Effect of ethanol ingestion on tryptophan metabolism in streptozotocin diabetic rats

Ingestion of ethanol by albino rats affected brain liver and plasma tryptophan contents in both normal and diabetic animals, although at different rates. Liver tryptophan was increased in both the groups, whereas tryptophan levels in brain and plasma of normal group were decreased and those of diabetic group were increased after the treatment. Similarly, while hepatic tryptophan dioxygenase activity was decreased in both the groups, activity of hepatic 3-hydroxykynureninase was increased only in normal rats and that of liver picolinic carboxylase was significantly decreased only in the diabetic group after ethanol administration.     

Chronic ethanol consumption induces histopathological changes and increases nitric oxide generation in the rat liver

In the present work we evaluated the effect of ethanol consumption in histopathological liver changes and several biochemical biomarkers employed in the detection of hepatic dysfunction. Male Wistar rats were treated with ethanol 20% (vol/vol) for 6 weeks. Histopathological investigation of livers from ethanol-treated animals revealed steatosis. Indices of hepatic function (transaminases) and mitochondrial respiration were not altered in ethanol-treated rats. Chronic ethanol consumption did not alter malondialdehyde (MDA) levels in the liver. Ethanol consumption induced a significant increase on hepatic nitrite and nitrate levels. Treatment with ethanol increased both mRNA expression and immunostaining of iNOS, but not eNOS. Finally, ethanol consumption did not alter hepatic levels of metalloproteinase (MMP)-2 and MMP-9. We conclude that alterations on biochemical biomarkers (nitrite and nitrate levels) and histopathology occurred in ethanol-treated rats, supporting the practice of including both types of evaluation in toxicity studies to detect potential ethanol-related hepatic effects. In our model of ethanol consumption, histopathological liver changes were accompanied by elevation in nitrite and nitrate levels indicating increased nitric oxide (NO) generation. Since iNOS-derived NO contributes to hepatic injury, the increased levels of NO described in our study might contribute to a progressive hepatic damage. Therefore, increases in NO generation may be an early indicator of ethanol-induced liver damage.     

Hepatic calcium-binding protein regucalcin concentration is decreased by streptozotocin-diabetic state and ethanol ingestion in rats

The alteration in calcium-binding protein regucalcin in the liver and serum of rats with streptozotocin (STZ)-diabetic state or ethanol ingestion was investigated. STZ (6.0 mg/100 g body weight) was subcutaneously administered in rats, and 1 or 3 weeks later they were sacrificed by bleeding. Liver regucalcin mRNA levels were not clearly altered by the diabetic state, as evidenced by Northern blotting using regucalcin cDNA (0.9 kb of open reading frame). Based on enzyme-linked immunoadsorbent assay (ELISA) with rabbit-anti-regucalcin IgG, hepatic regucalcin concentration was decreased about 50% of control levels by STZ treatment. However, serum regucalcin concentration was not significantly altered by STZ treatment. Meanwhile, when rats ingested ethanol (10 and 30%) in the drinking water for 2 weeks, liver regucalcin mRNA levels were clearly increased, although hepatic regucalcin concentration was significantly decreased. Serum regucalcin concentration was not appreciably altered. Serum transaminases (GOT and GPT) activities were significantly increased at 1 or 3 weeks after STZ administration in rats, while their activities were not altered by ethanol ingestion. The present study demonstrates that hepatic regucalcin concentration is decreased independent of mRNA expression in the STZ-diabetes and during ethanol ingestion in rats.     

Effects of acute ethanol administration on female rat liver as a function of aging

Female Fischer 344 rats, aged 4, 14, and 25 months, received 4.0 g/kg of ethanol by intraperitoneal (i.p.) injection. Blood alcohol concentrations 2.5, 6 and 16 hr after ethanol injection were similar in the three age groups. Hepatic glutathione (GSH) levels were diminished 6 hr after ethanol injection, and there were no age-dependent differences in the depleted levels (3.2 +/- 0.1, 3.5 +/- 0.2, and 3.0 +/- 0.5 micrograms GSH/g liver). However, GSH contents in livers of young-adult rats approached control levels after 16 hr, whereas they remained depressed in older rats. Serum levels of hepatic enzymes were significantly elevated 6 hr after ethanol administration. The increases were greater in middle-aged and old rats than in young-adult rats. The results suggest that middle-aged and old rats are more susceptible than young rats to the acute toxicity of ethanol.     

