Showing papers in "Neuro endocrinology letters in 2004"

The neurobiology of pleasure, reward processes, addiction and their health implications.

Abstract: Modern science begins to understand pleasure as a potential component of salutogenesis. Thereby, pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. Further, health implications related to pleasurable activities are analyzed. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors, i.e., motivational toxicity. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, endorphin and endogenous morphinergic mechanisms may play a role. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways. Thus, the concrete outcome of pleasant experiences may be a question of dose. Moderate pleasurable experiences are able to enhance biological flexibility and health. Hence, pleasure can be a resistance resource or may serve salutogenesis. Natural rewards are mediated by sensory organ stimulation, thereby exhibiting a potential association with complementary medical approaches. Trust and belief can be part of a self-healing potential connected with rewarding stimuli. Further, the placebo response physiologically resembles pleasure phenomena, since both involve brain's reward circuitry stimulation and subjective feelings of well-being. Pleasurable activities can stimulate personal growth and may help to induce healthy behavioral changes, including stress management. However, more research is needed to better understand the nature, neurobiology and maybe dangerous aspects of pleasure. Also, a possible involvement of endogenous morphinergic signaling has to be studied further.

Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?

Abstract: OBJECTIVES: This study examines the concept of clinical endocannabinoid defi ciency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional condi tions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clini cal utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.

Pharmacology of cannabinoids.

Abstract: Dronabinol (∆ 9 -tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.

Alzheimer disease: mercury as pathogenetic factor and apolipoprotein E as a moderator

Abstract: The etiology of most cases of Alzheimer’s disease (AD) is as yet unknown. Epidemiological studies suggest that environmental factors may be involved beside genetic risk factors. Some studies have shown higher mercury concentrations in brains of deceased and in blood of living patients with Alzheimer’s disease. Experimental studies have found that even smallest amounts of mercury but no other metals in low concentrations were able to cause all nerve cell changes, which are typical for Alzheimer’s disease. The most important genetic risk factor for sporadic Alzheimer’s disease is the presence of the apolipoprotein Ee4 allele whereas the apolipoprotein Ee2 allele reduces the risk of developing Alzheimer’s disease. Some investigators have suggested that apolipoprotein Ee4 has a reduced ability to bind metals like mercury and therefore explain the higher risk for Alzheimer’s disease. Therapeutic approaches embrace pharmaceuticals which bind metals in the brain of patients with Alzheimer’s disease. In sum, both the findings from epidemiological and demographical studies, the frequency of amalgam application in industrialized countries, clinical studies, experimental studies and the dental state of AD patients in comparison to controls suggest a decisive role for inorganic mercury in the etiology of AD.

The change of regional brain metabolism (18FDG PET) in panic disorder during the treatment with cognitive behavioral therapy or antidepressants.

Abstract: BACKGROUND: The goal of our study was to identify brain structures in patients with panic disorder (PD) that show changes in 18 FDG PET during the treatment with cognitive behavioral therapy (CBT) or antidepressants. METHOD: Twelve patients suffering from panic disorder were studied with [ 18 F]-2-fluoro-deoxy glucose positron emission tomography ( 18 FDG PET) scanning during resting state (condition of random episodic silent thinking, REST). After PET examination patients were randomly assigned to either cognitive behavioral treatment group (6 patients) or antidepressants treatment group (6 patients). After a 3 month period 18 FDG PET examination was repeated in both groups. Psychopathology was assessed using the rating scales HAMA, CGI and Panic Disorder Severity Scale (PDSS). Data were analysed using software for statistical parametric mapping (SPM99). RESULTS: The scores of psychopathology rating scales (CGI, HAMA, PDSS) decreased in both groups. Changes of 18 FDG uptake in the pharmacotherapy group: decreases were found in the a priori hypothesized regions in the right hemisphere, in the superior, middle, medial and inferior frontal gyrus, superior and middle temporal gyrus, and increases were detected in the a priori hypothesized regions, mainly in the left hemisphere in medial and middle frontal gyrus, superior, middle and transverse temporal gyrus. Changes of 18 FDG uptake in the CBT group: decreases were found in the a priori hypothesized regions of the right hemisphere in the inferior temporal gyrus, superior and inferior frontal gyrus, and increases were detected in the a priori hypothesized region, mostly in the left hemisphere: inferior frontal gyrus, middle temporal gyrus and insula. We did not detect changes in 18 FDG uptake in the limbic region (hippocampus, parahippocampal gyrus and amygdala). CONCLUSIONS: Changes in brain metabolism ( 18 FDG uptake) after the treatment either with CBT or with antidepressants were similar in number of brain areas, with prominent right-left difference. This is in concordance with the asymmetry of brain activity noted in patients with PD according to previous PET (and SPECT) studies.

Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurysmal SAH.

