Chronic Administration Of High Doses Research Articles

Abuse of Anabolic-Androgenic Steroids and Adverse Effects on Human Organ Health: A Review

Anabolic-androgenic steroids (AAS) are large groups of molecules structurally and functionally similar to the male hormone testosterone. The use of AAS is well known and widespread worldwide due to its androgenic and anabolic properties that can increase muscle mass and strength to support athlete performance. The prevalence of AAS worldwide reaches an incidence of 5% and is generally used by men aged 18-35. AAS has many side effects on the body's organs and is a serious problem for public health and athletics. This review aims to highlight the abuse of AAS and its detrimental effects on the health of human organs. Oxidative stress and apoptosis are common mechanisms that cause organ damage due to AAS use. Chronic administration of high doses of AAS results in cardiac dysfunction and increases the risks of life-threatening arrhythmias and sudden death. In addition, several organs that have the potential to be damaged by the use of AAS include the liver, kidneys, brain, musculoskeletal system, and reproductive organs. In this regard, education intervention and knowledge sharing are the important factors that should be used to raise awareness about preventing AAS abuse.

Lipid Profile Changes Induced by Chronic Administration of Anabolic Androgenic Steroids and Taurine in Rats.

Background and Objectives: Anabolic androgenic steroids (AAS), used as a therapy in various diseases and abused in sports, are atherogenic in supraphysiological administration, altering the plasma lipid profile. Taurine, a conditionally-essential amino acid often used in dietary supplements, was acknowledged to delay the onset and progression of atherogenesis, and to mitigate hyperlipidemia. The aim of the present study was to verify if taurine could prevent the alterations induced by concomitant chronic administration of high doses of AAS nandrolone decanoate (DECA) in rats. Materials and Methods: Thirty-two male Wistar rats, assigned to 4 equal groups, were treated for 12 weeks either with DECA (A group), taurine (T group), both DECA and taurine (AT group) or vehicle (C group). Plasma triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hepatic triglycerides (TGh) and liver non-esterified fatty acids (NEFA) were then determined. Results: DECA elevated TG level in A group vs. control (p = 0.01), an increase prevented by taurine association in AT group (p = 0.04). DECA decreased HDL-C in A group vs. control (p = 0.02), while taurine tended to increase it in AT group. DECA decreased TGh (p = 0.02) in A group vs. control. Taurine decreased TGh in T (p = 0.004) and AT (p < 0.001) groups vs. control and tended to lower NEFA (p = 0.08) in AT group vs. A group. Neither DECA, nor taurine influenced TC and LDL-C levels. Conclusions: Taurine partially prevented the occurrence of DECA negative effects on lipid profile, suggesting a therapeutic potential in several conditions associated with chronic high levels of plasma androgens, such as endocrine disorders or AAS-abuse.

Lavender essential oil ameliorates depression-like behavior and increases neurogenesis and dendritic complexity in rats

Depression is a major health issue that causes severe societal economic and health burden. Aromatherapy, a practice that uses essential oils for preventive and therapeutic purposes, represents a promising therapeutic alternative for the alleviation of depressive symptoms. Lavender essential oil (LEO) has been the focus of clinical studies due to its positive effect on mood. An animal model of chronic administration of high dose corticosterone to induce depression- and anxiety-like behavior and reduced neurogenesis was used to explore the biological changes brought by aromatherapy. Twenty-four adult male Sprague Dawley rats were randomly assigned into four groups: Control, corticosterone (Cort) group with high dose of corticosterone, LEO group with daily exposure to LEO by inhalation, and LEO + Cort. At the end of the 14-day treatment period, behavioral tests were carried out. Serum samples were collected 2–3 days after the 14-day period treatment and before perfusion to carry out biochemical analyses to measure BDNF, corticosterone and oxytocin. After perfusion, brains were collected for immunohistochemical analysis to detect BrdU and DCX positive cells in the hippocampus and subventricular zone. Results showed that treatment with LEO ameliorated the depression-like behavior induced by the chronic administration of corticosterone as observed in the LEO + Cort group. Cort treatment reduced the number of BrdU positive cells in the hippocampus and the subventricular zone. Treatment with LEO prevented the corticosterone-induced reduction in the number of BrdU positive cells (LEO + Cort group) demonstrating the neurogenic effect of LEO under high corticosterone conditions. Chronic administration of high dose of corticosterone significantly reduced the dendritic complexity of immature neurons. On the contrary, treatment with LEO increased dendritic complexity of immature neurons under high corticosterone conditions (LEO + Cort group). The improved neurogenesis and dendritic complexity observed in the LEO + Cort group demonstrated a clear restorative effect of LEO under high corticosterone conditions. However, 2–3 days after the treatment, the levels of BDNF were upregulated in the LEO and LEO + Cort groups. Furthermore, the concentration of oxytocin in serum, 2–3 days after the treatment, showed to be upregulated in the LEO group alone. The present study has provided evidence of the biological effect of LEO on neuroplasticity and neurogenesis. Also, this study contributes to the understanding of the mechanism of action of LEO in an animal model where depression- and anxiety-like behavior and reduced neurogenesis were induced by high corticosterone administration.

