Early-onset growth hormone deficiency results in diastolic dysfunction in adult-life and is prevented by growth hormone supplementation.

OBJECTIVE: The primary goal of growth hormone (GH) replacement is to promote linear growth in children with growth hormone deficiency (GHD). GH and insulin-like growth factor-1 (IGF-1) are also known to have roles in cardiac development and as modulators of myocardial structure and function in the adult heart. However, little is known about cardiac diastolic function in young adults with childhood onset GH deficiency in which GH treatment was discontinued following puberty. The aim of the study was to evaluate the effects of long standing GHD and peri-pubertal or continuous GH replacement therapy on diastolic function in the adult dwarf rat. DESIGN: The dwarf rat, which possesses a mutation in a transcription factor necessary for development of the somatotroph, does not exhibit the normal peri-pubertal rise in GH around day 28 and was used to model childhood or early-onset GHD (EOGHD). In another group of male dwarfs, GH replacement therapy was initiated at 4 weeks of age when GH pulsatility normally begins. Ten weeks after initiation of injections, GH-treated dwarf rats were divided into 2 groups; continued treatment with GH for 12 weeks (GH-replete) or treatment with saline for 12 weeks. This latter group models GH supplementation during adolescence with GHD beginning in adulthood (adult-onset GHD; AOGHD). Saline-treated heterozygous (HZ) rats were used as age-matched controls. At 26 weeks of age, cardiac function was assessed using invasive or noninvasive (conventional and tissue Doppler) indices of myocardial contractility and lusitropy. RESULTS: Systolic function, as determined by echocardiography, was similar among groups. Compared with HZ rats and GH-replete dwarfs, the EOGHD group exhibited significant reductions in myocardial relaxation and increases in left ventricular filling pressure, indicative of moderate diastolic dysfunction. This was further associated with a decrease in the cardiac content of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2), one of the important cardiac calcium regulatory proteins. Dwarfs supplemented with GH during the peri-adolescence stage, but not beyond (AOGHD), exhibited a subtle prolongation in the deceleration time to early filling. In contrast, continual GH replacement preserved diastolic function such that the cardiac phenotype of the GH-replete dwarfs resembled that of their age-matched HZ counterpart. DISCUSSION: Our data indicate that GHD during adolescence leads to overt diastolic dysfunction in early adulthood and this is prevented by continual GH replacement therapy. Since discontinuation of GH replacement following adolescence only mitigated the lusitropic deficits that were observed in untreated dwarfs, GH treatment into adulthood could be beneficial.

Persistence and efficacy of termiticides used in preconstruction treatments to soil in Mississippi.

Laboratory and field studies were conducted to determine the persistence and efficacy of termiticides used as preconstruction treatments against subterranean termites. Bifenthrin (0.067%), chlorpyrifos (0.75%), and imidacloprid (0.05%) ([AI]; wt:wt) were applied to soil beneath a monolithic concrete slab at their minimum labeled rates. Soil samples were taken from three depths (0-2.5, 2.6-7.6, and 7.7-15.2 cm) at six sampling times (0, 3, 6, 9, 12 and 48 mo) from sites in Harrison and Oktibbeha counties in Mississippi. Residue analyses were conducted on the 0-2.5- and 2.6-7.5-cm depths, and bioassays were conducted using all three depths. In field studies, significant termiticide degradation occurred between sampling times 0 and 48 mo for all termiticides. At all sampling times, the top 2.5 cm of soil contained more termiticide than the other depths. Time to 50% dissipation of termiticide in the 0-2.5-cm depth was 9, 6, and 2 mo for bifenthrin, chlorpyrifos, and imidacloprid, respectively. Termite mortalities in contact bioassays remained high for bifenthrin and chlorpyrifos throughout the 48-mo sampling period; however, mortality of termites exposed to imidacloprid-treated soil dropped after the initial sampling. Termites readily penetrated all termiticide-treated soil in bioassays of 52-mm soil cores at 48 mo. Percentage of mortality in these bioassays was 15, 43, and 13 for bifenthrin, chlorpyrifos, and imidacloprid respectively.

Chronic [D-Ala2]-growth hormone-releasing hormone administration attenuates age-related deficits in spatial memory.