Chronic low dose ethanol intake: biochemical characterization of liver mitochondria in rats

Liver mitochondria were isolated from male rats exposed for 2 months to low doses of ethanol (3% v/v in drinking water), a condition not associated with tolerance or dependence. The results show no significant changes in the content of reduced or oxidized glutathione in the liver mitochondria of ethanol treated rats with respect to controls. However, a slight but significant increase in lipid peroxidation, accompanied by an increased content of oxidized proteins, was found in ethanol exposed animals. Mitochondrial content of cytochrome complexes was not significantly affected by ethanol intake. The specific enzymatic activity of cytochrome oxidase showed, however, a significant decrease in ethanol-treated rats. The slight mitochondrial alterations found in the liver of rats exposed chronically to low doses of ethanol might represent the beginning of a more extensive damage previously observed in rats exposed to high doses of this substance.     

Modulation of prolactin binding sites in vitro by membrane fluidizers. IV. Differential effects on plasma membrane and Golgi fractions of male prostate and female liver in the rat

In vitro treatment of crude particulate fractions of male rat ventral prostate and female rat liver with membrane fluidizers (aliphatic alcohols) has been previously reported by us to increase prolactin (PRL) receptor levels, presumably by unmasking cryptic prolactin receptors. The objective of this study was to determine if similar in vitro treatment of purified plasma membrane- and Golgi-rich fractions of male rat prostate and female rat liver with ethanol produced differential effects on prolactin binding in these two subcellular fractions. The degree of fluidization was monitored by a fluorescence polarization method using 1,6-diphenylhexatriene. 125I-PRL specific binding to Golgi-rich fractions of male ventral prostate and female liver was approximately 4-fold higher than that observed in plasma membrane-rich fractions. The microviscosity parameter, inversely related to lipid fluidity, was consistently lower in Golgi-rich fractions than that in plasma membrane-rich fractions in both prostate and liver. In vitro ethanol treatment of prostatic and hepatic plasma membrane fractions produced a dose-related increase and then decline in prolactin binding and a maximal (60-75%) increase in prolactin binding was observed at 4.8% and 2.0% ethanol in prostatic and hepatic membranes, respectively. This in vitro treatment also produced a significant increase in apparent lipid fluidity of plasma membrane-rich fractions of prostate gland and liver. However, similar in vitro ethanol treatment of Golgi fractions of both prostate gland and liver exhibited little increase in prolactin binding without changing microviscosity. Our observations are consistent with the direct relationship between membrane fluidity and prolactin receptor levels. The changes in prostatic and hepatic plasma membrane fractions following in vitro ethanol treatment suggest that prolactin receptors located on the plasma membranes may be modulated (via membrane lipid microviscosity changes) in vivo to a greater extent by various physiological agents than those located within the Golgi fraction.     

Effect of chronic ethanol administration on gamma-glutamyltransferase activities in plasma and in hepatic plasma membranes of male and female rats

The effects of chronic ethanol administration on the activities of gamma-glutamyltransferase (GGT) in plasma and in hepatic plasma membranes of male and female rats are studied. The effects of alcohol on the lipid level in plasma are also investigated. After 4 weeks of treatment, GGT activity significantly increases in plasma either in male rats (131%, p less than 0.02) or in female ones (64%, p less than 0.05). In addition, chronic alcohol consumption simultaneously increases beta-lipoprotein and triglyceride levels in plasma only in male rats (181%, p less than 0.05 and 171%, p less than 0.01, respectively). In the liver, a significant elevation of GGT activity is observed in plasma membranes (146% in male rats, p less than 0.02, and 84% in female rats, p less than 0.02) but neither in homogenates nor in microsomal fractions. So, the variation of enzymatic activity in plasma as well as in hepatic plasma membranes is higher in male than in female rats. These results demonstrate, as for phenobarbital, that alcohol provokes an induction of GGT in rat liver only in the plasma membrane fraction.     

Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver

The involvement of oxidative stress in the pathogenesis of alcoholic diseases in the liver has been repeatedly confirmed. Resveratrol, a natural phytoalexin present in grape skin and red wine possesses a variety of biological activities including antioxidant. This study was conducted to evaluate whether resveratrol has a preventive effect on the main indicators of hepatic oxidative status as an expression of the cellular damage caused by free radicals, and on antioxidant defence mechanism during chronic ethanol treatment. Wistar rats were treated daily with 35% ethanol solution (3 g/kg/day i.p.) during 6 weeks and fed basal diet or basal diet containing 5 g/kg resveratrol. Control rats were treated with i.p. saline and fed basal diet. Experimentally, chronic ethanol administration leads to hepatotoxicity as monitored by the increase in the level of hepatic marker enzymes and the appearance of fatty change, necrosis, fibrosis and inflammation in liver sections. Ethanol also enhanced the formation of MDA in the liver indicating an increase in lipid peroxidation, a major end-point of oxidative damage, and caused drastic alterations in antioxidant defence systems. Particularly the activities of hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were found reduced by ethanol treatment while glutathione reductase (GR) activity was unchanged. Dietary supplementation with resveratrol during ethanol treatment inhibited hepatic lipid peroxidation and ameliorated SOD, GPx and CAT activities in the liver. Conclusively, we can suggest that resveratrol could have a beneficial effect in inhibiting the oxidative damage induced by chronic ethanol administration, which was proved by the experiments that we conducted on rats.     

GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia

It has been reported that growth hormone (GH)-releasing peptide-2 (GHRP-2), a ghrelin receptor agonist, has an anti-inflammatory effect. We investigated whether this GH secretagogue attenuates liver injury in LPS-treated rats. Wistar rats were simultaneously injected (ip) with LPS (1 mg/kg) and/or GHRP-2 (100 microg/kg). Serum levels of aspartate and alanine transaminases were measured as an index of liver damage. Circulating nitrites/nitrates and hepatic IGF-I and TNF-alpha were evaluated as possible mediators of GHRP-2 actions. LPS increased serum levels of transaminases and nitrites/nitrates. Moreover, LPS increased hepatic TNF-alpha and decreased hepatic IGF-I mRNAs. GHRP-2 administration attenuated the effects of LPS on transaminases, nitrites/nitrates, TNF-alpha, and IGF-I in vivo. This GHRP-2 effect does not seem to be due to modifications in food intake, since fasting did not modify serum levels of transaminases, serum nitrites/nitrates, and hepatic TNF-alpha mRNA both in vehicle rats and in LPS-injected rats. To elucidate whether GHRP-2 is acting directly on the liver, cocultures of hepatocytes and nonparenchymal cells and monocultures of isolated hepatocytes were incubated with LPS and GHRP-2. The ghrelin receptor agonist prevented an endotoxin-induced increase in transaminases and nitrite/nitrate release as well as in TNF-alpha mRNA and increased IGF-I mRNA from cocultures of hepatocytes and nonparenchymal cells, but not from monocultures. In summary, these data indicate that GHRP-2 has a protective effect on the liver in LPS-injected rats that seems to be mediated by IGF-I, TNF-alpha, and nitric oxide. Our data also suggest that the anti-inflammatory effect of GHRP-2 in the liver is exerted on nonparenchymal cells.     

Influence of static magnetic field on cadmium toxicity: Study of oxidative stress and DNA damage in rat tissues

In the present study, we investigated the effect of co-exposure to static magnetic field (SMF) and cadmium (Cd) on the biochemical parameters, antioxidant enzymes activity and DNA damage in rat tissues. Animals were treated with cadmium (CdCl₂, 40 mg/L, per os) in drinking water during 4 weeks. Cd treatment induced an increase of plasma lactate dehydrogenase (LDH) and transaminases levels. Moreover, Cd treatment increased malondialdehyde (MDA) and 8-oxodGuo levels in rat tissues. However, the antioxidant enzymes activity such as the glutathione peroxidase (GPx), catalase (CAT) and the superoxide dismutase (SOD) were decreased in liver and kidney, while we noted a huge increase of hepatic and renal cadmium content. Interestingly, the combined effect of SMF (128mT, 1 h/day during 30 consecutive days) and Cd (40 mg/L, per os) decreased the GPx and CAT activities in liver compared to cadmium treated group. However, the association between SMF and Cd failed to alter transaminases, MDA and 8-oxodGuo concentration.

Cd treatment altered antioxidant enzymes and DNA in liver and kidney of rats. Moreover, SMF associated to Cd disrupt this antioxidant response in liver compared to Cd-treated rats.     

