Biomedical subjects

Charles W Wilkinson

Publications and source records attributed to Charles W Wilkinson.

16 recordsLinked to original sources

PubMed2007

Antecedent hindbrain glucoprivation does not impair the counterregulatory response to hypoglycemia.

Recurrent hypoglycemia impairs hormonal counterregulatory responses (CRRs) to further bouts of hypoglycemia. The hypothalamus and hindbrain are both critical for sensing hypoglycemia and triggering CRRs. Hypothalamic glucose sensing sites are implicated in the pathogenesis of defective CRRs; however, the contribution of hindbrain glucose sensing has not been elucidated. Using a rat model, we compared the effect of antecedent glucoprivation targeting hindbrain or hypothalamic glucose sensing sites with the effect of antecedent recurrent hypoglycemia on CRR to hypoglycemia induced 24 h later. Recurrent hypoglycemia decreased sympathoadrenal (1,470 +/- 325 vs. 3,811 +/- 540 pg/ml in controls [t = 60 min], P = 0.001) and glucagon secretion (222 +/- 43 vs. 494 +/- 56 pg/ml in controls [t = 60]), P = 0.003) in response to hypoglycemia. Antecedent 5-thio-glucose (5TG) injected into the hindbrain did not impair sympathoadrenal (3,806 +/- 344 pg/ml [t = 60]) or glucagon (513 +/- 56 pg/ml [t = 60]) responses to subsequent hypoglycemia. However, antecedent 5TG delivered into the third ventricle was sufficient to blunt CRRs to hypoglycemia. These results show that hindbrain glucose sensing is not involved in the development of defective CRRs. However, neural substrates surrounding the third ventricle are particularly sensitive to glucoprivic stimulation and may contribute importantly to the development of defective CRRs.

Adrenocorticotropic Hormone↗

PubMed2006

Feeding and neuroendocrine responses after recurrent insulin-induced hypoglycemia.

Prior exposure to hypoglycemia impairs neuroendocrine counterregulatory responses (CRR) during subsequent hypoglycemia. Defective CRR to hypoglycemia is a component of the clinical syndrome hypoglycemia-associated autonomic failure (HAAF). Hypoglycemia also potently stimulates food intake, an important behavioral CRR. Because the increased feeding response to hypoglycemia is behavioral and not hormonal, we hypothesized that it may be regulated differently with recurrent bouts of hypoglycemia. To test this hypothesis, we simultaneously evaluated neuroendocrine CRR and food intake in rats experiencing one or three episodes of insulin-induced hypoglycemia. As expected, recurrent hypoglycemia significantly reduced neuroendocrine hypoglycemic CRR. Epinephrine (E), norepinephrine (NE) and glucagon responses 120 min after insulin injection were significantly reduced in recurrent hypoglycemic rats, relative to rats experiencing hypoglycemia for the first time. Despite these neuroendocrine impairments, food intake was significantly elevated above baseline saline intake whether rats were experiencing a first (hypoglycemia: 3.4+/-0.4 g vs. saline: 0.94+/-0.3 g, P<0.05) or third hypoglycemic episode (hypoglycemia: 3.8+/-0.3 g vs. saline: 1.2+/-0.3 g, P<0.05). These findings demonstrate that food intake elicited in response to hypoglycemia is not impaired as a result of recurrent hypoglycemia. Thus, neuroendocrine and behavioral (stimulation of food intake) CRR are differentially regulated by recurrent hypoglycemia experience.

Adaptation, Physiological↗

PubMed2006

Chronic daily ethanol and withdrawal: 6. Effects on rat sympathoadrenal activity during "abstinence".

We have reported that repetitive daily ethanol consumption increased anxiety-like behavior in rats 4 weeks after ethanol consumption had ceased, consistent with the persistently increased anxiety exhibited by abstinent alcoholics. Increased anxiety is associated with sympathoadrenal activation, so we have now also investigated ethanol-induced persistent changes in basal and stress-induced plasma epinephrine (E) and norepinephrine (NE) levels. Male Sprague-Dawley rats received liquid diet containing ethanol versus pair-fed isocaloric control liquid diet for 9 weeks. After 5 weeks' subsequent "abstinence" (i.e., no ethanol in the diet), the control rats exhibited low basal plasma E and NE, which were both increased by 150-300% within 5 min after transfer to a novel cage in a novel room, returning toward basal levels within 15 min. "Abstinent" ethanol-treated rats exhibited elevated basal E levels (195% of controls, P<.05), which were not significantly altered by transfer to novel environment; basal NE levels tended (P<.07) to be elevated and likewise were not altered by novel environment. These results suggest that daily ethanol consumption can induce persistent increases in sympathoadrenal activation during subsequent "abstinence," which are relatively refractory to further stimulation.