Abstract: Cytokines play a key role in mutual influence of the immunological, endocrine and CNS systems. It has been proven that proinflammatory ILs may intensify the cascade of biochemical changes in ischemic brain damage. Vasospasm, which may accompany SAH and often coexists with symptoms of DINDs, is the cause of ischemic changes in the brain. It is thought that immunological mechanisms may be one of the causes of degenerative-productive changes in vessel walls, in delayed vasospasm following SAH, which lead to substantial vasospasm and in consequence too cerebral ischemia. In the randomly selected group of patients, who underwent surgical treatment after aneurysmal SAH, we determined the concentration of IL-1 beta and IL-6 in CSF in the periods between Days 0 to 3; 4 to 7; and 8 to 15 after the occurrence of SAH. The presence and dynamics of development of vasospasm were assessed on the basis of increasing DINDs as well as CT and cerebral angiography. We examined the concentrations of ILs in CSF using radioimmunological methods, applying commercially available tests for their assessment. We found that in the period between 8 and 15 days after SAH, in increasing delayed vasospasm and DINDs, here is a statistically significant increase concentration of IL-1 beta in CSF (105.4 +/- 46.9 pg x ml-1; p<0.005), and no significant changes in patients without vasospasm and neurological deficits. On the other hand, we noted a statistically significant increase concentration of IL-6 in CSF (4802 +/- 1170 ng x ml-1; p<0.05) only in the acute phase after SAH (Days 0-3) in patients in poor clinical condition, in whom delayed vasospasm and cerebral ischemia developed later. This increase of ILs level in CSF is probably related to the intensity of the SAH, and secondarily aggravates the vasospasm and ischemic changes in the brain.

The beneficial effect of amalgam replacement on health in patients with autoimmunity.

Abstract: BACKGROUND Patients with certain autoimmune and allergic diseases, such as systemic lupus, multiple sclerosis, autoimmune thyroiditis or atopic eczema, often show increased lymphocyte stimulation by low doses of inorganic mercury in vitro. The patients often report clinical metal hypersensitivity, especially to nickel. OBJECTIVE AND METHODS In this study we examined the health impact of amalgam replacement in mercury-allergic patients with autoimmunity. The suitability of MELISA, an optimized lymphocyte stimulation test, for the selection of susceptible patients and monitoring of sensitization was also examined. Amalgam fillings were replaced with composites and ceramic materials. Follow-up health status and lymphocyte reactivity were assessed and evaluated half a year or later following amalgam removal. RESULTS Results of lymphocyte reactivity measured with MELISA indicate that in vitro reactivity after the replacement of dental amalgam decreased significantly to inorganic mercury, silver, organic mercury and lead. Out of 35 patients, 25 patients (71%) showed improvement of health. The remaining patients exhibited either unchanged health (6 patients, 17%) or worsening of symptoms (4 patients, 11%). The highest rate of improvement was observed in patients with multiple sclerosis, the lowest rate was noted in patients with eczema. The initial mercury-specific lymphocyte reactivity was significantly higher in the responder group, than in the non-responders, whose health was not improved by amalgam removal. All patients with health improvement after amalgam replacement showed reduced proliferation to inorganic mercury in follow-up MELISA. In vitro responses to phenylmercury and nickel did not differ between the groups. CONCLUSIONS Mercury-containing amalgam may be an important risk factor for patients with autoimmune diseases. MELISA is a valuable tool for selection of patients for amalgam replacement and also for monitoring of metal allergies.

Cardiovascular risk factors in middle-aged women with subclinical hypothyroidism.

Abstract: OBJECTIVES: Overt hypothyroidism (OH) is associated with premature atherosclerosis and coronary heart disease (CHD). Recently, C-reactive protein (CRP) and total homocysteine (tHct) emerged as additional independent cardiovascular risk factors. Subclinical hypothyroidism (SH), affecting as many as 15% of middle-aged women is not known to be associated with risk for CHD. DESIGN AND MEASUREMENTS: We measured CRP and tHct levels as well as conventional cardiovascular risk markers in 44 middle-aged women with newly diagnose SH. Results were compared with those obtained in 10 patients with OH and 19 euthyroid controls. RESULTS: In SH, tHct and CRP levels were not as augmented as compared to controls. Their mean systolic and diastolic blood pressure values were increased vs. controls (p<0.04;p<0.01, respectively). Mean values of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides, TC/HDL-C and LDL-C/HDL-C were not different in patients with SH compared to controls. Individual analysis revealed that the percentage of patients with SH having hypertension, hypertriglyceridemia, hypercholesterolemia, elevated TC/HDL-C and LDL-C/HDL-C ratios were higher than the percentage in controls. CRP positively correlated with BMI(r=0.29,p<0.02), and tHct positively correlated with age (r=0.24, p<0.05). CONCLUSIONS: Our findings suggest that subclinical hypothyroidism in middleaged women is associated with hypertension and dyslipidemia. CRP and tHct do not appear to contribute to the increased risk for CHD in these patients.

The epidemiology of preterm birth.

Abstract: Preterm birth is a major clinical problem, accounting for 47% of all neonatal deaths. The preterm delivery rate in UK is approximately 7%, and rates of preterm birth are steadily increasing. The diagnosis of preterm labour is difficult and most interventions to halt labour are unsuccessful. Despite this, the lack of good data hinders high quality research. The West Midlands has the highest perinatal mortality in the UK and a Perinatal Institute was set up in 2000 to address this, and aid improvements in care. Survival rates amongst preterm infants have changed dramatically over the last decade, with 88% survival for 2728 weeks, and 21% for > or =24 weeks (depending on birth weight). Risk factors include lower social class, less education, single marital status, low income, younger maternal age, low body weight, ethnicity, smoking, poor housing along with medical factors such as induction, premature rupture of membranes, infection, multiple pregnancy intrauterine death, fetal and uterine abnormalities and chorioamnionitis. Data from further detailed, robust studies are required to facilitate a comprehensive understanding of risk factors and their relationship with each other. Only then will it be possible to influence the adverse outcomes described.

