine may play an important role in human teratology where multifactorial causes have been implicated in problems such as neural tube closure defects.     

Effect of sodium valproate on the secretion of proopiomelanocortin derived peptides from cultured rat anterior pituitary cells

We examined effects of sodium valproate, a gamma amino butyric acid (GABA)-transaminase inhibitor, on the secretion of immunoreactive (IR)-ACTH and IR-beta-endorphin/LPH from cultured rat anterior pituitary cells to determine whether sodium valproate has a direct action on the secretion of ACTH and its related peptides from the cultured rat anterior pituitary gland. During the 3 h incubation, the basal secretion of IR-ACTH and IR-beta-endorphin/LPH decreased to 50.8% and 58.3%, respectively, of the control concentration after adding 10(-7) M sodium valproate into the incubation media and to 67.7% and 69.3%, respectively, of the control levels with 10(-8) M sodium valproate. However, sodium valproate at a concentration of 10(-6) M or 10(-9) M did not affect the basal concentration of IR-ACTH and IR-beta-endorphin/LPH. Sodium valproate at a concentration of 10(-7) M significantly attenuated the stimulated release of IR-ACTH and IR-beta-endorphin/LPH by 10(-9) or 10(-10) M of ovine corticotrophin releasing factor. These results indicate that sodium valproate could directly effect rat anterior pituitary cells to suppress both basal and stimulated release of proopiomelanocortin derived peptides and this supports the hypothesis that sodium valproate has a direct effect at the pituitary corticotroph in reducing plasma ACTH.     

Regulation of the estrous cycle by neutrophils via opioid peptides

We found previously that neutrophil-depleted mice exhibited significant blockading of both the regular estrous cycle and cyclic changes of steroid hormone levels. In this study, we aimed at elucidation of the underlying mechanism. To examine the possibility that an increase in bacteria in the vaginal vault of neutrophil-depleted mice causes blockading of the estrous cycle, we treated neutrophil-depleted mice with antibiotics but failed to restore the estrous cycle. We then examined another possibility that neutrophils regulate the estrous cycle via opioid peptides, because opioid peptides regulate steroidogenesis in theca and granulosa cells in the ovaries, and because neutrophils contain opioid peptides. In support of this possibility, naloxone, an opioid antagonist, blocked the estrous cycle and a μ opioid receptor agonist restored the estrous cycle in neutrophil-depleted mice. Pro-opiomelanocortin was immunohistochemically detected in peripheral blood neutrophils but not in ones that had infiltrated into the ovaries. i.v. injection of anti-MIP-2 polyclonal Ab caused blockading of the estrous cycle, whereas MIP-2 was detected in the ovaries, suggesting a role of MIP-2 in the regulation of the estrous cycle. Moreover, i.v. injection of MIP-2 decreased the pro-opiomelanocortin signal in peripheral blood neutrophils and caused blockading of the estrous cycle. Together, these results suggest that neutrophils maintain the estrous cycle via opioid peptides.     

Cannulation of the equine oviduct and chemical analysis of oviduct fluid

Siliconized rubber tubes were used to cannulate one oviduct in 7 mares, and secretions were collected in a polycarbonate container located externally, in the region of the left paralumbar fossa. Secretion rates were recorded daily during the estrous cycle. Concentrations of calcium, magnesium, sodium, potassium, inorganic phosphorus and glucose were determined in the oviduct fluids secreted throughout the estrous cycle. Secretion rates were greatest during estrus (days 1-9), with a significant decrease (P<.01) noted during nonestrus (days 10-21). Concentrations of all constitutents measured were low during estrus, with a marked elevation in concentration during the nonestrus period. Histologic examination of oviducts following long-term cannulation demonstrated infiltration of lymphocytes, plasma cells, and small areas of degenerated epithelium.     

Sodium valproate and brainstem energetics

The effect of the anticonvulsant sodium valproate on cerebral brainstem energy metabolism has been investigated. Stupor and coma were produced in mice by the intraperitoneal injection of sodium valproate at a dose of 600 mg/kg. Glucose, glycogen, ATP, and phosphocreatine were measured in small tissue samples from the ascending reticular activating system. Levels of all metabolites were either normal or elevated in precoma and comatose mice as compared to controls. These data are consistent with the concept that sodium valproate does not have a primary action through depletion of high energy phosphates.     