The age-related decline in growth hormone is one of the most robust endocrine markers of biological aging and has been hypothesized to contribute to the physiological deficits observed in aged animals. However, there have been few studies of the impact of this hormonal decline on brain aging. In this study, the effect of long-term subcutaneous administration of [D-Ala2]-growth hormone-releasing hormone (GHRH) on one measure of brain function, memory, was investigated. Animals were injected daily with 2.3 microg of [D-Ala2]-GHRH or saline from 9 to 30 months of age, and the spatial learning and reference memory of animals were assessed by using the Morris water maze and compared with those of 6-month-old animals. Results indicated that spatial memory decreased with age and that chronic [D-Ala2]-GHRH prevented this age-related decrement (24% improvement in the annulus-40 time and 23% improvement in the number of platform crossings compared with saline treated, age-matched controls; p < .05 each). No changes were noted in sensorimotor performance. [D-Ala2]-GHRH attenuated the age-related decline in plasma concentrations of insulinlike growth factor-1 (IGF-1) (p <.05). These data suggest that growth hormone and IGF-1 have important effects on brain function, that the decline in growth hormone and IGF-1 with age contributes to impairments in reference memory, and that these changes can be reversed by the chronic administration of GHRH.

Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats.

N-Methyl-D-aspartate (NMDA) receptors have been reported to have an important role in synaptic plasticity and neurodegeneration. Two major subtypes of these receptors, NMDAR1 and NMDAR2, are present in brain and heterogeneity of these receptors have been reported to define specific functional responses. In this study, the effects of age and chronic insulin-like growth factor-1 (IGF-1) administration on NMDA receptor density and subtype expression were investigated in frontal cortex, CA1, CA2/3 and the dentate gyrus of the hippocampus of young (10 months), middle-aged (21 months) and old (30 months) male Fisher 344xBrown Norway (F1) rats. No age-related changes in (125)I-MK-801 binding or NMDAR1 protein expression were observed in hippocampus or frontal cortex. However, analysis of NMDAR2A and NMDAR2B protein expression in hippocampus indicated a significant decrease between 21 and 30 months of age and administration of IGF-1 increased these receptor subtypes. In cortex, NMDAR2A and NMDAR2B protein expression were not influenced by age or IGF-1 treatment, although NMDAR2C protein expression decreased with age and this decline was not ameliorated by IGF-1 administration. These data demonstrate that NMDA receptor subtypes are altered with age in a regional and subtype specific manner. We conclude that both age and IGF-1 regulate the expression of NMDA receptor subtypes and suggest that age-related changes in NMDA receptor heterogeneity may result in functional changes in the receptor that have relevance for aging.

Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats.

The present study was designed to assess the impact of moderate caloric restriction (60% of ad libitum fed animals) on cerebral vascular density and local cerebral blood flow. Vascular density was assessed in male Brown-Norway rats from 7-35 months of age using a cranial window technique. Arteriolar density, arteriole-arteriole anastomoses, and venular density decreased with age and these effects were attenuated by moderate caloric restriction. Analysis of local cerebral blood using [14C]iodoantipyrine indicated that basal blood flow decreased with age in CA1, CA3 and dentate gyrus of hippocampus; similar trends were evident in cingulate, retrosplenal, and motor cortex. Basal blood flow was increased in all brain regions of moderate caloric restricted old animals (compared to old ad libitum fed animals) and no differences were observed between ad libitum fed young and caloric restricted older animals. In response to a CO2 challenge to maximally dilate vessels, blood flow increased in young and old ad libitum fed animals, but a similar increase was not observed in caloric restricted old animals. We conclude that a decrease in cerebral vasculature is an important contributing factor in the reduction in blood flow with age. Nevertheless, vessels from young and old animals have the capacity to dilate in response to a CO2 challenge and, after CO2, no differences are observed between the two age-groups. These results are consistent with the hypothesis that aged animals fail to adequately regulate local cerebral blood flow in response to physiological stimuli. Moderate caloric restriction increases microvascular density and cerebral blood flow in aged animals but tissues exhibit little or no increase in blood flow in response to CO2 challenge. The cause of this deficient response may indicate that vessels are maximally dilated in aged calorically restricted animals or that they fail to exhibit normal regulatory control.

