Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Depression and bipolar disorder are associated with reduced neural plasticity and deficits in memory, attention and executive function. Drug treatments for these affective disorders have insufficient clinical effects in a large group and fail to reverse cognitive deficits. There is thus a need for more effective treatments which aid cognitive function. Erythropoietin (Epo) is involved in neuroplasticity and is a candidate for future treatment of affective disorders. The investigators have demonstrated that a single dose of Epo improves cognitive function and reduces neurocognitive processing of negative emotional information in healthy and depressed individuals similar to effects seen with conventional antidepressants. The current study adds to the previous findings by investigating whether repeated Epo administration has antidepressant effects in patients with treatment resistant depression and reverses cognitive impairments in these patients and in patients with bipolar disorder in remission.</p> <p>Methods/design</p> <p>The trial has a double-blind, placebo-controlled, parallel-group design. 40 patients with treatment-resistant major depression and 40 patients with bipolar disorder in remission are recruited and randomised to receive weekly infusions of Epo (Eprex; 40,000 IU) or saline (NaCl 0.9%) for 8 weeks. Randomisation is stratified for age and gender. The primary outcome parameters for the two studies are: depression severity measured with the Hamilton Depression Rating Scale 17 items (HDRS-17) <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> in study 1 and, in study 2, verbal memory measured with the Rey Auditory Verbal Learning Test (RAVLT) <abbrgrp><abbr bid="B2">2</abbr><abbr bid="B3">3</abbr></abbrgrp>. With inclusion of 40 patients in each study we obtain 86% power to detect clinically relevant differences between intervention and placebo groups on these primary outcomes.</p> <p>Trial registration</p> <p>The trial is approved by the Local Ethics Committee: H-C-2008-092, Danish Medicines Agency: 2612-4020, EudraCT: 2008-04857-14, Danish Data Agency: 2008-41-2711 and ClinicalTrials.gov: NCT 00916552.</p

Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men

&lt;p&gt;Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake (v˙ O2 max).&lt;/p&gt; &lt;p&gt;Purpose: This study defined the time course of changes in Hbmass, v˙ O2 max as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field.&lt;/p&gt; &lt;p&gt;Methods: 19 trained men received rHuEpo injections of 50 IUNkg21 body mass every two days for 4 weeks. Hbmass was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v˙ O2 max and 3,000 m time trial performance were measured pre, post administration and at the end of the study.&lt;/p&gt; &lt;p&gt;Results: Relative to baseline, running performance significantly improved by ,6% after administration (10:3061:07 min:sec vs. 11:0861:15 min:sec, p,0.001) and remained significantly enhanced by ,3% 4 weeks after administration (10:4661:13 min:sec, p,0.001), while v˙ O2 max was also significantly increased post administration (60.765.8 mLNmin21Nkg21 vs. 56.066.2 mLNmin21Nkg21, p,0.001) and remained significantly increased 4 weeks after rHuEpo (58.065.6 mLNmin21Nkg21, p = 0.021). Hbmass was significantly increased at the end of administration compared to baseline (15.261.5 gNkg21 vs. 12.761.2 gNkg21, p,0.001). The rate of decrease in Hbmass toward baseline values post rHuEpo was similar to that of the increase during administration (20.53 gNkg21Nwk21, 95% confidence interval (CI) (20.68, 20.38) vs. 0.54 gNkg21Nwk21, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration compared to baseline (13.761.1 gNkg21, p&#60;0.001).&lt;/p&gt; &lt;p&gt;Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated v˙ O2 max and Hbmass.&lt;/p&gt

Erythropoietin: a multimodal neuroprotective agent

The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and stimulates angiogenesis and neurogenesis. These mechanisms underlie its potent tissue protective effects in experimental models of stroke, cerebral hemorrhage, traumatic brain injury, neuroinflammatory and neurodegenerative disease. The preclinical data in support of the use of EPO in brain disease have already been translated to first clinical pilot studies with encouraging results with the use of EPO as a neuroprotective agent