Animals↗

PubMed2006

Comparative evaluation of a new immunoradiometric assay for corticotropin.

We have characterized the performance of a commercial two-site immunoradiometric assay for manual in vitro diagnostic measurement of plasma corticotropin from Scantibodies Laboratory. We compared the results with those of a similar commonly used assay from Nichols Institute Diagnostics that has recently been withdrawn from production. The lower detection limit, range of the standard curve, cross-reactivity, and intra-assay and inter-assay imprecision of the two assays are very similar. Measurement of clinical samples and a series of samples from an experimental subject demonstrate high correlations between the two assays. These factors, together with recent clearance by the United States Food and Drug Administration for manual in vitro diagnostic measurement, make the Scantibodies corticotropin immunoradiometric assay an appropriate replacement for the Nichols assay.

Adrenocorticotropic Hormone↗

PubMed2005

Roles of acetylation and other post-translational modifications in melanocortin function and interactions with endorphins.

Phylogenetic, developmental, anatomic, and stimulus-specific variations in post-translational processing of POMC are well established. For melanocortins, the role of alpha-N-acetylation and the selective activities of alpha, beta, and gamma forms are of special interest. Acetylation may shift the predominant activity of POMC products between endorphinergic and melanocortinergic actions-which are often in opposition. This review addresses: (1) variations in POMC processing; (2) the influence of acetylation on the functional activity of alpha-MSH; (3) state- and stimulus-dependent effects on the proportional distribution of forms of melanocortins and endorphins; (4) divergent effects of alpha-MSH and beta-endorphin administration; (5) potential roles of beta- and gamma-MSH.

Acetylation↗

PubMed2005

Salivary cortisol and memory function in human aging.

OBJECTIVE: To examine the association of salivary cortisol with cognitive changes in a 3 year longitudinal study. Previous studies have suggested that elevated glucocorticoid concentrations alter hippocampal neuronal morphology, inhibit neurogenesis, and impair cognition. METHODS: Salivary cortisol samples were collected at home by 79 cognitively intact older persons (mean age 78+/-7 years) at 08:00, 15:00 and 23:00h, and collections were repeated annually for 3 years. Cognitive function was also assessed annually. RESULTS: The mean cortisol level of samples taken at three times of day and the cortisol concentration at 23:00h were significantly associated with poorer performance on tasks of declarative memory and executive function. Of 46 subjects who completed the entire 3 year study, higher initial cortisol concentration at 23:00h predicted a decline in performance of delayed paragraph recall. CONCLUSION: These results partially confirm previous findings that high cortisol is associated with impaired declarative memory function in non-demented older persons. In addition, our data show that high salivary cortisol concentrations predict a decline in memory function over the next 3 years.

Aged↗

PubMed2005

Reduced anorexigenic efficacy of leptin, but not of the melanocortin receptor agonist melanotan-II, predicts diet-induced obesity in rats.

Leptin gains access to the central nervous system where it influences activity of neuronal networks involved in ingestive behavior, neuroendocrine activity, and metabolism. In particular, the brain melanocortin (MC) system is important in leptin signaling and maintenance of energy balance. Although leptin or MC receptor insensitivity has been proposed to be associated with obesity, the present study compared central leptin and MC receptor stimulation on some of the above-mentioned parameters and investigated whether these treatments predict proneness to diet-induced obesity (DIO) in outbred Wistar rats. Third-cerebroventricular administration of equi-anorexigenic doses of leptin and of the MC agonist melanotan-II caused comparable increases in plasma ACTH and corticosterone levels and c-Fos-labeling in approximately 70% of paraventricular hypothalamic (PVN) neuronal cell bodies containing CRH. This reinforces involvement of paraventricular CRH neurons in the short-term neuroendocrine and ingestive effects of leptin and melanocortins. In the DIO prediction study, anorexigenic efficacy of melanotan-II was not correlated with any parameter linked to DIO but was highly correlated with MC in situ binding (with labeled [Nle(4),D-Phe(7)]alpha-MSH) as well as CRH immunoreactivity in the PVN of DIO rats. This suggests intricate relationships among MC signaling, the CRH system, and ingestive behavior unrelated to DIO. In the same animals, leptin's anorexigenic efficacy was not correlated with PVN MC in situ binding or CRH immunoreactivity but correlated inversely to post-DIO plasma leptin, liver weight, and abdominal adiposity, the latter being correlated to insulin resistance. Thus, differences in leptin but not MC signaling might underlie DIO, visceral obesity, and insulin resistance.