A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support.

Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation.

Differential expression of skeletal muscle genes following administration of clenbuterol to exercised horses.

BackgroundClenbuterol, a beta2-adrenergic receptor agonist, is used therapeutically to treat respiratory conditions in the horse. However, by virtue of its mechanism of action it has been suggested that clenbuterol may also have repartitioning affects in horses and as such the potential to affect performance. Clenbuterol decreases the percent fat and increases fat-free mass following high dose administration in combination with intense exercise in horses. In the current study, microarray analysis and real-time PCR were used to study the temporal effects of low and high dose chronic clenbuterol administration on differential gene expression of several skeletal muscle myosin heavy chains, genes involved in lipid metabolism and the β2-adrenergic receptor. The effect of clenbuterol administration on differential gene expression has not been previously reported in the horse, therefore the primary objective of the current study was to describe clenbuterol-induced temporal changes in gene expression following chronic oral administration of clenbuterol at both high and low doses.ResultsSteady state clenbuterol concentrations were achieved at approximately 50 h post administration of the first dose for the low dose regimen and at approximately 18–19 days (10 days post administration of 3.2 μg/kg) for the escalating dosing regimen. Following chronic administration of the low dose (0.8 μg/kg BID) of clenbuterol, a total of 114 genes were differentially expressed, however, none of these changes were found to be significant following FDR adjustment of the p-values. A total of 7,093 genes were differentially expressed with 3,623 genes up regulated and 3,470 genes down regulated following chronic high dose administration. Of the genes selected for further study by real-time PCR, down-regulation of genes encoding myosin heavy chains 2 and 7, steroyl CoA desaturase and the β2-adrenergic receptor were noted. For most genes, expression levels returned towards baseline levels following cessation of drug administration.ConclusionThis study showed no evidence of modified gene expression following chronic low dose administration of clenbuterol to horses. However, following chronic administration of high doses of clenbuterol alterations were noted in transcripts encoding various myosin heavy chains, lipid metabolizing enzymes and the β2-adrenergic receptor.

Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium.In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties.Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively.Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10−8M÷10−6M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10−10M and 10−8÷10−6M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors.Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension.

Chronic Administration of High Doses of Nandrolone Decanoate on the Pituitary-Gonadal Axis in Male Rats.

Background:Anabolic-androgenic steroids (AAS) are abused by athletes.Objectives:The present study was designed to evaluate chronic administration of high doses of nandrolone decanoate (ND) on the pituitary-gonadal axis and hematological parameters in normal male rats.Materials and Methods:Thirty Wistar-Albino male rats were divided assigned to control (C), placebo (P) and test (T) groups (n = 10). Group T received 15 mg/kg intramuscular (IM) ND for eight weeks. Group P received the same volume of peanut oil, but group C did not receive any agent during the trial period. At the end, animals were anesthetized, killed and blood samples collected from cervical vessels. Serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels were determined by sensitive rat gonadotropins kit, using ELISA methods. Serum testosterone and hematological parameters were measured by ordinary laboratory methods. Obtained data was analyzed using SPSS 17 by ANOVA and Tukey statistical tests. Results were expressed as Mean ± SD. Statistical difference considered significantly by P < 0.05.Results:Serum testosterone, LH, FSH, weight gain, food and water intake in group T were significantly decreased compared to other groups (P < 0.05). In addition erythrocyte, leucocytes, hemoglobin and hematocrit in group T were significantly increased compared to those of other groups (P < 0.05).Conclusions:Chronic administration of high doses of ND can alter serum FSH, LH and testosterone and hematological parameters in male rats.

Synthesis and Characterization of Ganciclovir Long Chain Lipid Prodrugs.

Ganciclovir (GCV) is indicated for the treatment of human cytomegalo virus (HCMV) retinitis in immunocompromised patients. Sub-optimal physicochemical properties prevent GCV from reaching therapeutic concentrations in back of the eye (retina) tissue after oral and intravenous administration. Chronic high dose administration results in systemic toxicity. Local intravitreal injections suffer from poor ocular bioavailability and require repeated administration which can cause retinal detachment, retinal/vitreal hemorrhage and endophthalmitis. In the current study, we synthesized long chain acyl ester derivatives of GCV to improve lipophilicity and bioavailability. Ester conjugates (C5, C10 and C13 mono- and di-(O-acyl)) of GCV were synthesized in one step reaction following conventional esterification reaction. Purity of the novel prodrugs was determined with reversed phase high performance liquid chromatography. Conjugation of long lipid chain to GCV was confirmed with proton (1H) and carbon (13C) nuclear magnetic resonance and mass spectroscopy. Also, melting point and lipophilicity for the prodrugs and GCV were determined. MTS assay was used to assess in vitro toxicity of GCV and its long chain lipid prodrugs on human retinal pigment epithelial cell line (ARPE-19) cells. Results indicated that long chain lipid GCV prodrugs are nontoxic, safe and well-tolerated by ARPE-19 cells. These results suggest that novel long chain lipid GCV prodrugs may be further evaluated for ocular delivery and treatment of HCMV retinitis.