Controlled trial of sodium valproate in severe epilepsy.

In a double-blind crossover trial sodium valproate or placebo was added to the existing anticonvulsant treatment of 20 patients with chronic uncontrolled epilepsy. Sodium valproate 1200 mg/day significantly reduced the frequency of both tonic-clonic and minor seizures in these patients. Only mild and transient side effects occurred (drowsiness, ataxia, and nausea), and these may have been due to the effect of adding sodium valproate to existing phenobarbitone or phenytoin treatment. Further controlled trials are needed to assess more fully the efficacy of this drug in various types of epilepsy.     

Up-regulation of hippocampal glutamate transport during chronic treatment with sodium valproate

Excessive glutamatergic neurotransmission has been implicated in some neurodegenerative disorders. It would be of value to know whether glutamate transport, which terminates the glutamate signal, can be up-regulated pharmacologically. Here we show that chronic treatment of rats with the anti-epileptic drug sodium valproate (200 mg or 400 mg/kg bodyweight, twice per day for 90 days) leads to a dose-dependent increase in hippocampal glutamate uptake capacity as measured by uptake of [(3)H]glutamate into proteoliposomes. The level of glutamate transporters EAAT1 and EAAT2 in hippocampus also increased dose-dependently. No effect of sodium valproate on glutamate transport was seen in frontal or parietal cortices or in cerebellum. The hippocampal levels of glial fibrillary acidic protein and glutamine synthetase were unaffected by valproate treatment, whereas the levels of synapsin I and phosphate-activated glutaminase were reduced by valproate treatment, suggesting that the increase in glutamate transporters was not caused by astrocytosis or increased synaptogenesis. A direct effect of sodium valproate on the glutamate transporters could be excluded. The results show that hippocampal glutamate transport is an accessible target for pharmacological intervention and that sodium valproate may have a role in the treatment of excitotoxic states in the hippocampus.     

Fluctuations of hippocampal neuronal protein levels over the estrous cycle in the rat

Hippocampal function is known to be estrous-cycle-dependent but information on estrous-cycle-dependent protein expression is limited. It was therefore the aim to study protein levels of the neuronal network over the estrous cycle in the hippocampus of female rats and in males showing protein chemical neuroanatomy in this area. Female and male OFA Sprague-Dawley rats were used and females were grouped to proestrous, estrous, metestrous and diestrous by using vaginal smears. Hippocampal tissue was taken, proteins extracted, run on two-dimensional gel electrophoresis and proteins were identified by mass spectrometry methods (MALDI-TOF-TOF and nano-LC-ESI-MS/MS). Spot volumes were quantified with specific software. A Synapsin-1 expression form was differentially regulated between proestrous and diestrous, a Synapsin IIa expression form was differentially regulated between proestrous and metestrous, the sum of ERC-2 proteins organizing the cytomatrix at the nerve terminals active zone was showing sex-dependent levels in the proestrous phase and Neurofilament triplet L protein was differentially expressed between the estrous phase and males. The findings may represent estrous-cycle-dependent hippocampal synaptic function that has been shown already in terms of electrophysiology and neuroanatomy. Neurofilament changes over the estrous cycle may reflect endoskeleton changes over the estrous cycle. We learn from this study, although increasing complexity of protein knowledge, that the estrous cycle and not only the sex per se has to be taken into account for design of future studies and interpretation of previous work at the protein level.     

Fluctuation of Aquaporin 1, 5, and 9 Expression in the Pig Oviduct during the Estrous Cycle and Early Pregnancy

