Biomedical subjects

R A Menzies

Publications and source records attributed to R A Menzies.

At least 19 recordsLinked to original sources

PubMed2001

Plasma interleukin-1beta, prolactin, ACTH and corticosterone responses to endotoxin after damage of the anterior hypothalamic area.

This report concerns the use of an animal model described by us [J Submicrosc Cytol Pathol 1995;27:83-89] to investigate neural and endocrine sites for endotoxin (ENDO, E. coli 055:B5, 200 microg/100 g body weight in saline intravenously) effects on immunomodulatory hormone and cytokine release. Plasma interleukin-1beta (IL-1beta), prolactin (PRL), ACTH and corticosterone responses to ENDO after neurotoxic damage of neurons residing in the anterior hypothalamic area (AHA) were studied in freely behaving male rats. Excitotoxic cell damage in the AHA was produced by bilaterally injecting N-methyl-DL-aspartate (NMA) in artificial cerebrospinal fluid (aCSF) into this brain site. Injections of comparable volumes of aCSF alone served as controls for brain damage associated with the treatment. In both experimental brain manipulations before ENDO challenge the rise in plasma IL-1beta concentrations in response to ENDO was reduced by 2-fold at 1 h and 3- to 5-fold at 3 h when compared to controls. Nevertheless, experimental and control brain manipulations did not modulate the expected rise in corticosterone concentrations after ENDO exposure which rose 5-fold above the baseline level in all animals. However, AHA manipulation did reduce plasma ACTH and prolactin concentrations differentially. Introduction of either NMA or the control injection of aCSF alone into AHA reduced plasma ACTH concentrations by 2-fold at 0.5 and 1 h after ENDO. However, there was a greater reduction in the rise of plasma PRL concentrations after ENDO found in NMA-treated groups versus rats receiving control aCSF. These results demonstrate that variable-size hypothalamic damage (a larger lesion produced in AHA by NMA treatment vs. a smaller lesion control after aCSF) can result in a differential blunting of PRL, IL-1beta and ACTH release into blood in the face of robust, unmodulated corticosterone increases. In summary, these findings revealed a consistent predominant influence of ENDO on adrenal release of corticosterone as a concomitant to differential IL-1beta, ACTH and PRL release after AHA cell loss. In conclusion, these results constitute further evidence for hypothalamic orchestration of a balance between immunotropic and immunosuppressive neuroendocrine-immune events during acute bacterial infection of mammals.

Adrenocorticotropic Hormone↗

PubMed1995

In vivo release of interleukin-1 beta into hypothalamic extracellular fluid in rats: effects of repeated sampling.

Interleukin-1 beta (Il-1 beta) concentrations in extracellular fluid (ECF) withdrawn at 10-min intervals through a push-pull cannula (PPC) located in the hypothalamus were studied in freely behaving male rats for 1 h at 24 and 72 h and again at 7 days after PPC implantation. Il-1 beta concentrations in ECF were similar in the latter. However, when ECF was sampled at 3 h and again 7 days after PPC implantation, Il-1 beta concentrations were greatly elevated at 7 days when compared to all other intervals. These results demonstrate how the relationships between Il-1 beta measured in ECF and the conditions of measurement appear to be integral parts of a whole intracerebral system: cytokine concentrations appear to be inextricably bound to intrahypothalamic conditions created by the sampling device presence and frequency of use.

Animals↗

PubMed1995

Variable tissue reactions and endocrine responses to a jugular catheter.

Although the use of soft catheter materials allows for safe long-term venous access in humans and animals, a significant percentage of individuals react adversely. We have studied a group of 52 male rats over 30 days (d) for the category and degree of tissue responses to silicone-based catheters implanted in the jugular vein. Included in this evaluation was blood withdrawal at multiple intervals for assay of plasma hormones corticosterone (CORT) and prolactin (PRL) as they were correlated with the immune phenomena associated with early (5-7d) obstruction of the catheter tip. The intravascular portion of all catheters were covered with a transparent sheath which was composed of endothelial cells, smooth muscle cells, fibroblasts and numerous collagen fibers. Early blockage of catheters was the result of large white masses (wm) enclosing the tip which were continuous with the sheath. The wm consisted of: a) an inner zone nearest the catheter in some regions predominantly composed of numerous platelets and in others granulocytes and platelets; b) a middle zone containing numerous neutrophils; c) an outer zone containing a few inflammatory cells and many spaces filled with red blood cells. Rats that developed a wm blockage 7-10d after catheter placement had higher plasma CORT levels (3-5d post implant) when compared to those of animals with catheters remaining open 3-4 weeks. When viewed together, these observations describe a subset of a larger population of rats that have a local intravascular inflammatory reaction to silicone-based catheters. This preparation may be a useful model for investigating reported differences in human reactivity to silicone-based prostheses.