Salivary cortisol in panic: are males more vulnerable?

Abstract: OBJECTIVES: The underlying mechanisms of panic attacks (PA’s) are still unclear. Theories focusing on these mechanisms differ in their description of the relationship between panic and fear. The main controversy concerns whether a PA resembles the classical flight response, or whether it is qualitatively differ ent from fear. According to the first theory, a PA would result in hypothalamicpituitary-adrenal axis (HPA-axis) activation, whereas according to the second, it would not. So far, inconclusive results have been reported in studies measuring HPA-axis activity after laboratory evoked PA’s. The present study was designed to assess cortisol levels following a 35% CO2 challenge in Panic Disorder (PD) patients compared to healthy volunteers as a measurement of HPA-axis activity. DESIGN: Twenty-three PD patients and 20 healthy volunteers participated in the study. Cortisol was determined in saliva at regular intervals before and after the challenge. Furthermore, attention was paid to possible gender effects. RESULTS: Although the 35% CO2 inhalation induced a significant increase in anxiety, no cortisol increase was found. Moreover, there was no difference between patient and control cortisol values following the 35% CO2 challenge, whereas the delta anxiety scores were far more pronounced in the patient group. Interestingly, male PD patients showed higher cortisol values. CONCLUSIONS: This study may be in accordance with the view that PA’s are not accompanied by an important HPA-axis activation. There are some indications for aberrant cortisol secretion in male PD patients. Further research needs to confirm whether male and female PD patients differ in their underlying mecha nisms related to HPA-axis activity.

The endocannabinoid-CB receptor system: Importance for development and in pediatric disease.

Abstract: Endogenous cannabinoids (endocannabinoids) and their cannabinoid CB1 and CB2 receptors, are present from the early stages of gestation and play a number of vital roles for the developing organism. Although most of these data are collected from animal studies, a role for cannabinoid receptors in the developing human brain has been suggested, based on the detection of "atypically" distributed CB1 receptors in several neural pathways of the fetal brain. In addition, a role for the endocannabinoid system for the human infant is likely, since the endocannabinoid 2-arachidonoyl glycerol has been detected in human milk. Animal research indicates that the Endocannabinoid-CB1 Receptor ('ECBR') system fulfills a number of roles in the developing organism: 1. embryonal implantation (requires a temporary and localized reduction in anandamide); 2. in neural development (by the transient presence of CB1 receptors in white matter areas of the nervous system); 3. as a neuroprotectant (anandamide protects the developing brain from trauma-induced neuronal loss); 4. in the initiation of suckling in the newborn (where activation of the CB1 receptors in the neonatal brain is critical for survival). 5. In addition, subtle but definite deficiencies have been described in memory, motor and addictive behaviors and in higher cognitive ('executive') function in the human offspring as result of prenatal exposure to marihuana. Therefore, the endocanabinoid-CB1 receptor system may play a role in the development of structures which control these functions, including the nigrostriatal pathway and the prefrontal cortex. From the multitude of roles of the endocannabinoids and their receptors in the developing organism, there are two distinct stages of development, during which proper functioning of the endocannabinoid system seems to be critical for survival: embryonal implantation and neonatal milk sucking. We propose that a dysfunctional Endocannabinoid-CB1 Receptor system in infants with growth failure resulting from an inability to ingest food, may resolve the enigma of "non-organic failure-to-thrive" (NOFTT). Developmental observations suggest further that CB1 receptors develop only gradually during the postnatal period, which correlates with an insensitivity to the psychoactive effects of cannabinoid treatment in the young organism. Therefore, it is suggested that children may respond positively to medicinal applications of cannabinoids without undesirable central effects. Excellent clinical results have previously been reported in pediatric oncology and in case studies of children with severe neurological disease or brain trauma. We suggest cannabinoid treatment for children or young adults with cystic fibrosis in order to achieve an improvement of their health condition including improved food intake and reduced inflammatory exacerbations.

Maternal-fetal attachment: searching for a new definition.

Abstract: Maternal-fetal attachment is the purest source of the powerful attachment relationship, the gradual internalisation of the life within unspoilt by the realities and complexities of early parenting. This qualitative study searches for a definition of attachment utilising a phenomenological framework. An opportunity sample of 10 women in the final trimester of pregnancy was interviewed. Interviews were transcribed and analysed using Glaser & Strauss's (1967) constant comparative methodology. Thirteen key themes were identified, of these 4 were specific to parenting experience. A novel finding contrary to earlier studies was that women reported their overwhelming emotion was not love but an innate desire to protect. Protection, the developmental nature of attachment and importance of the emotional and physical support of a partner or parent form the kernel of an evolving paradigm.

Hyperprolactinemia after low dose of amisulpride.