Effects of neonatal treatment with MSG (Monosodium glutamate) on hypothalamo- pituitary- thyroid axis in adult male rats

Neonatal administration of MSG leads to a syndrome of endocrine dysfunction characterised by reduced growth, obesity and hypogonadism. The aim of the present investigation was to gain information on the structure and function of the pituitary-thyroid axis in MSG-treated rats. Neonatal Wistar rats received an S.C. MSG (4 mglg body weight) or hyperosmotic saline (controls) on days 2, 4, 6, 8 and 10 of life. Histological and morphometrical studies were carried out on the thyroids of rats during the 4th month of life. Plasma TSH, T3, and T4 were measured by RIA kits. MSG-treated rats showed stunted growth, obesity and decreased pituitary weight. MSG administration resulted in increases in thyroid weight, absolute volumes of epithelium, colloid and stroma, and blood T3 level while T4 level remained unchanged. In enlarged thyroid gland, percentage fractions occupied by epithelium, colloid and stroma were similar to those observed in control rats. The results obtained suggest that the rat hypothalamic centres involved in regulation of the pituitary-thyroid axis are slightly affected by neonatal MSG treatme

Visual parameters of Polish special schools students

The purpose of this study was to coduct a visual screening of students in special schools with a set of tests chosen by the faculty and staff of the Department of Optometry and Visual System Biology of Poznań University of Medical Sciences. Students mentally handicapped (N = 318) between the age of 7 and 22 (mean age 14.4 ± 2.84) were screened. Group 1 were children aged 7 to 12 (n = 65), group 2 were subjects aged 13 to 16 (n = 167) and group 3 included people aged between 17 and 22 (n = 86). The scope of the screening included: auto-refractometer (Shin-Nippon A type) without cycloplegia, visual acuity for distance, positive lens test +1.00 D (diopter), spatial vision (stereo) at near, color vision and near point of convergence. 72 children (22.6%) were prescribed correction, but only 30 children actually wore glasses on a permanent basis (9.4%). Of those not using correction (n = 288): in group 1 the adopted criteria for visual acuity for the right eye were not met by the 38% of the respondents or 35% for the left eye; group 2 – 36% of the respondents failed (right eye) and 31% (left eye); 50% of students in group 3 did not meet the visual acuity criterion. Stereo was failed in groups 1 and 3 by almost 60% while in group 2 the test was failed by 47% of the respondents. The results of the refraction revealed a small degree of myopia in each eye of 38% in the entire sample. Hyperopia was found in 42% (right eye) of the students whereas 44% (left eye) in the entire sample. Astigmatism ranging from 0.75 to 2.00 D was noted in the case of 32% of people. This study indicates the need for a systematic vision screening, more than just visual acuity at distance, among the students in special schools

Comparison of reading speed, phonological decoding, and comprehension in the group of children with anisometropic amblyopia and control group

The purpose of this study was to compare the reading speed, phonological decoding, and comprehension between a group of children with anisometropic amblyopia (amblyopic group) (N = 21) and a group without visual problems (control group) (N = 37). Mean (± SD) age in amblyopic group was 10.3 ± 1.7 and 10.7 ± 1.3 years in control group (p = 0.130). The reading speed measurement was conducted with the use of Konopnicki test, phonological decoding and comprehension using the Prolexia tests – string words test and string sentences test. All reading tests were made binocularly with spectacle correction (subjective refraction result). The median (range) of the Konopnicki test in the amblyopic group was 62 words per minute (from 32 to 108), while 92 words per minute (from 51 to 125) in the control group (p < 0.0001). The mean (± SD) of the string words test for amblyopic group was 3 min and 55 s (± 1.68), while in control group it was 2 min and 55 s (± 0.95) (p < 0.0001). Median (range) of the string sentences test for amblyopic group was 4.18 min (from 1.52 to 10.32) and for control group was 2.50 min (from 1.30 to 5.12) (p < 0.0001). This study indicates that children with anisometropic amblyopia achieve significantly worse results in reading speed, phonological decoding, and comprehension