Thirteen mammalian aquaporin (AQPs) isoforms with a unique tissue-specific pattern of expression have been identified. To date, 11 isoforms of AQP have been reported to be expressed in female and male reproductive systems. The purpose of our study was to determine the localization and quantitative changes in the expression of AQP1, 5 and 9 within the pig oviduct during different stages of the estrous cycle and early pregnancy. The results demonstrated that AQP1, 5, and 9 were clearly detected in all studied stages of the estrous cycle and pregnancy. AQP1 was localized within oviductal blood vessels. In cyclic gilts, the expression of AQP1 protein did not change significantly between days 10–12 and 14–16 but increased on days 2–4 and 18–20. AQP5 was localized in smooth muscle cells and oviductal epithelial cells. The expression of AQP5 protein did not change significantly between days 10–12 and 14–16 of the estrous cycle but increased on days 2–4 and 18–20. The anti-AQP9 antibody labeled epithelial cells of the oviduct. The expression of AQP9 did not change significantly between days 10–12 and 14–16 of the estrous cycle but increased on days 2–4 and 18–20. In pregnant gilts, expression of AQP1, 5, and 9 did not change significantly in comparison with the estrous cycle. Therefore, a functional and distinctive collaboration seems to exist among diverse AQPs in water handling during the different oviductal phases in the estrous cycle and early pregnancy.     

Announcement

Abstract

The Gastrin content has been estimated in the antral mucosae of male and female rats in different phases of the estrous cycle. Gastrin content appears to be highest in the rats at di‐estrous cycle end lowest in the rats at pro‐estrous. There is not much difference between the gastrin content at estrous and pro‐estrous. The gastrin content in the antral mucosa of male rats is higher than in rats a both estrous and pro‐estrous but it is about the same amount in rats at di‐estrous. The possible role of the circulating sex hormones on the storage of gastrin in the antral mucosa of rats has been discussed.     

The Presentation Rate of Chemical Signals of the Domestic Cat <Emphasis Type="Italic">Felis catus</Emphasis> Affects the Reproductive Status of the House Mouse

The effects of the presentation rate of the domestic cat chemical L-felinine (0.05%) on the regulation of the estrous cycle in the house mouse were studied. It has been found that L-felinine has an interspecific effect and affects regulation of the estrous cycle in the house mouse. It has been observed that the effect may be diverse depending upon the mode of exposure to L-felinine. Chronic exposure of mice to the cat chemical signal resulted in an activating effect that significantly increased the ovulation rate within a fixed time interval, whereas regular intermittent exposure to L-felinine caused a significant reduction in the number of cyclic females comparing to the control group, as well as lengthening of the estrous cycle in cycling females. It has also been indicated that repeated exposure to the chemical signal in a regular intermittent mode throughout the experiment did not cause habituation in mice; on the other hand, a similar effect was weaker when exposure to L-felinine was in the spontaneous mode.     

Evidence of ovulation in goats (Capra hircus ) with short estrous cycle and its occurrence in the tropics

The influence of season and exposure to buck on the length of the estrous cycle were determined in 32 normally cycling native goats of different ages and parity. The estrous cycle durations were classified as short, medium and long. Ten goats (31%) exhibited medium length estrous cycles; 22 animals (69%) exhibited a combination of short, medium and long estrous cycles. Of the 155 estrous cycles studied, 15% were short, 72% were medium and 13% were long. Short estrous cycles were significantly shorter (P < 0.01) in estrus duration than medium or long estrous cycles. Significant differences (P < 0.05) for estrous cycle length and estrus duration were found between does but not within does. The presence of a buck for 8 to 16 h showed no significant effect on the length of the estrous cycle or on estrus duration, but a 24-h exposure period to a buck yielded shorter estrous cycles and estrus duration than found in the unexposed control group. Estrous cycles were significantly shorter (P < 0.01) in October, when rainfall is 57.9% of the annual total, and significantly longer (P < 0.01) in February, when rainfall is low at 0.2% of the annual total. A negative linear relationship (r = -0.87) was observed between estrous cycle and rainfall. Twenty-eight (90.3 %) of the short estrous cycles were ovulatory. The short cycles had a relatively lower ovulation rate than medium and long estrous cycles. The results indicate that the short estrous cycle in goats is associated with ovulation, and its occurrence in the tropics is related to rainfall.     