Alterations in insulin-like growth factor-1 gene and protein expression and type 1 insulin-like growth factor receptors in the brains of ageing rats.

Ageing in mammals is characterized by a decline in plasma levels of insulin-like growth factor-1 that appears to contribute to both structural and functional changes in a number of tissues. Although insulin-like growth factor-1 has been shown to provide trophic support for neurons and administration of insulin-like growth factor-1 to ageing animals reverses some aspects of brain ageing, age-related changes in insulin-like growth factor-1 or type 1 insulin-like growth factor receptors in brain have not been well documented. In this series of studies, insulin-like growth factor-1 messenger RNA and protein concentrations, and type 1 insulin-like growth factor receptor levels were analysed in young (three to four- and 10-12-month-old), middle-aged (19-20-month-old) and old (29-32-month-old) Fisher 344 x Brown Norway rats. Localization of insulin-like growth factor-1 messenger RNA throughout the lifespan revealed that expression was greatest in arteries, arterioles, and arteriolar anastomoses with greater than 80% of these vessels producing insulin-like growth factor-1 messenger RNA. High levels of expression were also noted in the meninges. No age-related changes were detected by either in situ hybridization or quantitative dot blot analysis of cortical tissue. However, analysis of insulin-like growth factor-1 protein levels in cortex analysed after saline perfusion indicated a 36.5% decrease between 11 and 32 months-of-age (P<0.05). Similarly, analysis of type 1 insulin-like growth factor receptor messenger RNA revealed no changes with age but levels of type 1 insulin-like growth factor receptors indicated a substantial decrease with age (31% in hippocampus and 20.8 and 27.3% in cortical layers II/III and V/VI, respectively). Our results indicate that (i) vasculature and meninges are an important source of insulin-like growth factor-1 for the brain and that expression continues throughout life, (ii) there are no changes in insulin-like growth factor-1 gene expression with age but insulin-like growth factor-1 protein levels decrease suggesting that translational deficiencies or deficits in the transport of insulin-like growth factor-1 through the blood-brain barrier contribute to the decline in brain insulin-like growth factor-1 with age, and (iii) type 1 insulin-like growth factor receptor messenger RNA is unchanged with age but type 1 insulin-like growth factor receptors decrease in several brain regions. We conclude that significant perturbations occur in the insulin-like growth factor-1 axis with age. Since other studies suggest that i.c.v. administration of insulin-like growth factor-1 reverses functional and cognitive deficiencies with age, alterations within the insulin-like growth factor-1 axis may be an important contributing factor in brain ageing.

Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals.

Moderate caloric restriction (60% of ad libitum intake) is an important model to investigate potential mechanisms of biological aging. This regimen has been reported to decrease the number of pathologies and increase life span in all species tested to date. Although moderate caloric restriction induces a wide range of physiological changes within the organism, adaptive changes within the endocrine system are evident and serve to maintain blood levels of glucose. These alterations include an increase in growth hormone secretory dynamics and a decline in plasma levels of IGF-1. These endocrine compensatory mechanisms can be induced at any age, and we have proposed that these alterations mediate some of the beneficial aspects of moderate caloric restriction. Numerous studies indicate that growth hormone and IGF-1 decrease with age and that administration of these hormones ameliorates the deterioration of tissue function evident in aged ad libitum-fed animals, suggesting that the absence of these hormones contributes to the phenotype of aging. Nevertheless, IGF-1 is an important risk factor in age-related pathologies including lung, breast, and prostate cancer. From these studies, we propose that endocrine compensatory mechanisms induced by moderate caloric restriction (including increased growth hormone and decreased IGF-1) decrease the stimulus for cellular replication, resulting in a decline in pathologies and increased life span observed in these animals. These findings have important implications for potential mechanisms of moderate caloric restriction and suggest that neuroendocrine compensatory mechanisms exert a key role on the actions of moderate caloric restriction on life span.

Distribution and levels of insulin-like growth factor I mRNA across the life span in the Brown Norway x Fischer 344 rat brain.