Abstract: Objectives Amisulpride in antipsychotic doses can induce hyperprolactinemia. The aim of this study was to prove whether the same is true for low doses of amisulpride. Methodology Plasma prolactin levels were measured in 5 males and 5 females with depressive symptoms who were treated with 50 mg of amisulpride per day as an augmentation to antidepressants (n=5), benzodiazepine anxiolytics (n=8) or in monotherapy (n=1). Six of these patients were assessed prior to onset of amisulpride treatment and after 10 days of amisulpride use. Four patients had been using amisulpride for more than a month. Results There was a significant increase of prolactin levels from mean 16+/-6 ng/ml to 113+/-65 ng/ml (median 14.5 ng/ml to median 92 ng/ml; Wilcoxon matched pair test, p=0.027). All patients had hyperprolactinemia (30-200 ng/ml). The prolactinemia was significantly higher in females (mean 160+/-50 ng/ml; median 198 ng/ml) than in males (mean 48+/-12 ng/ml; median 48 ng/ml; Mann-Whitney U test, p=0.041). Conclusion Even low doses of amisulpride used as an augmentation to antidepressant treatment, benzodiazepines or in monotherapy seem to be associated with hyperprolactinemia. The co-medication of antidepressants and benzodiazepines can potentially increase intensity of prolactinemia.

The hypothalamic-pituitary-thyroid axis and melatonin in humans: possible interactions in the control of body temperature.

Abstract: OBJECTIVE: Melatonin plays a role in the regulation of biological rhythms, body temperature presents circadian variations with lower levels during nighttime, when melatonin levels are very high, and thyroid hormones influence shiver inde pendent thermogenesis. We have investigated on possible interactions between the hypothalamic-pituitary-thyroid axis and melatonin in the control of body temperature in humans. METHODS: Peripheral blood samples for thyrotropinreleasing hormone (TRH), thyroid-stimulating hormone (TSH), free-thyroxine (FT4), melatonin levels determination and body temperature measurements were obtained every four hours for 24-hours starting at 0600h in a controlled temperature and light-dark environment from ten healthy males, aged 38–65 (mean age ±s.e. 57.4±3.03, mean body mass index ±s.e. 25.5±0.75). We calculated fractional variation and correlation on single time point hormone serum levels and tested whether the time-qualified data series showed consistent pattern of circadian var iation. RESULTS: A statistically significant difference was evidenced for the frac tional variation of daytime TSH serum levels (0600h–1000h vs. 1000h–1400h, p=0.01, 1000h–1400h vs. 1400h–1800h, p=0.0001, 1400h–1800h vs. 1800h– 2200h, p=0.001) and for the fractional variation of FT4 serum levels at 1800h– 2200h vs. 2200h–0200h (p=0.02). FT4 serum levels correlated positively with TRH serum levels at 1000h (r=0.67, P=0.03) and at 1400h (r=0.63, p=0.04), negatively with TSH serum levels at 2200h (r=–0.67, p=0.03), negatively with melatonin serum levels at 2200h (r=–0.64, p=0.04) and at 0200h (r=–0.73, p=0.01). TRH serum levels correlated positively with TSH serum levels at 0200h (r=0.65, p=0.04) and at 0600h (r=0.64, p=0.04). Body temperature correlated positively with FT4 serum levels at 1000h (r=0.63, p=0.04) and negatively with melatonin serum levels at 0200h (r=–0.64, p=0.04). A clear circadian rhythm was validated for body temperature (with acrophase in the morning) and melatonin, TRH and TSH secretion (with acrophase at night), while FT4 serum level changes presented ultradian periodicity (with acrophase in the morning). CONCLUSION: Changes of TSH serum levels are smaller and those of FT4 are greater at night,

On the application of cannabis in paediatrics and epileptology.

Abstract: An initial report on the therapeutic application of delta 9-THC (THC) (Dronabinol, Marinol) in 8 children resp. adolescents suffering from the following conditions, is given: neurodegenerative disease, mitochondriopathy, posthypoxic state, epilepsy, posttraumatic reaction. THC effected reduced spasticity, improved dystonia, increased initiative (with low dose), increased interest in the surroundings, and anticonvulsive action. The doses ranged from 0.04 to 0.12 mg/kg body weight a day. The medication was given as an oily solution orally in 7 patients, via percutaneous gastroenterostomy tube in one patient. At higher doses disinhibition and increased restlessness were observed. In several cases treatment was discontinued and in none of them discontinuing resulted in any problems. The possibility that THC-induced effects on ion channels and transmitters may explain its therapeutic activity seen in epileptic patients is discussed.

Glucocorticoid-dependency of increased adiposity in a model of hypothalamic obesity.

Abstract: UNLABELLED It is known that rats treated, at neonatal age, with monosodium L-glutamate (MSG) develop neuroendocrine and metabolic abnormalities, resulting in a phenotype of hypothalamic obesity, characterized by increased adiposity, corticosteronemia and leptinemia. OBJECTIVE We explored whether adrenal manipulations could result in the reversion of this phenotype of hypothalamic obesity. EXPERIMENTAL DESIGNS Newborn male rats, treated with MSG or vehicle (CTR), were submitted to sham operation, bilateral adrenalectomy (ADX) or bilateral adrenal enucleation (AE) on day 120 of age. Animals were examined 21 days after ADX, combined or not with corticosterone (B) substitution (ADX+B), and on days 21 and 35 after AE. Food intake, body weight and body fat mass were monitored; additionally circulating levels of insulin, leptin, ACTH and B were measured. RESULTS Our data indicate that: a) normalization of basal B circulating levels in, 21 day-ADX and -AE, MSG rats fully reversed hyperinsulinemia, hyperleptinemia and significantly decreased body fat mass; and b) recovery of hypercorticosteronemia in, 35 day-AE, MSG rats fully restored this phenotype of hypothalamic obesity. CONCLUSION Our study strongly supports that high glucocorticoid production is the main factor responsible for the development of enhanced adiposity in MSG rats and, importantly, that this abnormality could be reversed by an appropriate therapy.