Effect of neonatal treatment with MSG (Monosodium glutamate) on thyroid of the adult male rats

Monosodium glutamate (MSG), administered to newborn rats produces extensive lesions in neurons of the arcuate nuclei of the hypothalamus. The cells represent the site of neurohormone production, including the production of both growth-hormone releasing hormone (GHRH) and somatostatin. Studies were performed on male Wistar strain rats, subcutaneously injected with MSG, at 4 mglg body weight, on days 2, 4, 6, 8 and 10 of life. When the rats reached the age of 18 months, they were additionally stimulated with a single dose of TSH (Ambinon). When the rats reached the age of 6, 12, or 18 months, their thyroids were isolated and fixed in Bouin's solution. In HE-stained preparations, planimetric and volumetric proportions occupied by the epithelia1 fraction, colloid and stroma, the number of thyroid follicles per mm2 and the thickness of epithelium were determined. Serum T3 and T4 levels were quantified by RIA. Significance of differences was tested using Student's t test. The weight of experimental rat thyroids showed no significant variations as compared to the controls but were greatest in the group of 12-month-old rats. The same was noted for the volumetric fractions of epithelium, colloid and stroma. The planimetric fractions occupied by epithelium, colloid and stroma in the thyroid remained unchanged and amounted to 60%, 31 % and 9%, respectively. The number of follicles per mm2 thyroid cross-section in the MSG-treated 6-, 12- or 18- month-old rats was 131.3, 116.2 and 130.4, respectively, and did not differ from control values. Thickness of follicular epithelium showed no significant variations. Serum T3 levels in the rats examined after 6, 12 or 18 months were increased by 67%, 89% and 33%, respectively, as compared to serum T4 levels. When compared to the controls, the serum T4 level was lower only in the 12-month-old MSG-treated rats and the serum T3 level was higher in 18-month-old MSG-treated rats. The ability of the thyroid to respond to Ambinon stimulation was preserved. The results of our investigations suggest that the rat hypothalamic centers involved in regulation of the pituitary-thyroid axis are slightly affected by neonatal administration of MSG

Neonatal treatment with monosodium glutamate MSG structure of the TSH-immunoreactive pituitary cells

Glutamic acid represents the most abundant stimulatory neurotransmitter in the central nervous system. Monosodium glutamate (MSC), subcutaneously administered to newborn rats in the perinatal period, induces lesions in 80 to 90% of the neurocytes of arcuate nuclei in the hypothalamus. These nuclei are the site of production of numerous stimulatory and inhibitory hormones including growth hormone releasing hormone (GHRH). The present studies were performed on male Wistar strain rats, subcutaneously injected on days 2, 4, 6, 8, and 10 of postnatal life with MSC at a dose of 4 mglg body weight. Eighteen-month-old rats were additionally treated with Ambinon. When the animals reached the ages of 6 or 12 months, their body weight, body length and weight of pituitary were determined. On parafrin sections, using imrnunohistochemical techniques, TSHimmunoreactive cells were detected and characterised by computerised image analysis. The results were subjected to statistical analysis using Student's t test. The rats which were perinatally treated with MSC and examined after 6 or 12 months of life were obese and shorter than control rats by 7% and 10% respectively. They also exhibited a reduction in the weight of the pituitary of 30% and 40% respectively in the two age groups. The proportion of TSH-immunoreactive cells in the pituitary remained unchanged and amounted to 4.5% in the 6-month-old and 5.4% in the 12-month-old rats respectively. The number of TSH-positive cells per mm 2 area remained unchanged. The area and circumference of the cells in the 12-month-old rats were reduced by 22% and 18%, respectively. Perinatal injury to hypophyseal arcuate nuclei induced by monosodium glutamate injection, was not associated with any significant alterations in pituitary structure, as defined by the proportion of pituitary volume occupied by TSH-immunoreactive cells