Previous studies have reported changes in insulin-like growth factor I (IGF-I) mRNA expression during early postnatal development of the rat brain. Although changes in IGF-I gene expression have been documented in a wide range of central nervous system structures during early development and investigated in the hippocampus during aging, no study has compared changes in IGF-I gene expression in different brain regions across the life span. The present study assessed the distribution of IGF-I gene expression using in situ hybridization in rats aged 2-30 months. Dot blots were used as a quantitative assessment of cortical IGF-I mRNA. Results indicate that both the distribution and levels of brain IGF-I mRNA do not change significantly between 2 and 30 months of age in the rat. However, in spite of relatively constant levels of mRNA, other studies from our laboratory have demonstrated that cortical IGF-I protein levels decrease 36.6% between 11 and 32 months of age, suggesting that IGF-I function is decreased with increasing age.

Ethanol suppresses growth hormone-mediated cellular responses in liver slices.

Previous studies indicate that both acute and chronic ethanol administration inhibit protein synthesis and decrease the secretion of insulin-like growth factor-1 (IGF-1). Although IGF-1 synthesis and secretion are regulated by growth hormone secretion from the pituitary gland, we assessed whether ethanol inhibits tissue response to growth hormone. Liver slices from male Sprague-Dawley rats were prepared, placed into F-12 media, and incubated at 37 degrees C with [3H]leucine, and either 0.25 or 1 nM rat growth hormone and 0, 37 (physiological levels), or 175 mM (toxic levels) ethanol. Tissues were removed at 0, 15, 30, and 60 min. Protein synthesis increased linearly during this time period, and administration of growth hormone (1 nM) significantly increased protein synthetic rate by 48% (p < 0.01), whereas addition of 37 or 175 mM ethanol attenuated the effects of growth hormone (p < 0.01). Analysis of IGF-1 mRNA indicated a 2-fold increase in response to growth hormone (p < 0.01), whereas ethanol administration decreased the growth hormone-induced rise of IGF-1 mRNA. Ethanol (175 mM) inhibited the release of IGF-1 into the media (p < 0.05). Ethanol did not alter growth hormone receptor binding, and exposure of tissue slices to ethanol did not influence the number of growth hormone receptors or the affinity of growth hormone for its receptor. Our results demonstrate that (1) growth hormone is a potent acute regulator of IGF-1 mRNA and IGF-1 peptide release, (2) ethanol inhibits growth hormone-induced protein synthesis and induction of IGF-1 gene expression, and (3) the inhibitory effects of ethanol on growth hormone occur without changing growth hormone receptor number or binding characteristics. We conclude that ethanol suppresses growth hormone-induced signal transduction, resulting in a decrease in IGF-1 gene expression.

Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age.

Several investigations have clearly indicated that plasma concentrations of insulin-like growth factor I (IGF-I) decrease with age and contribute to the decrease in tissue function that is characteristic of aging animals and man. Plasma IGF-I is regulated by GH released from the pituitary gland, and although data demonstrate a decline in GH secretion with age, GH receptor (GHR) density in liver tissue has been reported to increase. In this study, the effects of aging on GHR signal transduction were assessed in hepatic tissue to determine whether alterations in the response to GH contribute to the decline in IGF-I. Liver slices from female C57BL/6 mice (10, 17, and 31 months old) were prepared in medium and stimulated with GH. Basal GHR binding increased more than 2-fold in 31-month-old animals compared to that in either 10- or 17-month-old animals (P < 0.01), whereas the Ka values were similar in the three age groups. However, GH (2 nM)-induced IGF-I gene expression decreased dramatically with age (P < 0.01). In 10-month-old animals, GH-induced phosphorylation of the GHR complex was maximal 10 min after the addition of hormone, whereas GH-induced MAP kinase activity was maximal at 15 min. GH-induced JAK2 kinase and GHR complex phosphorylation as well as MAP kinase activity were significantly lower in 31-month-old animals than in either the 10- or 17-month-old groups (P < 0.05). The results of this study demonstrate that GH induces phosphorylation of JAK2 and the GHR complex, activates MAP kinase, and increases the expression of IGF-I messenger RNA in liver. In 17-month-old animals, decreases in IGF-I gene expression were evident that were not directly associated with diminished GHR complex phosphorylation or MAP kinase activity. By 31 months, there was a decrease in IGF-I gene expression that was associated with a marked decline in JAK2 and GHR complex phosphorylation. These data suggest that the signal transduction pathway for GH is impaired with age and that these changes may contribute to the decline in IGF-I gene expression.