Animals↗

PubMed2005

Usefulness of relative lymphocyte count as an independent predictor of death/urgent transplant in heart failure.

The usefulness of low relative lymphocyte count as an independent predictor of death/urgent transplant in patients with heart failure (HF) and the association between low relative lymphocyte count and neurohormone and cytokine activation were investigated. Relative lymphocyte count, clinical variables, neurohormones, and cytokines were measured in 129 outpatients with HF. Follow-up extended to a mean of 3.0 +/- 1.2 years for death/urgent transplant. Low relative lymphocyte count was independently associated with a 3.4-fold increased risk of death/urgent transplant. Relative lymphocyte count was positively associated with hemoglobin and inversely associated with age, jugular venous pressure, creatinine, leukocyte count, and soluble tumor necrosis factor receptor-1. There was only a borderline inverse association with cortisol levels during evening hours.

Biomarkers↗

PubMed2005

Effects of chronic glucocorticoid administration on insulin-degrading enzyme and amyloid-beta peptide in the aged macaque.

Insulin-degrading enzyme (IDE) has been identified as a candidate protease in the clearance of amyloid-delta (Abeta) peptides from the brain. IDE activity and binding to insulin are known to be inhibited by glucocorticoids in vitro. In Alzheimer disease (AD), both a decrease in IDE levels and an increase in peripheral glucocorticoid levels have been documented. Our study investigated the effects of glucocorticoid treatment on IDE expression in vivo in 12 nonhuman primates (Macaca nemestrina). Year-long, high-dose exposure to the glucocorticoid cortisol (hydrocortisone acetate) was associated with reduced IDE protein levels in the inferior frontal cortex and reduced IDE mRNA levels in the dentate gyrus of the hippocampus. We assessed Abeta40 and Abeta42 levels by ELISA in the brain and in plasma, total plaque burden by immunohistochemistry, and relative Abeta1-40 and Abeta1-42 levels in the brain by mass spectrometry. Glucocorticoid treatment increased Abeta42 relative to Abeta40 levels without a change in overall plaque burden within the brain, while Abeta42 levels were decreased in plasma. These findings support the notion that glucocorticoids regulate IDE and provide a mechanism whereby increased glucocorticoid levels may contribute to AD pathology.

Aging↗

PubMed2004

Physiological regulation of hypothalamic IL-1beta gene expression by leptin and glucocorticoids: implications for energy homeostasis.

Interleukin-1beta (IL-1beta) is synthesized in a variety of tissues, including the hypothalamus, where it is implicated in the control of food intake. The current studies were undertaken to investigate whether hypothalamic IL-1beta gene expression is subject to physiological regulation by leptin and glucocorticoids (GCs), key hormones involved in energy homeostasis. Adrenalectomy (ADX) increased hypothalamic IL-1beta mRNA levels twofold, measured by real-time PCR (P < 0.05 vs. sham-operated controls), and this effect was blocked by subcutaneous infusion of a physiological dose of corticosterone. Conversely, hypothalamic IL-1beta mRNA levels were reduced by 30% in fa/fa (Zucker) rats, a model of genetic obesity caused by leptin receptor mutation (P = 0.01 vs. lean littermates), and the effect of ADX to increase hypothalamic IL-1beta mRNA levels in fa/fa rats (P = 0.02) is similar to that seen in normal animals. Moreover, fasting for 48 h (which lowers leptin and raises corticosterone levels) reduced hypothalamic IL-1beta mRNA levels by 30% (P = 0.02), and this decrease was fully reversed by refeeding for 12 h. Thus leptin and GCs exert opposing effects on hypothalamic IL-1beta gene expression, and corticosterone plays a physiological role to limit expression of this cytokine in both the presence and absence of intact leptin signaling. Consistent with this hypothesis, systemic leptin administration to normal rats (2 mg/kg ip) increased hypothalamic IL-1beta mRNA levels twofold (P < 0.05 vs. vehicle), an effect similar to that of ADX. These data support a model in which expression of hypothalamic IL-1beta is subject to opposing physiological regulation by corticosterone and leptin.

Adrenalectomy↗

PubMed2004

Chronic cortisol exposure promotes the development of a GABAergic phenotype in the primate hippocampus.