Oxidative stress and inflammatory signaling in cerulein pancreatitis.

Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.

Melatonin attenuates dexamethasone-induced spatial memory impairment and dexamethasone-induced reduction of synaptic protein expressions in the mouse brain

Chronic stress or prolonged exposure to high levels of glucocorticoid induces neuropathological alterations, such as dendritic atrophy of hippocampal or cortical neurons. The chronic administration of high doses of dexamethasone (DEX), a synthetic glucocorticoid receptor agonist, impairs long-term memory and motor coordination, reduces body weight and induces mortality in mice. DEX is typically administered clinically for a prolonged period. Therefore, we are interested in studying the mechanism by which chronic DEX administration affects cognitive function. In this study, we attempted to explore whether chronic DEX administration alters the process of memory formation and to determine the mechanism underlying the detrimental effect of DEX. The results showed that mice treated with DEX for 21 consecutive days had significantly impaired spatial memory in the Morris Water Maze task. Mice treated with DEX had prolonged water maze performance latencies and spent less time in the target quadrant compared to the control group. Furthermore, DEX reduced brain-derived neurotrophic factor (BDNF), N-methyl-d-aspartate (NMDA) receptor subunit (NR2A/B), calcium/calmodulin-dependent protein kinase II (CaMKII) in both the prefrontal cortex and hippocampus and synaptophysin in the prefrontal cortex. We also investigated whether melatonin, a hormone synthesized in the pineal gland, could protect against DEX-induced changes in spatial memory and synaptic plasticity. The results showed that mice pretreated with melatonin prior to the DEX treatment had shorter escape latencies and remained in the target quadrant longer compared to the group only treated with DEX. Melatonin significantly prevented a DEX-induced reduction in the expression of NR2A/B, BDNF, CaMKII and synaptophysin. The results from the present study demonstrate that melatonin pretreatment prevents cognitive impairment caused by DEX. However, the precise mechanism by which melatonin affects cognitive function requires further investigation.

Influence of chronic administration of anabolic androgenic steroids and taurine on haemostasis profile in rats

Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone with thrombogenic potential in high doses and long-term administration. Taurine, a widely distributed amino-sulfonic acid, is known for its beneficial effects in hypercoagulable states. In order to assess the impact of chronic administration of high doses of AAS and taurine upon haemostasis process in rats, 40 male Wistar rats were divided into four equal groups: control group (group C) - no treatment; androgen group (group A) - received 10 mg/kg per week of nandrolone decanoate (DECA); taurine (group T) - received oral supplementation of 2% taurine in drinking water; androgen and taurine group (group AT) - concomitant administration of DECA and taurine. After 12 weeks, blood samples were collected and haemostasis parameters were assessed with the thrombelastographic (TEG) analysis system: reaction time, clot kinetics (K, α), final clot strength, coagulation index and the clot lysis (Ly30). Nandrolone significantly decreased reaction time in group A compared with control (P<0.001), whereas taurine significantly increase reaction time (P=0.01), and this effect was maintained in group AT compared with group A (P=0.009). Similar differences between groups have been recorded for the clot kinetics parameters K, α. The final clot strength and coagulation index were significantly increased in group A versus group C (P=0.04, respectively P<0.001), but not in group AT versus group C (P>0.05). There were no differences in clot lysis, as shown by Ly30. Nandrolone produces an accelerated clot development and an increased clot firmness in Wistar rats. Taurine association ensures a protective effect against this hypercoagulable state, partially restoring the altered parameters of the coagulation profile.