Moderate caloric restriction alters the subcellular distribution of somatostatin mRNA and increases growth hormone pulse amplitude in aged animals.

Although growth hormone secretion decreases with age in both animals and man, its potential role in the regulation of biological aging is unknown. In a series of experiments, age-related changes in growth hormone secretory dynamics were compared in ad libitum fed and moderately calorically restricted male Brown-Norway rats. These animals exhibit an increase in both mean and maximal lifespan in response to caloric restriction. In addition, the subcellular distribution of somatostatin mRNA was compared since previous data indicated that somatostatin secretion increases with age and has an important role in the age-related decline in growth hormone pulse amplitude. In ad libitum fed animals, growth hormone secretory dynamics decreased with age and were associated with a decline in total somatostatin mRNA levels. However, analysis of somatostatin mRNA precipitating with polyribosomes revealed a significant increase with age (p < 0.05). When data were expressed as polysomal/total mRNA, levels in 25-month-old animals increased 94 and 104% compared to 6- or 16-month-old animals, respectively (p < 0.01). Growth hormone secretory dynamics decreased in young animals maintained on a moderate caloric restricted diet, but by 26 months growth hormone pulse amplitude increased and was indistinguishable from young ad libitum fed animals. In addition, the moderate caloric-restricted animals failed to exhibit the decline in total somatostatin mRNA or the increase in polyribosome-associated somatostatin mRNA characteristic of the ad libitum fed 25-month-old animals. Our results suggest that altered regulation of somatostatin mRNA at the translational level may be a contributing factor in the decrease in growth hormone secretion observed in aging animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor-1 stimulation of protein synthesis is attenuated in cerebral cortex of aging rats.

It has been postulated that brain aging and the accompanying neurodegenerative processes associated with aging result from a deterioration of mechanisms that regulate the maintenance of basic cellular processes. In the present study, it was hypothesized that decreased availability and/or diminished responsiveness of tissues to growth factors such as insulin-like growth factor-1 may be partly responsible for decreases in total protein synthesis previously observed in aging animals. Male Brown Norway rats (5-7 and 27-28 months old) were used to determine (1) whether in vivo protein synthesis in cortex, hippocampus, hypothalamus and cerebellum decreases with age and (2) whether these deficiencies are associated with age-related alterations in response to insulin-like growth factor-1, des (1-3) IGF-1 or insulin. Analysis of in vivo protein synthesis rates revealed a decline of 20% in cortex of old rats (P < 0.05) but no changes were observed in hippocampus, hypothalamus, or cerebellum. Stimulation of cortical slices in vitro with insulin-like growth factor-1, des (1-3) insulin-like growth factor-1, or insulin increased protein synthesis rates in young animals, but the response to these growth factors was blunted in old animals. Analysis of type 1 insulin-like growth factor receptor densities by quantitative autoradiography demonstrated age-related decreases in receptor levels in cerebellar cortex and dentate gyrus of the hippocampus but no changes in cortex. Regional distribution of type 1 insulin-like growth factor receptors within each of these tissues did not appear to change with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Moderate caloric restriction increases type 1 IGF receptors and protein synthesis in aging rats.

Insulin-like growth factor-1 (IGF-1) is an anabolic hormone that mediates the actions of growth hormone (GH) and is found at lower concentrations in aged animals. These decreases in GH and IGF-1 appear to have important physiological consequences for aging, since protein synthesis decreases with age, and administration of GH and/or IGF-1 has been shown to increase protein synthesis. The present study was designed to determine (a) the relationship between the age-related changes in rates of tissue protein synthesis and plasma IGF-1 concentrations, (b) type 1 IGF receptor density in tissues and (c) whether long-term moderate caloric restriction, which is known to increase life-span, affects these relationships. Male Brown Norway rats were fed ad libitum or caloric-restricted (60% ad libitum) from 14 weeks of age and sacrificed at different ages. In ad libitum fed animals there were age-related decreases in plasma IGF-1 concentrations (14%) and in the rates of protein synthesis of the heart (36%) and liver (38%). Type 1 IGF receptor density remained constant in all tissues with age. The caloric-restricted animals exhibited plasma IGF-1 concentrations 33 to 42% lower than the ad libitum fed animals. However, rates of protein synthesis increased by 70 and 30% in heart and diaphragm, and this increase was associated with 60 to 100% increases in type 1 IGF receptor densities when compared with ad libitum fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the HemoCue beta-glucose photometer and reflotron for open heart surgery.