The effect of Vigabatrin, Lamotrigine and Gabapentin on the fertility, weights, sex hormones and biochemical profiles of male rats.

Abstract: PURPOSE A case control study was conducted to assess the effect of Sabril (Vigabatrin), Lamictal (Lamotrigine) and Neurontin (Gabapentin) on fertility in male rats. Their effect on the body and organs weight and certain biochemical profiles including total serum protein, cholesterol, triglycerides, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum testosterone, and FSH levels were also measured. METHODS several parameters, concerning fertility were measured in 40 albino male rats of Sprague Dawley strain, they were divided into 4 groups, group one received vehicle (distilled water), group two received Vigabatrin in a dose of 200 mg/kg body weight, group three received Lamotrigine in a dose of 30 mg/kg body weight, and group four received Gabapentin 100 mg/kg body weight. All the male rats in these groups received the different medications for a complete reproductive cycle (60 days). After 24 hours of the last dose, the animals were weighed and autopsied under light ether anesthesia. Parameter of fertility that has been measured in this study includes: sperm count and motility, weight of different reproductive organs, germ cell and interstitial cell population, serum testosterone and FSH levels and assessment of pregnancies in females mixed with tested males. Biochemical profiles such as serum cholesterol, serum triglycerides, serum bilirubin, SGOT, SGPT level are all measured. The results of the histological, histometerical studies and biochemical profiles were compared to that of the control group, and the significance of these results was measured using student's "t" test. RESULTS There was significant reduction in the body weight and the weight of the testes, epididymis, seminal vesicles, ventral prostate, and vas deferens in the antiepileptic fed male rats in comparison to the control group (p > 0.001). There was significant reduction in testicular cells population dynamics including both germinal cell types and interstitial cell types in the antiepileptic fed male rats in comparison to the control group. There was also significant reduction in histometrical parameters and sperm dynamics in the antiepileptic fed male rats histologies in comparison to the control group. There was significant reduction in both testosterone and FSH levels (p < 0.001) in the antiepileptics fed male rats in comparison to the control group. There was also significant reduction in pregnancy rate observed in female rats exposed to the tested male rats among antiepileptic fed male rats compared to controls. The results of biochemical profiles assessment showed significant reduction in serum glucose, serum cholesterol, serum triglycerides levels and significant increase in serum bilirubin, SGOT, and SGPT levels in antiepileptics fed male rats in comparison to the control group. CONCLUSIONS Fertility rate and other parameters concerned with fertility, sex hormones and certain biochemical profiles were significantly disturbed in male rats fed with three of the second-generation antiepileptic drugs Vigabatrin, Lamotrigine, and Gabapentin, indicating a possible toxic effect of these three medications on sexual organs, liver, and lipid metabolism.

Investigation of the influence of training status on the relationship between the acute exercise and serum leptin levels in obese females.

Abstract: Objective Recent studies have concluded that an energy expenditure by an acute exercise session has no immediate effect on leptin levels while some showed a decline in leptin levels. The purpose of this study was to investigate any possible effects of training status of the subjects on acute exercise-leptin relationship in obese patients. Materials and methods Fourteen obese sedentary females were enrolled to the study and effects of acute incremental exercise on serum leptin levels were determined at rest and at maximal exercise performance. Then, they participated to a 12-weeks endurance aerobic training programme performed in the laboratory on a computer controlled cycle ergometer and their leptin levels were re-evaluated and the leptin-acute exercise relationships obtained under different training levels in the same group of subjects were compared. The body compositions were determined by bioelectrical impedance. Pre and post training blood samples were taken at rest and at the maximal exercise performance. Serum leptin levels were analysed in duplicate by RIA. Data were evaluated using, paired t and Pearson's tests. Results Leptin levels were not acutely affected by the incremental exercise either before (23.62+/-3.5 ng/ml and 22.62+/-3.6 ng/ml) or after (13.13+/-3.4 ng/ml and 13.82+/-3.6 ng/ml) endurance training. The marked decrease in leptin levels following training was closely correlated with fat mass loss R= 0.899 (P= 0.0001). Conclusions This study indicates that an increase in energy expenditure by acute exercise has no significant acute effect on leptin level regardless of the training status of the subjects and decrease in leptin levels after a 12-weeks endurance aerobic training programme are closely associated with the fat mass loss.

5-Hydroxyindoleacetic acid and homovanillic acid concentrations in cerebrospinal fluid in patients with Alzheimer's disease, depression and mild cognitive impairment.

Abstract: In this study we investigated the cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in Alzheimer (AD) patients (n=75), patients with mild cognitive impairment (MCI, n=9) and patients with depression (n=7). CSF HVA was significantly elevated in AD with depression (Geriatric Depression Scale, 15 point version GDS>5) in comparison to AD without depression (p<0.05, ANOVA) and CSF HVA showed a significant positive correlation with the GDS score of AD-patients (p=0.03, Spearman Rho: 0.38, Spearman Rank Correlation). In the group of AD patients CSF 5-HIAA was positively correlated with cerebrospinal fluid beta-amyloid 1-42 (Abeta42), p<0.05, Spearman Rho: 0.3, Spearman Rank Correlation, but not with CSF tau. Additionally, there was a significant positive correlation between cerebrospinal fluid 5-HIAA and HVA in the group of AD patients (p<0.0001, Rho: 0.47, Spearman Rank correlation). Neither 5-HIAA nor HVA in CSF could differentiate between mild cognitive impairment, depression and AD. The results of this study support the hypothesis that the serotonergic system plays a role in the course of AD. They further suggest an important role of dopamine metabolism in depression within AD patients.