Glucocorticoids regulate plasticity and survival of hippocampal neurons. Aberrant exposure to this steroid hormone can result in neurodegeneration, perhaps secondary to disruption of calcium homeostasis. Calbindin, a calcium-binding protein that buffers excess calcium, may protect against neurodegeneration resulting from overabundance of intracellular calcium. In this study, we examined whether chronic treatment (1 year) with cortisol enhances hippocampal calbindin expression in primates. Calbindin is a marker for inhibitory neurons and the dentate gyrus is known to adopt an inhibitory phenotype in response to extreme conditions such as seizures. Thus, we hypothesized that chronic cortisol exposure may also promote a GABAergic phenotype. Therefore, we examined the expression of the GABA-synthesizing enzyme glutamic acid decarboxylase. The expression of brain-derived neurotrophic factor, which is responsive to glucocorticoids, was also examined. Our results demonstrate significant increases in calbindin, glutamic acid decarboxylase and brain-derived neurotrophic factor in several regions of the primate hippocampus, including the dentate gyrus and CA3, in response to chronic cortisol exposure. These results suggest that chronic cortisol exposure may shift the balance towards a GABAergic phenotype, perhaps as part of a compensatory feedback mechanism to dampen the initial excitatory effects of glucocorticoids in the hippocampus.

Animals↗

PubMed2004

Inactivation of the DMH selectively inhibits the ACTH and corticosterone responses to hypoglycemia.

We have previously reported that repeated bouts of insulin-induced hypoglycemia (IIH) in the rat result in blunted activation of the paraventricular, arcuate, and dorsomedial hypothalamic (DMH) nuclei. Because DMH activation has been implicated in the sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) responses to stressors, we hypothesized that its blunted activation may play a role in the impaired counterregulatory response that is also observed with repeated bouts of IIH. In the present study, we evaluated the role of normal DMH activation in the counterregulatory response to a single bout of IIH. Local infusion of lidocaine (n = 8) to inactivate the DMH during a 2-h bout of IIH resulted in a significant overall decrease of the ACTH response and a delay of onset of the corticosterone response compared with vehicle-infused controls (n = 9). We observed suppression of the ACTH response at time (t) = 90 and 120 min (50 +/- 12 and 63 +/- 6%, respectively, of control levels) and early suppression of the corticosterone response at t = 30 min (59 +/- 13% of the control level). The epinephrine, norepinephrine, and glucagon responses were not altered by DMH inactivation. Our finding suggests that DMH inactivation may play a specific role in decreasing the HPA axis response after repeated bouts of IIH.

Adrenocorticotropic Hormone↗

PubMed2002

Inactivation of the PVN during hypoglycemia partially simulates hypoglycemia-associated autonomic failure.

The anatomic connections of the paraventricular nucleus of the hypothalamus (PVN) are such that it is ideally situated to modulate and/or control autonomic responses to a variety of stressors, including hypoglycemia. In our experimental model of hypoglycemia-associated autonomic failure (HAAF), a syndrome in which the counterregulatory response to hypoglycemia is partially compromised via unknown mechanisms, activation of the PVN is blunted (15). We hypothesized that this blunted PVN activation during HAAF may be sufficient to cause the impaired counterregulatory response. To test this hypothesis, we anesthetized the PVN with lidocaine during insulin-induced hypoglycemia in rats and measured counterregulatory hormone levels. PVN inactivation decreased indexes of the sympathoadrenal response (plasma epinephrine and norepinephrine) and the hypothalamic-pituitary axis response (ACTH). Inactivation decreased the peak epinephrine response to hypoglycemia by almost half (-42 +/- 6% from control; P = 0.04) and the peak norepinephrine response by 34 +/- 5% (P = 0.01). The peak plasma ACTH levels attained were suppressed by 35 +/- 6% (P = 0.02). Adrenal corticosterone and pancreatic glucagon responses were not impaired. This pattern of neuroendocrine response is unlike that previously seen with our HAAF model. Control infusions of lidocaine >or=1 mm anterior or posterior to the PVN did not simulate this neuroendocrine pattern. Thus it appears that decreased PVN activation, as occurs with HAAF, may be involved in specific components of HAAF (i.e., blunting the sympathoadrenal and hypothalamic-pituitary-adrenocortical axis response), but not in others (i.e., blunting the glucagon response).

Adrenocorticotropic Hormone↗

PubMed2002

The modulatory effects of corticosteroids on cognition: studies in young human populations.