Effects of dexamethasone on insulin receptor in aging

The aim of this study was to examine the effects of dexamethasone (Dex) on functional properties of the rat insulin receptor (IR). Male Mill Hill hooded rats, 3, 6, 12, 18 and 21 months old, were injected with Dex (4 mg/kg) and rat liver and erythrocytes were used for experiments 18 h after Dex administration. Treatment with Dex lowered the specific binding (SB) of insulin (INS) in the liver of 3- and 18-month-old rats and concentration of INS binding sites (N1, N2) and the dissociation constant of low-affinity binding sites (Kd2) in the liver of 6- and 18-month-old rats. In addition, Dex treatment lowered the liver IR protein level in all analyzed groups, except 21-month-old rats where it remained unchanged, but raised the IR mRNA level in 18-month-old rats. In erythrocytes, treatment with Dex decreased SB and Kd2 (in animals 3 and 6 months old) and N1 (in ones 3 and 18 months old). Following Dex treatment, the INS plasma level increased (in rats 3, 18 and 21 months old), while glucose (Glu) concentration increased in 3 and 12 months old, but decreased in 6- and 21-month-old rats. In summary, Dex exerts the strongest effect on the erythrocyte IR of 3- and 6-month-old rats and the hepatic IR of 18-month-old rats. IR in both tissues is almost insensitive to Dex in 12- and 21-month-old rats. The pattern of age-related changes of IR induced by Dex does not correlate with changes of plasma Glu and INS.     

Effect of age increase on metabolism and toxicity of ethanol in female rats

Age-dependent change in the effects of acute ethanol administration on female rat liver was investigated. Female Sprague-Dawley rats, each aged 4, 12, or 50 weeks, received ethanol (2 g/kg) via a catheter inserted into a jugular vein. Ethanol elimination rate (EER), most rapid in the 4 weeks old rats, was decreased as the age advanced. Hepatic alcohol dehydrogenase activity was not altered by age, but microsomal p-nitrophenol hydroxylase activity was significantly greater in the 4 weeks old rats. Relative liver weight decreased with age increase in proportion to reduction of EER. Hepatic triglyceride and malondialdehyde concentrations increased spontaneously in the 50 weeks old nai;ve rats. Ethanol administration (3 g/kg, ip) elevated malondialdehyde and triglyceride contents only in the 4 and the 12 weeks old rats. Hepatic glutathione concentration was increasingly reduced by ethanol with age increase. Ethanol decreased cysteine concentration in the 4 weeks old rats, but elevated it significantly in the older rats. Inhibition of gamma-glutamylcysteine synthetase activity by ethanol was greater with age increase, which appeared to be responsible for the increase in hepatic cysteine. The results indicate that age does not affect the ethanol metabolizing capacity of female rat liver, but the overall ethanol metabolism is decreased in accordance with the reduction of relative liver size. Accordingly induction of acute alcoholic fatty liver is less significant in the old rats. However, progressively greater depletion of glutathione by ethanol in older rats suggests that susceptibility of liver to oxidative damage would be increased as animals grow old.     

Exposure to a Northern Contaminant Mixture (NCM) Alters Hepatic Energy and Lipid Metabolism Exacerbating Hepatic Steatosis in Obese JCR Rats

Non-alcoholic fatty liver disease (NAFLD), defined by the American Liver Society as the buildup of extra fat in liver cells that is not caused by alcohol, is the most common liver disease in North America. Obesity and type 2 diabetes are viewed as the major causes of NAFLD. Environmental contaminants have also been implicated in the development of NAFLD. Northern populations are exposed to a myriad of persistent organic pollutants including polychlorinated biphenyls, organochlorine pesticides, flame retardants, and toxic metals, while also affected by higher rates of obesity and alcohol abuse compared to the rest of Canada. In this study, we examined the impact of a mixture of 22 contaminants detected in Inuit blood on the development and progression of NAFLD in obese JCR rats with or without co-exposure to10% ethanol. Hepatosteatosis was found in obese rat liver, which was worsened by exposure to 10% ethanol. NCM treatment increased the number of macrovesicular lipid droplets, total lipid contents, portion of mono- and polyunsaturated fatty acids in the liver. This was complemented by an increase in hepatic total cholesterol and cholesterol ester levels which was associated with changes in the expression of genes and proteins involved in lipid metabolism and transport. In addition, NCM treatment increased cytochrome P450 2E1 protein expression and decreased ubiquinone pool, and mitochondrial ATP synthase subunit ATP5A and Complex IV activity. Despite the changes in mitochondrial physiology, hepatic ATP levels were maintained high in NCM-treated versus control rats. This was due to a decrease in ATP utilization and an increase in creatine kinase activity. Collectively, our results suggest that NCM treatment decreases hepatic cholesterol export, possibly also increases cholesterol uptake from circulation, and promotes lipid accumulation and alters ATP homeostasis which exacerbates the existing hepatic steatosis in genetically obese JCR rats with or without co-exposure to ethanol.     