Maternal and fetal hypothalamo-pituitary-adrenal axis: different response depends upon the mode of parturition.

Abstract: Objectives The changes in corticotropin releasing hormone (CRH), adrenocorticotropin hormone (ACTH), cortisol and dehydroepiandrosterone (DHEA) in maternal and fetal plasma were estimated in two group of women undergoing labour after oxytocin induction, or elective cesarean section to correlate changes in maternal and fetal HPA axis to the different stressor conditions. Materials and methods Blood was sampled from a maternal peripheral vein two days before labour, during the second stage of labour and on the second postnatal day, and also from umbilical vessels just after delivery. Hormone concentrations were measured by RIA and ELSA methods. The maternal plasma CRH concentration before and after labour was similar in both studied groups. Results Plasma CRH levels measured before labour in both groups were similar, but during labour after oxytocin infusion declined, and was in group of women with elective cesarean section rose, after the delivery there was no difference between groups. The plasma ACTH prior to the delivery was at the same level in all subjects, during the third stage of labour ACTH rose in the both groups, but was statistically higher in group with oxytocin infusion. The concentrations of cortisol before delivery was similar in both groups, then rose to the same level during the delivery and then declined to the level observed before delivery. The DHEA concentration was similar in both groups, did not change during the labour, there was no difference between its level in the umbilical vein and artery. In the group with oxytocin-induction there was no correlation between maternal CRH and ACTH or cortisol concentration, but such a correlation occurred in the group with elective cesarean section. The concentration of ACTH and DHEA in umbilical artery was similar in both groups but the concentrations of CRH and cortisol in umbilical artery in group of newborns delivered after elective cesarean section were statistically higher. Conclusion The activity of the mother's HPA axis is partially inhibited rather by psychological stressors, than events connected with mode of parturition. The newborn's HPA axis responds in a specific way to mother's HPA-axis. The communication between mother's and newborn's HPA is possibly related to many other factors than placental CRH and ACTH. It is necessary to consider effects of central CRH and ACTH on the fine-tune regulation of HPA axis in the late pregnancy and parturition, not detectable due to the high levels of placental hormones.

Reticuline exposure to invertebrate ganglia increases endogenous morphine levels.

Abstract: OBJECTIVES Given the presence of morphine, its metabolites and precursors in mammalian and invertebrate tissues, it became important to determine if exposing tissues to an opiate alkaloid precursor, reticuline, would result in increasing endogenous morphine levels. METHOD Endogenous morphine levels were determined by high pressure liquid chromatography coupled to electrochemical detection and radioimmunoassay following incubation of Mytilus edulis pedal ganglia with reticuline. Nitric oxide (NO) release was determined in real-time via an amperometric probe. Mu opiate receptor affinity for opiate alkaloid precursors was determined by a receptor displacement assay. RESULTS Morphine is present in the pedal ganglia of Mytilus edulis (1.43 +/- 0.41 ng/mg +/- SEM ganglionic wet weight). Ganglia incubated with 50 ng of reticuline, a morphine precursor in plants, for 1 hour exhibited a statistical increase in their endogenous morphine levels (6.7 +/- 0.7 ng/mg tissue wet weight; P<0.01). This phenomenon is concentration dependent. The increase in ganglionic morphine levels occurs gradually over the 60 min incubation period, beginning 10 minutes post reticuline addition. We show that reticuline (10(-6) M) does not stimulate ganglionic NO release in a manner resembling that of morphine (10(-6) M), which releases NO seconds after its exposure to the ganglia and lasts for 5 minutes. With reticuline, there is a 3 minute delay, which is followed by an extended release period. Furthermore, in binding displacement experiments both reticuline and salutaridine (another morphine precursor) exhibit no binding affinity for the pedal ganglia mu opiate receptor subtype. This finding is further substantiated using the positive control of human monocytes where the mu3 opiate receptor subtype has been cloned. CONCLUSION Taken together, we surmise that the morphine's precursors are being converted to morphine. The experiments strongly indicate that pedal ganglia can synthesize morphine from reticuline.

Direct measurement of free radicals in the brain cortex and the blood serum after nociceptive stimulation in rats.

Abstract: The concentrations of ROS were measured in samples of the sensorimotor brain cortex and in the rat blood. We measured the following parameters: The six lines spectra, nitroxide radical, free hydroxyl radical and singleton oxygen. Their concentration was measured under physiological conditions, after the nociceptive stimulation and after the application of melatonin, both in normal and stimulated animals. In the brain cortex only the singleton oxygen decreased after the nociceptive stimulation, whereas the nitroxide radicals and six lines spectra increased. The free hydroxyl radicals did not change significantly. In the blood serum the six lines spectra and nitroxide radical increased, the concentration of the free hydroxyl radicals did not change. Melatonin increased both the hydroxyl and nitroxide radicals. There was a non-significant decrease in the six lines spectra. The estimation of ROS can be used as a tool for detecting metabolic changes and the consequences of different environmental influences, in our case the influence of nociception and melatonin.