Animals↗

PubMed1993

Infusion of iron into the rat substantia nigra: nigral pathology and dose-dependent loss of striatal dopaminergic markers.

Iron has recently been suggested to contribute to the pathogenesis of Parkinson's disease (PD) because of the finding of increased iron levels in the substantia nigra pars compacta (SNc) above those of control patients. Iron is capable of catalyzing numerous reactions which could lead to free radical formation and oxidative damage to DNA, proteins, lipid membranes, and other biological molecules. Neurodegeneration in the SNc of the PD brain may be a consequence of increased iron, which promotes these cytotoxic reactions. To test whether excess iron could play a causative role in the degeneration of nigral neurons, we infused 1.25-6.3 nmol of iron into the rat substantia nigra (SN) unilaterally utilizing two different infusion protocols. All infusates were isosmotic and pH-balanced in a citrate-bicarbonate vehicle. Animals were decapitated at either 1 or 2 months postinfusion. Striatal tissue was assayed for biogenic amines by HPLC and the remaining brainstem was processed for histological analysis. Iron-stained coronal sections revealed 1) no left/right staining difference with vehicle infusion, 2) a dose-dependent iron accumulation in the infused SN that was restricted to the zona compacta and dorsal-most zona reticularis when the lowest iron concentration was infused, and 3) a dose-dependent reduction in SN volume. Thionine-stained sections revealed neuronal loss and accompanying reactive gliosis within an area that corresponded closely to that of increased iron staining. These degenerative changes were more extensive in animals infused via a side-by side vs. a sequential protocol. Neurochemically, there was a highly significant correlation between the amount of iron infused intranigrally and magnitude of reductions in striatal DA, DOPAC, and HVA within the ipsilateral striatum. These data indicate that iron infusion into the SN can cause degenerative changes within the SN and that these changes can be restricted to the SNc region when low amounts of iron are infused. The data further support the hypothesis that iron-induced degeneration may contribute to the pathogenesis of PD.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Interleukin-1 beta stimulates adrenocorticotropin and corticosterone release in 10-day-old rat pups.

Interleukin-1 (IL-1) is a cytokine secreted in response to immunological challenge which has effects in many physiological systems in adult models. Among the central nervous system effects of IL-1 are its ability to alter sleep patterns, body temperature, and certain neuroendocrine parameters including the release of ACTH and corticosterone (B) in vivo. This study investigated the ability of IL-1 to induce ACTH and B release in 10-day-old rats. This age was chosen due to a well documented phenomenon, the stress hyporesponsive period (SHRP), in which rodents display a blunted pituitary-adrenal response to stressors during the first 2 postnatal weeks (postnatal days 3-14). Administration of IL-1 to rat pups during the SHRP resulted in robust ACTH and B increases. Data are discussed in terms of the site of action and ontogeny of negative feedback mechanisms in the hypothalamic-pituitary-adrenal axis.

Adrenal Cortex↗

PubMed1992

Effects of exercise on immune functions of undernourished mice.

Regular moderate exercise may modulate the response to a stressor and thus improve immune functions in conditions commonly associated with immunodepression and elevated levels of stress hormones. For example, anorexia nervosa patients, many of whom engage in regular aerobic exercise, generally have normal immune function and viral disease resistance in spite of their severe undernutrition. To test the hypothesis that exercise can prevent undernutrition-induced immunodepression, mice were fed a nutritionally complete, semi-purified diet, either ad libitum or in restricted quantities to induce 25% loss of initial weight over 3 weeks. Half the animals from each dietary group were run on a treadmill for 30 min/day, 5 days/week. Exercise had no effect on several measures of nutritional status. Spleen weight and blastogenic response to lipopolysaccharide were significantly increased by exercise in undernourished mice. In vivo antibody response to sheep red blood cells, and in vitro splenic responses to concanavalin A and phytohemagglutin were not significantly affected by exercise. Serum corticosterone level was increased by food restriction and significantly decreased by exercise in the undernourished mice. Within a treatment group there were no significant correlations between serum corticosterone level and any immune system measure. Hypothalamic concentration of uric acid was increased in food restriction groups and concentration of norepinephrine was increased in exercise groups. The results suggest that regular exercise may help prevent undernutrition-induced immunodepression, possibly through modulation of the stress response.

Analysis of Variance↗

PubMed1992

Human recombinant interferon alpha inhibits naloxone binding to rat brain membranes.