The HemoCue beta-glucose photometer (Angelholm, Sweden) was evaluated for use in monitoring blood glucose in both diabetic and nondiabetic patients undergoing open heart surgery. Because occasional discrepancies were noted in patients with low total proteins when the Reflotron (Boehringer Mannheim, Indianapolis, IN) was used for this purpose, the effects of protein and hematocrit on glucose results from both instruments were investigated and compared with plasma values from a Paramax 720 ZX (Baxter Healthcare, Irvine, CA). Linear-regression analysis of the HemoCue results (y) versus Paramax (x) yielded y = 0.956x + 0.35, r2 = 0.980, with Sy/x = 0.57 mmol/L (10.3 mg/dL). Results from the Reflotron (y) versus Paramax (x) yielded y = 1.075x - 0.10, r2 = 0.964, with Sy/x = 0.99 mmol/L (17.8 mg/dL). Bias plots of (HemoCue-Paramax) or (Reflotron-Paramax) versus glucose, hematocrit, or protein showed no effect of glucose on the results from either instrument and no effect of protein or hematocrit on the HemoCue findings. The Reflotron, however, showed a positive bias of up to 3.5 mmol/L (63 mg/dL) at protein concentrations between 30-40 g/L (3.0-4.0 g/dL) and a possible positive bias at low hematocrit levels.

The regulation and mechanisms of action of growth hormone and insulin-like growth factor 1 during normal ageing.

The decrease in tissue function that is observed in ageing animals has been linked to the decline in rates of protein synthesis. These changes may be caused, in part, by reduced secretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). It is well established that growth hormone-releasing hormone (GHRH) and somatostatin have an important role in the regulation of GH secretion and results from several studies suggest that an age-related increase in release of somatostatin has an important role in altering the secretion of GH. When the amounts of somatostatin mRNA were examined, there was a decrease in the aged rats but the amount of somatostatin mRNA bound to polysomes increased in these animals. This suggests that translational regulatory mechanisms are compromised in ageing animals. Moderate dietary restriction, which has been shown to increase life span, increases the amplitude of GH pulses and the capacity of tissues to synthesize protein. We have used the caloric restriction model to investigate the regulation and roles of GH and IGF-1 during ageing. Our results suggest that neuroendocrine regulation of GH secretion plays an important role in the process of biological ageing and that part of the beneficial effects of moderate dietary restriction may be mediated by altering the GH, IGF-1 axis.

Long-term suppression of insulin-like growth factor-1 in rats after in utero ethanol exposure: relationship to somatic growth.

It has been established that consumption of alcohol during pregnancy has profound developmental and behavioral effects on the fetus and offspring. The present studies were undertaken to examine the consequences of in utero ethanol exposure on the regulation of insulin-like growth factors (IGFs) in relation to observed somatic growth deficits. Ad libitum, pair- and ethanol-fed female rats were maintained on liquid diet from day 2 of pregnancy through parturition. Pups were sacrificed at birth or cross-fostered to nonexperimental mothers and sacrificed at 10, 20 and 40 days of age. Body and brain weights of ethanol-exposed pups were reduced compared to either ad libitum or pair-fed animals; however, brain to body weight ratios were not different between groups. In ethanol-treated offspring, plasma IGF-1 concentrations were reduced 14 to 40% compared to ad libitum or pair-fed animals at birth, 10 and 20 days of age, with a nonsignificant reduction observed at 40 days of age. Plasma IGF-2 concentrations were not different between any treatment group at any age, suggesting that the ethanol-induced reduction in IGF-1 was a selective effect of prenatal ethanol exposure. Although IGF-binding proteins were generally not affected before 20 days in prenatally exposed rats, significant reductions were observed in 20- and 40-day-old ethanol-exposed pups. These results suggest that long-term reductions in plasma IGF-1 concentrations contribute to the reduced body and brain weights observed in ethanol-treated pups, and lend further support to the importance of the IGF and IGF-binding proteins in pre- and postnatal growth and development.