Light and electron microscopic examination of pineal gland in rats exposed to constant light and constant darkness.

Abstract: OBJECTIVE: This study was aimed to examine the pineal gland of rats exposed to constant light and darkness at light and electron microscopic level. DESIGN: For this purpose 18 male Wistar rats were used. Animals were divided into three groups. Rats in group I (Control) were kept under 12 hrs light: 12 hrs dark conditions. Rats in group II were exposed to constant darkness, while rats in group III were exposed to constant light for 6 weeks. At the end of the experiment, all animals were killed by decapitation. The pineal glands of rats were removed, then processed for light and electron microscopy. RESULTS: In our study, extensive number of pinealocytes was observed in the structure of pineal gland of rats exposed to constant darkness and some of the observed pinealocytes were determined to contain double nucleoli. Furthermore, mitochondria and lipid droplets in the cytoplasm of pinealocytes were increased and rough endoplasmic reticulum sacs were enlarged in this group. Whereas, in rats those exposed to the constant light, a decrease in pinealocyte intensity was associated with increase in the connective tissue between parenchymal cells. Additionally, mitochondria and lipid droplets in the cytoplasm of cells were decreased. CONCLUSIONS: It was observed that the pinealocyte cell activity of rats exposed to constant darkness was increased but decreased in rats exposed to constant light.

Possible effects of melatonin on thymus gland after pinealectomy in rats.

Abstract: OBJECTIVES: The purpose of this study was to investigate the effects of pinealectomy and pinealectomy plus melatonin administration on thymus weight and histology in adult Wistar-albino rats. METHODS: The animals were divided into three groups. Group I and Group II were designated as control (sham-pinealectomized) and pinealectomized rats, respectively. They received 10% ethanol (0.1 ml per day s.c.) alone. The rats in Group III were pinealectomized and daily injected with melatonin (3 mg/kg/0.1 ml 10% ethanol per day s.c.) commencing on the day seven after surgical operation. Injections were applied for two months. RESULTS: The thymus atrophied and its weight decreased after pinealectomy (p<0.001). The cortico-medullary boundary could not be distinguished and in the thymus induced a loss of lymphoid elements, increased number of phagocytic macrophages and enlarged blood vessels. Melatonin prevented the thymic involution. CONCLUSIONS: These results suggest that pinealectomy decreases thymus weight and that long-term administration of melatonin restores thymus weight to normal levels.

Effects of long-term use Topiramate on fertility and growth parameter in adult male rats.

Abstract: Purpose A case control study was conducted to assess the effects of long-term ingestion of Topiramate on fertility, body and reproductive organ weight and level of sex hormones in Sprague-Dawley male rats. Methods Ten adult male rats were exposed to Topiramate diets at a concentration of 100 mg /kg for 60 days. Another ten control male rats received vehicle (distilled water). After 24 hours of the last dose, animals were autopsied under light anesthesia. Several parameters including, body and reproductive organ weight, sperm count and motility, serum testosterone, FSH, levels of cholesterol, triglyceride, SGOT and SGPT were all measured. Assessment of pregnancies in females mixed with tested males was also measured. The results of histological, histometrical and biochemical profiles were compared to that of the control group, and the significance of these results was measured using student's ''t'' and Chi- square tests. Results Long-term ingestion of Topiramate for 60 days caused a significant decrease in spermatogenesis in seminiferous tubules of the testes. Sperm motility and density were also significantly reduced in cauda epididymides and testes of the treated group. The body weights and weight of reproductive organs (testes, epididymides, ventral prostate and seminal vesicle) were decreased considerably. Hormonal assay also showed significant decrease in testosterone levels. Testicular cell population dynamics also demonstrated a decrease in the number of both primary and secondary spermatocytes and spermatids in the treatment group. The number of female rats impregnated by male rats on long-term Topiramate diet had decreased. The number of implantations and the number of viable fetuses were also notably decreased in female rats impregnated by male rats ingested Topiramate. Histometry of reproductive organs confirmed these results. Conclusion these results confirm that the long-term Topiramate ingestion produces adverse effects on fertility and reproductive system in adult male rat.

Intermittent hypoxia causes a suppressed pituitary growth hormone through somatostatin.

Abstract: OBJECTIVES The aim of this study was to investigate the response of the growth hormone (GH) in rat anterior pituitary to intermittent hypoxia (IH) and its modulation by hypothalamic somatostatin (SS). SETTING AND DESIGN To observe the hypoxic response, rats were exposed to simulated altitude hypoxia (2 km or 5 km) in a hypobaric chamber for various days (4 h/d); to clarify SS-involvement, rats were pretreated with SS antagonist (cysteamine, CSH, 200 mg/kg/d, s.c.) then exposed to IH (5 km) for 2d. The GH mRNA and immunostaining GH in pituitary as well as immunostaining SS in median eminence (ME) of hypothalamus were assayed by RT-PCR and immuno-histochemistry, respectively. RESULTS IH of 5 km altitude (IH5) markedly suppressed the body weight gain (BWG) of rats from 1d to 10d, and it was returned to control level henceforth, while no significant influence was showed in the group of IH of 2 km altitude (IH2). IH5 for 2 and 5d significantly decreased GH mRNA expression in the pituitary. The pituitary immunostaining GH was remarkably increased in groups of IH2 for 5, 10, and 15 d, and in groups of IH5 for 2, 5, and 10d. Immunostaining SS in ME was significantly reduced in group of IH2 for 5d, and in groups of IH5 for 2d and 5d. Pretreatments (s.c.) with SS antagonist (CSH) significantly reversed IH5-caused increase of immunostaining GH and reduction of mRNA levels in pituitary. CONCLUSIONS IH may cause a short-term and recoverable suppression of GH release, and reduce GH mRNA expression in anterior pituitary, which may depend on the intensity and duration of the hypoxia. This suppression may be due to a modulation of hypoxia-activated SS.

Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis?

Abstract: Accelerated development of secondary sexual characteristics or sexual precocity is a well-known entity. Most authors recognize two groups of patients, those described as having central precocious puberty (CPP) and those with precocious pseudopuberty. CPP results from premature activation of the hypothalamic-pituitary-gonadal axis and pseudopuberty is caused by lesions that secrete gonadotropin-like substances or hormones. The onset of CPP is usually before age 8 in females and age 9 in males; however, there is contention that the age of onset is much earlier and also differs depending on the patients' race. Previously reported causes of CPP include intracranial neoplasm, infection, trauma, hydrocephalus and Angelman's syndrome. Pineal cysts are usually asymptomatic incidental findings, but have been associated with CPP. We present an interesting case of a patient with CPP and an associated pineal cyst. We review the literature on the pathogenesis of CPP and associated pineal cyst, the neuroendocrine relationship between the pineal gland and puberty and the neurosurgical role in these cases.

The influence of chronic exposure to low frequency pulsating magnetic fields on concentrations of FSH, LH, prolactin, testosterone and estradiol in men with back pain.

Abstract: Objectives There is widespread public concern that electromagnetic fields might be hazardous. However, studies on the biological effects of magnetic fields (MFs) have not always been consistent. Influence of extremely-low frequency MFs used in physiotherapy on endocrine system was rarely examined. Therefore, the aim of the present study was to investigate the concentrations of some pituitary (FSH, LH, prolactin) and sex (testosterone, estradiol) hormones in men with back pain exposed to magnetic fields applied during magnetotherapy or magnetostimulation over the period of three weeks. Material and methods The study was performed on 20 men aged 28-62 years (mean+/-SEM: 46.4+/-2.0 years) suffering from chronic low back pain who underwent magnetotherapy (10 patients, mean age+/-SEM: 48.4 years, range: 28-62 years) or subjected to magnetostimulation (10 patients, mean age+/-SEM: 44.3 years, range: 34-52 years) for 15 days (daily at 10:00 h, with weekend breaks). Blood samples were collected at 08:00 before magnetic field application, one day and one month following the application. Concentrations of hormones were measured by micromethod of chemiluminescence. Results Both magnetotherapy and magnetostimulation lowered levels of prolactin. The levels of LH decreased significantly one month after magnetotherapy in comparison with the baseline whereas following magnetostimulation slight but insignificant increase was observed. Estradiol concentrations were significantly lower one day and one month following magnetosimulation in comparison to the baseline and did not change after magnetotherapy. No statistically significant changes were observed in levels of FSH and testosterone after either magnetotherapy or magnetosimulation at any time examined. Conclusion Magnetic fields applied in physiotherapy exert no or very subtle effect on concentrations of FSH, LH, prolactin, testosterone, and estradiol in men.

Vitamin B 12 plasma concentrations in Alzheimer disease.

Abstract: In this contribution we investigated the correlation between plasma vitamin B12 levels and cognitive impairment in Alzheimer's disease. We could demonstrate a significant inverse correlation when the MMSE scores of those patients with the lowest 10% Vitamin B12 plasma levels ( 598 ng/ml): p=0.008, Spearman-Rho= -0.36. MMSE in the upper percentile of plasma B12 levels was 20.0 +/- 4.6 and in the lower percentile 15.7 +/- 6.1, resulting in a difference of 4.3 MMSE points. We conclude, that vitamin B12 deficiency could aggravate or accelerate the course of Alzheimer disease as vitamin B12 possesses neuroprotective and anti-inflammatory properties.

Leptin gene expression in the hypothalamus and pituitary of pregnant pigs.

Abstract: Background Leptin, the 16-kDa peptide hormone product of the ob gene, is a regulatory hormone secreted mainly by adipose tissue. Recent studies have shown leptin production by other tissues, including rat hypothalamus, rat and human pituitary, rat skeletal muscle, kidney and stomach, human and porcine placenta, human mammary epithelial cells as well as endometrial tissues. This hormone is a central modulator of food intake, metabolism and neuroendocrine functions. Objectives The aim of the study was to detect and locate porcine leptin gene expression in the different areas of the hypothalamus and pituitary on days 14-16 and 30-32 of pregnancy in pigs. Method Leptin gene expression was analysed by RT-PCR method. PCR products were subjected to sequencing analysis. Results Leptin mRNA was expressed in the medial basal hypothalamus, preoptic area, stalk median eminence, anterior pituitary, posterior pituitary and adipose tissue on days 14-16 and 30-32 of pregnancy. Sequence analysis of the 258 bp product from the hypothalamus and pituitary confirmed 99% homology with the corresponding region of porcine leptin cDNA sequence. Conclusion Leptin mRNA expression in the porcine hypothalamus and pituitary gland implies its paracrine and/or autocrine role in the regulation of hypothalamic-pituitary axis activity.