Regulation of certain central nervous system (CNS) functions by the immune system may involve interferons (IFNs) acting through opioid receptors. Human recombinant interferon alpha (hrIFN alpha), as well as natural IFN alpha, have been reported to modulate a variety of physiological CNS functions both in vivo and in vitro. If the mechanism is via opioid receptors then IFN alpha should inhibit the binding of certain opioid radioligands to brain membranes. This study reports the inhibitory effect of hrIFN alpha on the binding of 3H-naloxone to rat brain membranes in vitro. The inhibitory effect at 37 degrees C is hrIFN alpha concentration dependent over the range of 500 to 6000 antiviral units per ml (U/ml) with 500 micrograms of membrane protein. The presence of NaCl (100mM) increases specific binding of naloxone and attenuates the inhibitory effect of hrIFN alpha. The inhibitory effect of hrIFN alpha is sensitive to temperature with maximum inhibition observed at 37 degrees C, and less as incubation temperature is reduced. These data suggest that IFN alpha may modulate certain physiologic functions via opioid pathways in the brain.

Animals↗

PubMed1992

Sexual pheromones in lipids and other fractions from urine of the male mole rat, Spalax ehrenbergi.

Spalax ehrenbergi mole rats are blind, solitary, territorial, aggressive, subterranean rodents with a yearly breeding season that peaks in December and January. We confirm here an earlier report that estrous females are attracted to substances present in the urine of homospecific as compared to heterospecific adult males. We have also found that nonestrous female mole rats show avoidance behavior to the same homospecific urine. Our objective was to ascertain the nature of the pheromone(s) and gain insight as to its possible role in reproductive isolation and speciation. An active principle, detected in either two- or three-choice behavior tests, was found to be extractable from urine by methylene chloride (CH2Cl2) and mainly found in the neutral lipid fraction. Total lipids were chromatographed by thin layer chromatography on silica gel G60 plates. Most of the activity was found in a zone bounded by Rfs 0.2 and 0.7. Cholesterol, other sterols, and ethyl esters of fatty acids chromatographed in this zone as determined by standards and staining. Ethyl esters of fatty acids were also detected in this fraction by GC/MS analysis. Although a large amount of activity was found in lipids, it only accounted for about 1% of that found in urine. Some activity may have been destroyed or lost during the extraction procedure and some may remain in a lipid insoluble form. Preliminary tests of lipid extracts of various portions of the male urogenital tract revealed pheromonal activity present, particularly in tissues associated with testes, epididymis, prostate, and bladder.

Animals↗

PubMed1992

Thymic regulation of the hypothalamic-pituitary-gonadal axis.

The thymus gland and the cells that it regulates produce a number of soluble factors that are capable of indirectly modulating the immune system via reproductive neuroendocrine circuits. Studies dating to the turn of the century were designed to evaluate the effects of partially purified thymic extracts in treating various reproductive disorders as well as changes in gonadal tissue weights. More recent studies have focused on the chemical nature of the factors responsible for regulating reproductive function. A number of factors have been described. These include thymosin beta 4 which has been found to stimulate the release of luteinizing hormone releasing hormone and luteinizing hormone (LH). Other factors such as interleukin-1 (IL-1) have been found to inhibit the release of these two peptides. IL-1 has also been found to alter the expression of LH receptors in rat granulosa cells. Certain interferons have been found capable of suppressing estrogen and progesterone release. While many of the studies have been carried out using adult animal models, there is increasing evidence that exposure to cytokines during early development can have long lasting if not permanent effects upon the reproductive axis. These and related topics are the subject of this review.

Animals↗

PubMed1991

Neuroimmunopharmacologic effects of drugs of abuse.

Direct studies linking drugs of abuse with changes in neurotransmitters and subsequent effects on the immune system are not abundant. One can, however, hypothesize that an indirect effect can occur since a variety of neurotransmitters known to be acted on by various drugs of abuse can, in turn, be correlated with changes in immunity. These changes most likely are mediated via alterations in the autonomic nervous system or the ratio of hormones regulated by the pituitary gland. In addition, there is sound evidence to suspect that the immune system might be capable of altering either the induction of tolerance or the severity of withdrawal symptoms. An increasing body of evidence indicates that IL-1, IFN-alpha, as well as C3a and C5a of the complement cascade, are capable of acting on central catecholamines within the brain. The possibility that immune system peptides are capable of regulating neurotransmitters is further suggested by the evidence of neuropsychiatric side effects during the course of clinical trials. Since a variety of drugs of abuse can directly alter immunocompetence as evidenced by the results of in vitro protocols described elsewhere in this volume, one could speculate that certain behavioral manifestations of drug addiction may be modulated, in part, by immunologic status.

Animals↗

PubMed1974