Prostaglandin metabolism in the ovine corpus luteum: catabolism of prostaglandin F(2alpha) (PGF(2alpha)) coincides with resistance of the corpus luteum to PGF(2alpha)

To examine possible mechanisms involved in resistance of the ovine corpus luteum to the luteolytic activity of prostaglandin (PG)F(2alpha), the enzymatic activity of 15-hydroxyprostaglandin dehydrogenase (PGDH) and the quantity of mRNA encoding PGDH and cyclooxygenase (COX-2) were determined in ovine corpora lutea on Days 4 and 13 of the estrous cycle and Day 13 of pregnancy. The corpus luteum is resistant to the action of PGF(2alpha) on Days 4 of the estrous cycle and 13 of pregnancy while on Day 13 of the estrous cycle the corpus luteum is sensitive to the actions PGF(2alpha). Enzymatic activity of PGDH, measured by rate of conversion of PGF(2alpha) to PGFM, was greater in corpora lutea on Day 4 of the estrous cycle (P < 0.05) and Day 13 of pregnancy (P < 0.05) than on Day 13 of the estrous cycle. Levels of mRNA encoding PGDH were also greater in corpora lutea on Day 4 of the estrous cycle (P < 0. 01) and Day 13 of pregnancy (P < 0.01) than on Day 13 of the estrous cycle. Thus, during the early estrous cycle and early pregnancy, the corpus luteum has a greater capacity to catabolize PGF, which may play a role in the resistance of the corpus luteum to the actions of this hormone. Levels of mRNA encoding COX-2 were undetectable in corpora lutea collected on Day 13 of the estrous cycle but were 11 +/- 4 and 44 +/- 28 amol/microgram poly(A)(+) RNA in corpora lutea collected on Day 4 of the estrous cycle and Day 13 of pregnancy, respectively. These data suggest that there is a greater capacity to synthesize PGF(2alpha), early in the estrous cycle and early in pregnancy than on Day 13 of the estrous cycle. In conclusion, enzymatic activity of PGDH may play an important role in the mechanism involved in luteal resistance to the luteolytic effects of PGF(2alpha).     

Changes of Body Temperature and Thermoregulation in the Course of the Ovarian Cycle in Laboratory Mice

In the course of the ovarian cycle, numerous physiological functions, particularly body temperature, undergo pronounced changes. The role played in cycle-dependent changes by activity is still a matter of debate. In female laboratory mice, body temperature and motor activity have been measured telemetrically, every 10 min for one month, while the stage of the estrous cycle was determined by means of vaginal smears. The circadian rhythm of body temperature underwent regular infradian changes corresponding to the sexual cycle, with body temperature higher on the days of estrous. Also, the level of motor activity was slightly elevated on days of estrous, though less consistently so. As shown by the method of purification, the temperature increase on the days of estrous was not caused by the higher activity but, presumably, rather by hormonal changes around the time of ovulation. After removing the direct effect of motor activity on the body temperature, the difference between estrous and non-estrous days was even more marked. The purification method also enabled the gradient of temperature change per unit activity, a measure of thermoregulatory efficiency, to be estimated. This gradient was lower on the days of estrous, mainly because of the higher temperatures then, but also partly due to changed thermoregulatory mechanisms. Thus, it would seem that hormones not only increase the body temperature in estrous but also promote-heat loss mechanisms. Despite the quite marked cycle-dependent changes in body temperature, it was not possible to use the temperature profile on a particular day to classify that day as an estrous or a non-estrous day; only a consideration of data from several consecutive days allowed this determination to be made.     

Asynchrony in the estrous cycles of golden hamsters (Mesocricetus auratus)

The golden hamster has been described as exhibiting estrous cycle synchrony caused by social dominance. This has recently been reexamined by J. C. Schank (2000, Horm. Behav. 38, 94-101) with the aid of computer simulations. He concluded that there is no evidence for cycle synchrony among golden hamsters. In the present article we confirm this theoretical approach with the help of long-term experiments. Indeed, estrous cycle asynchrony was observed. Singly housed female golden hamsters in phase with their neighbors and in physical contact desynchronized their 4-day cycles after 2 or 3 weeks. Asynchrony was caused mainly by stochastic 5-day cycles. Statistical analysis was performed using a Monte-Carlo bootstrap approach. Based on the empirical data, an individual-based computer model was developed to simulate the dynamics of cycle desynchronization. Potential advantages were deduced for the population level. It emerged that estrous cycle asynchrony led to higher reproductive success for females where the probability of fertilization was low (e.g., after hibernation, poor habitat).