Diurnal changes in the glucose and glycogen levels of the blood and liver of rats in chronic consumption of alcohol and after its withdrawal

Chronic ethanol ingestion by rats exerts almost no effect on the diurnal rhythms of the blood and hepatic glucose concentrations. The rhythm of liver glycogen alters substantially in ethanol-fed animals, the phase of the rhythm being shifted and the daily mean level of glycogen being reduced by a factor of 2. Much more drastic disturbances in carbohydrate metabolism occur after ethanol withdrawal than with ethanol consumption. The diurnal rhythm of liver glycogen becomes inverted in phasing, and the rhythmic amplitude reduced greatly as compared with controls. Both the blood and hepatic glucose concentrations are maintained at nearly constant levels for 18-21 h after ethanol withdrawal, but then the level of blood glucose sharply falls, while that of hepatic glucose somewhat increases. The liver cytosolic water/blood plasma water gradient of glucose 24 h after ethanol withdrawal achieves a value of 4 and remains low 24 h later. The liver glycogen level remains relatively high over the 24 h period after ethanol withdrawal despite the severe hypoglycemia, that can be a result of a limitation of the liver cell membrane permeability for glucose.     

Injected tryptophan increases brain but not plasma tryptophan levels more in ethanol treated rats

In previous studies, long term treatment with ethanol has been shown to enhance brain 5-hydroxytryptamine 5-(HT) metabolism by increasing the activity of the regulatory enzyme tryptophan hydroxylase and or availability of circulating tryptophan secondarily to an inhibition of hepatic tryptophan pyrrolase. In the present study ethanol treatment given for two weeks decreased hepatic apo-tryptophan pyrrolase but not total tryptophan pyrrolase activity in rats. Tryptophan levels in plasma and brain did not increase significantly. But there was a marked increase of 5-HT but not 5-hydroxyindoleacetic acid (5-HIAA) concentration in brain, suggesting a possible increase in the activity of tryptophan hydroxylase. The effect of a tryptophan load on brain 5-HT metabolism was therefore compared in controls and ethanol treated rats. One hour after tryptophan injection (50 mg/kg i.p.) plasma concentrations of total and free tryptophan were identical in controls and ethanol treated rats, but the increases of brain tryptophan 5-HT and 5-HIAA were considerably greater in the latter group. The results are consistent with long term ethanol treatment enhancing brain serotonin metabolism and show that brain uptake/utilization of exogenous tryptophan is increased in ethanol treated rats and may be useful to understand the role and possible mechanism of tryptophan/serotonin involvement in mood regulation.     

Injected tryptophan increases brain but not plasma tryptophan levels more in ethanol treated rats

In previous studies, long term treatment with ethanol has been shown to enhance brain 5-hydroxytryptamine 5-(HT) metabolism by increasing the activity of the regulatory enzyme tryptophan hydroxylase and or availability of circulating tryptophan secondarily to an inhibition of hepatic tryptophan pyrrolase. In the present study ethanol treatment given for two weeks decreased hepatic apo-tryptophan pyrrolase but not total tryptophan pyrrolase activity in rats. Tryptophan levels in plasma and brain did not increase significantly. But there was a marked increase of 5-HT but not 5-hydroxyindoleacetic acid (5-HIAA) concentration in brain, suggesting a possible increase in the activity of tryptophan hydroxylase. The effect of a tryptophan load on brain 5-HT metabolism was therefore compared in controls and ethanol treated rats. One hour after tryptophan injection (50 mg/kg i.p.) plasma concentrations of total and free tryptophan were identical in controls and ethanol treated rats, but the increases of brain tryptophan 5-HT and 5-HIAA were considerably greater in the latter group. The results are consistent with long term ethanol treatment enhancing brain serotonin metabolism and show that brain uptake/utilization of exogenous tryptophan is increased in ethanol treated rats and may be useful to understand the role and possible mechanism of tryptophan/serotonin involvement in mood regulation.     