Effects of aging and dietary restriction on tissue protein synthesis: relationship to plasma insulin-like growth factor-1.

Insulin-like growth factor-1 (IGF-1) decreases with age in many species and appears to have an important role in the age-related decline in capacity for protein synthesis with age. The goals of these studies were to determine whether (a) ad libitum fed mice demonstrate age-related decreases in IGF-1, (b) the relationship between IGF-1 and age-related changes in protein synthetic capacity in ad libitum fed animals, and (c) whether moderate dietary restriction (which increases both life span and protein synthetic capacity) delays age-related changes in protein synthesis and plasma IGF-1. These studies indicate that (a) in ad libitum fed animals, plasma IGF-1 decreases with age between 10 and 15 months and moderate dietary restriction decreases plasma IGF-1 in young but not older animals, and (b) the temporal changes in protein synthesis are tissue specific; moderate dietary restriction either increases or prevents the age-related decline in tissue protein synthesis. Results suggest that in normal aging, decreases in IGF-1 are associated with the decline in protein synthesis but that other regulatory mechanisms appear to have an important role in this process. Dietary restriction decreases plasma IGF-1 in young animals and either increases protein synthesis or prevents the age-related decline in protein synthesis, suggesting that the effects of dietary restriction are not mediated via increases in plasma IGF-1.

Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins.

The purpose of these studies was to determine more accurately the relationship between IGF-1 and life span, and to determine whether moderate dietary caloric restriction alters the age-related changes in IGF-1. Studies included an assessment of plasma IGF-1, hepatic IGF-1 mRNA, and plasma IGF-1 binding proteins (IGF-1-BP). Rats (6, 12, 22, and 28 months of age) were fed ad libitum or maintained on a diet 60% of ad libitum. In ad libitum fed animals, plasma IGF-1 decreased by 20% between 6 and 28 months of age. Similar age-related declines were observed in dietary restricted animals but levels were generally 14-25% lower at each age group. IGF-1 mRNA levels demonstrated similar decreases with age in ad libitum fed animals, but in dietary restricted animals, levels plateaued at 22 and 28 months. IGF-1 binding protein analysis revealed 3 bands at approximate molecular weights of 40k, 30k, and 24k. All bands demonstrated a decrease in relative IGF-1-BP concentration with age, as well as a decrease in the 40k and 30k binding proteins after dietary restriction. These results indicate that (a) aging in ad libitum fed animals is associated with decreases in plasma IGF-1, IGF-1-BP, and IGF-1 mRNA levels; and (b) long-term dietary restriction decreases plasma IGF-1 and IGF-1-BP levels in each age group although the age-associated decreases in IGF-1 mRNA levels are prevented by dietary restriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Tromantadine: inhibitor of early and late events in herpes simplex virus replication.

Unlike amantadine (1-adamantanamine), tromantadine (N-1-adamantyl-N-[2-(dimethyl amino)ethoxy]acetamide hydrochloride) inhibits herpes simplex virus type 1 (KOS strain)-induced cytopathic effect and virus replication with limited toxicity to the cells. Vero and HEp-2 cells tolerated up to 2 mg of tromantadine per 2 X 10(6) cells for 24-, 48-, or 96-h incubation periods with little change in cell morphology. Treatment of the cells with 10 to 50 micrograms of tromantadine reduced herpes simplex virus-induced cytopathic effect. Treatment with 100 to 500 micrograms of tromantadine inhibited herpes simplex virus-induced cytopathic effect and reduced virus production. Complete inhibition of virus production was observed with treatments of 500 micrograms to 1 mg. The antiherpetic activity of tromantadine was dependent upon the viral inoculum size and the time of addition of the compound with respect to infection. Virion synthesis and viral polypeptide synthesis were inhibited by addition of tromantadine at the time of infection or 4 h postinfection. The results are consistent with tromantadine inhibition of an early event in herpes simplex virus infection, before macromolecular synthesis, and a late event, such as assembly or release of virus.