In the present article, we report on two studies performed in young human populations which tested the cognitive impact of glucocorticoids (GC) in situations of decreased or increased ratio of mineralocorticoid (MR) and glucocorticoid (GR) receptor occupation. In the first study, we used a hormone replacement protocol in which we pharmacologically decreased cortisol levels by administration of metyrapone and then restored baseline cortisol levels by a subsequent hydrocortisone replacement treatment. Memory function was tested after each pharmacological manipulation. We observed that metyrapone treatment significantly impaired delayed recall, while hydrocortisone replacement restored performance at placebo level. In the second study, we took advantage of the circadian variation of circulating levels in cortisol and tested the impact of a bolus injection of 35 mg of hydrocortisone in the late afternoon, at a time of very low cortisol concentrations. In a previous study with young normal controls, we injected a similar dose of hydrocortisone in the morning, at the time of the circadian peak, and reported detrimental effects of GC on cognitive function. Here, when we injected a similar dose of hydrocortisone in the afternoon, at the time of the circadian trough, we observed positive effects of GC on memory function. The results of these two studies provide evidence that GC are necessary for learning and memory in human populations.

Adrenocorticotropic Hormone↗

PubMed2002

Stress hormone levels of children of depressed mothers.

Research suggests that disruptions in early caretaking can have long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response. Children of depressed mothers are at increased risk for developing internalizing problems in part because of disruptions in their caretaking environment. The present study investigated whether children of depressed mothers exhibit elevated salivary cortisol levels. Salivary cortisol samples were collected from 45 7- to 8-year-old children of mothers with a history of depression and 29 children of nondepressed mothers. Samples were collected soon after arrival to the laboratory and after a mild laboratory stressor and at home after wakeup and before bedtime. Children who had elevated levels of intemalizing symptoms and whose mothers had a history of depression showed elevated laboratory baseline cortisol levels. Children who were reported to have clinically significant internalizing symptoms were also more likely to show an elevated stress response to a mild laboratory stressor. When the longitudinal history of maternal depression was examined, matemal depression during the child's first 2 years of life was the best predictor of elevations in baseline cortisol at age 7 years. This study provides evidence that internalizing symptoms exist in conjunction with a more reactive hormonal stress system in children of depressed mothers. The results also provide preliminary evidence that exposure to maternal depression in the first 2 years of life may be related to children's cortisol levels later in life.

Arousal↗

PubMed2002

Chronic daily ethanol and withdrawal: 3. Forebrain pro-opiomelanocortin gene expression and implications for dependence, relapse, and deprivation effect.

BACKGROUND: Although forebrain pro-opiomelanocortin (POMC)-producing neurons seem to mediate or modulate many responses to ethanol consumption, changes in activity of this opiomelanocortinergic system in response to chronic ethanol consumption, withdrawal, and subsequent abstinence remain unresolved. METHODS: We investigated the effects of chronic daily ethanol consumption, withdrawal, and subsequent abstinence on adult male Sprague-Dawley rat forebrain opiomelanocortinergic activity as reflected by changes in hypothalamic POMC messenger RNA (mRNA) content by using a well characterized liquid diet model that we have previously demonstrated to accurately simulate not only daily oral ethanol consumption quantity and pattern, but also both neuroendocrine and behavioral changes characteristic of actively drinking and subsequently abstinent alcoholics. RESULTS: After 7 weeks of daily ethanol consumption at night and withdrawal during the day, evening mediobasal hypothalamus POMC mRNA concentrations were suppressed versus both ad libitum-fed and pair-fed controls. Morning POMC mRNA concentrations were also suppressed versus ad libitum-fed controls and tended to be decreased versus pair-fed controls. Three weeks after gradual removal of ethanol from the diet, mediobasal hypothalamus POMC mRNA concentrations were increased relative to ad libitum-fed and pair-fed controls. Plasma concentrations of corticosterone, testosterone, and leptin were also altered by the daily ethanol/withdrawal treatment and by subsequent abstinence. CONCLUSIONS: Because each of these hormones has been demonstrated to modify forebrain POMC gene expression under some conditions, the overall changes in forebrain opiomelanocortinergic regulation in response to chronic daily ethanol/withdrawal and subsequent abstinence probably reflect, at least in part, regulation by multiple endocrine mechanisms, together with responses to stress, development of tolerance during chronic daily ethanol consumption, and rebound of function after termination of this consumption. Overall, the demonstrated changes in forebrain POMC gene expression are consistent with significant roles for forebrain opiomelanocortinergic regulation in mediating alcohol dependence, propensity to relapse, and the alcohol deprivation effect.

Alcohol-Related Disorders↗