Short-term Effects of Ethanol Intoxication on Ascorbic Acid and Lipid Metabolism and on Drug-metabolizing Enzymes in Liver of Rats

The effects of one-time ethanol intoxication on ascorbic acid and lipid metabolism and on drug-metabolizing enzymes in liver of rats were investigated. Male Donryu rats that had been fed semi-purified feed were given 5 g/kg ethanol solution (25%, w/v) via a stomach tube and killed 16 h after intubation. The amount of ascorbic acid excreted in the urine after ethanol administration increased, but renal and adrenal concentrations of ascorbic acid decreased. The serum levels of total cholesterol, high-density-lipoprotein cholesterol, triglycerides, phospholipids, and non-esterified fatty acids were elevated in rats given ethanol, but hepatic level of total lipids, cholesterol, triglycerides, phospholipids were not. The hepatic concentrations of cytochrome P-450 and cytochrome b₅ did not increase, but this large dose of ethanol increased the activities of aminopyrine N-demethylase and cytochrome c reductase.

These results indicated that the single dose of ethanol affected the ascorbic acid and lipid metabolism of rats, and induced drug-metabolizing enzymes in their liver.     

Hyperglycaemia, stress oxidant, liver dysfunction and histological changes in diabetic male rat pancreas and liver: protective effect of 17 beta-estradiol

Oxidative stress is thought to play a crucial role in the pathogenesis of chronic diabetic complications. We investigated the protective effects of 17 beta-estradiol (E2) on alloxan-induced stress oxidant, hepatic dysfunction and histological changes in male rats liver and pancreas. Our results showed that 17 beta-estradiol could attenuate the increase of blood glucose in plasma and normalise the hepatic glycogen level. In addition, E2 enhanced superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) (by 207, 52 and 72%, respectively, as compared to diabetic rats), reduced lipid peroxidation in the hepatic tissue (by 54%) and improved the liver dysfunction parameters by the significant decrease of gamma-glytamyl transferase (GGT), phosphatases alkalines (PAL), lactate deshydrogenase (LDH) and aspartate and lactate transaminases (AST and ALT) activities which increased in diabetic rats. Moreover, 17 beta-estradiol treatment in diabetic rats protects against alloxan-induced pancreatic beta-cells and hepatic cells damages.     

Effect of a potent iNOS inhibitor (ONO-1714) on acetaminophen-induced hepatotoxicity in the rat

Overproduction of nitric oxide (NO) in the liver has been implicated as an important event in endotoxin shock and in other models of hepatic inflammation and injury. The present study was undertaken to evaluate the effect of ONO-1714, a potent and specific inhibitor of inducible NO synthase (iNOS), on acetaminophen-induced hepatotoxicity in the rats. Oral administration of ONO-1714 dose-dependently inhibited NOx (NO2- and NO3-) accumulation in rat plasma after lipopolysaccharide (LPS) treatment. Intraperitoneal acetaminophen at 1 g/kg caused damage to the centrilobular regions of the liver and increase in serum alanine and aspartate transaminase (ALT and AST, respectively) levels accompanied by elevated plasma NOx levels after 24 h. Oral administration of ONO-1714 at 10 and 100 microg/kg dose-dependently reduced the acetaminophen-induced hepatic tissue damage and the increases in serum ALT and AST levels. ONO-1714 also blocked the increase in plasma NOx concentrations. These findings demonstrate that oral ONO-1714, an iNOS inhibitor, protects against acetaminophen-evoked hepatic inflammation/injury, strongly suggesting that NO produced by iNOS plays a key role in the pathogenesis of this drug-induced hepatotoxicity.     

Hypothalamic luteinizing hormone-releasing hormone (LHRH) and LH secretion in aging female rats

Age-related changes in hypothalamic luteinizing hormone-releasing hormone (LHRH) and luteinizing hormone (LH) secretion were studied in young (6 months), middle-aged (12 months) and old (18 months) female rats. The LHRH levels in the mid-hypothalamic area were higher in intact middle-aged and old females than in young ones. Additionally, there was no age difference in the hypothalamic LHRH levels in male rats. In order to clarify the significance of this age-related increase in female rats, we examined the effects of progesterone treatment in estrogen-primed ovariectomized young and old rats on the LHRH levels in the median eminence (ME) and on plasma LH levels. We found phasic changes in ME-LHRH and plasma LH levels in estrogen-primed rats following progesterone treatment in rats of both ages, but the progesterone-induced change in ME-LHRH levels tended to be delayed in old rats compared with young females. This delay may correspond to the delayed onset, slow and low magnitude of plasma LH increase in old females. The ME-LHRH levels were generally higher in old rats than in young rats. Nevertheless, we found that the increase in plasma LH in response to progesterone treatment in estrogen-primed ovariectomized females was smaller in old rats than young rats. These results suggest that the LHRH secretory mechanism changes with age in female rats. Such alterations may result in the accumulation of LHRH in the mid-hypothalamic area and an increase in ME-LHRH.