Glycemic Control and Chronic Dosing of Rhesus Monkeys with a Fusion Protein of Iduronidase and a Monoclonal Antibody Against the Human Insulin Receptor

Hurler's syndrome, or mucopolysaccharidosis type I, is a lysosomal storage disorder caused by mutations in the gene encoding the lysosomal enzyme iduronidase (IDUA). The disease affects both peripheral tissues and the central nervous system (CNS). Recombinant IDUA treatment does not affect the CNS, because IDUA does not cross the blood-brain barrier (BBB). To enable BBB penetration, human IDUA was re-engineered as an IgG-IDUA fusion protein, where the IgG domain is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb penetrates the brain from the blood via transport on the endogenous BBB insulin receptor and acts as a molecular Trojan horse to deliver the fused IDUA to the brain. Before human testing, the HIRMAb-IDUA fusion protein was evaluated in a 6-month weekly dosing toxicology study at doses of 0, 3, 9, and 30 mg/kg/week of the fusion protein administered to 40 rhesus monkeys. The focus of the present study is the effect of chronic high dose administration of this fusion protein on plasma glucose and long-term glycemic control. The results show that the HIRMAb has weak insulin agonist activity and causes hypoglycemia at the high dose, 30 mg/kg, after intravenous infusion in normal saline. When dextrose is added to the saline infusion solution, no hypoglycemia is observed at any dose. An intravenous glucose tolerance test performed at the end of the 6 months of chronic treatment showed no change in glucose tolerance at any dose of the HIRMAb-IDUA fusion protein.

Genome-wide gene expression effects in B6C3F1 mouse intestinal epithelia following 7 and 90 days of exposure to hexavalent chromium in drinking water

Chronic administration of high doses of hexavalent chromium [Cr(VI)] as sodium dichromate dihydrate (SDD) elicits alimentary cancers in mice. To further elucidate key events underlying tumor formation, a 90-day drinking water study was conducted in B6C3F1 mice. Differential gene expression was examined in duodenal and jejunal epithelial samples following 7 or 90days of exposure to 0, 0.3, 4, 14, 60, 170 or 520mg/L SDD in drinking water. Genome-wide microarray analyses identified 6562 duodenal and 4448 jejunal unique differentially expressed genes at day 8, and 4630 and 4845 unique changes, respectively, in the duodenum and jejunum at day 91. Comparative analysis identified significant overlap in duodenal and jejunal differential gene expression. Automated dose–response modeling identified >80% of the differentially expressed genes exhibited sigmoidal dose–response curves with EC50 values ranging from 10 to 100mg/L SDD. Only 16 genes satisfying the dose-dependent differential expression criteria had EC50 values <10mg/L SDD, 3 of which were regulated by Nrf2, suggesting oxidative stress in response to SDD at low concentrations. Analyses of differentially expressed genes identified over-represented functions associated with oxidative stress, cell cycle, lipid metabolism, and immune responses consistent with the reported effects on redox status and histopathology at corresponding SDD drinking water concentrations. Collectively, these data are consistent with a mode of action involving oxidative stress and cytotoxicity as early key events. This suggests that the tumorigenic effects of chronic Cr(VI) oral exposure likely require chronic tissue damage and compensatory epithelial cell proliferation.

2-Phenylethylamine, a constituent of chocolate and wine, causes mitochondrial complex-I inhibition, generation of hydroxyl radicals and depletion of striatal biogenic amines leading to psycho-motor dysfunctions in Balb/c mice

Behavioral and neurochemical effects of chronic administration of high doses of 2-phenylethylamine (PEA; 25–75 mg/kg, i.p. for up to 7 days) have been investigated in Balb/c mice. Depression and anxiety, as demonstrated respectively by increased floating time in forced swim test, and reduction in number of entries and the time spent in the open arms in an elevated plus maze were observed in these animals. General motor disabilities in terms of akinesia, catalepsy and decreased swimming ability were also observed in these animals. Acute and sub-acute administration of PEA caused significant, dose-dependent depletion of striatal dopamine, and its metabolites levels. PEA caused dose-dependent generation of hydroxyl radicals in vitro in Fenton's reaction in test tubes, in isolated mitochondrial fraction, and in vivo in the striatum of mice. A significant inhibition of NADH-ubiquinone oxidoreductase (complex-I; EC: 1.6.5.3) activity suggests the inhibition in oxidative phosphorylation in the mitochondria resulting in hydroxyl radical generation. Nissl staining and TH immnunohistochemistry in brain sections failed to show any morphological aberrations in dopaminergic neurons or nerve terminals. Long-term over-consumption of PEA containing food items could be a neurological risk factor having significant pathological relevance to disease conditions such as depression or motor dysfunction. However, per-oral administration of higher doses of PEA (75–125 mg/kg; 7 days) failed to cause such overt neurochemical effects in rats, which suggested safe consumption of food items rich in this trace amine by normal population.

Acute cardiovascular response in anabolic androgenic steroid users performing maximal treadmill exercise testing

The purpose of this study was to investigate the cardiovascular effects of anabolic androgenic steroid (AAS) use, specifically the hemodynamic response, during maximal treadmill exercise testing by comparing the exercise response between users of AAS (U-AAS) and non-AAS users (N-AAS). Twenty-four men (n=12; 29+/-3.4 years and n=12; 29.5+/-8.2 years for the U-AAS and N-AAS groups, respectively) with regular participation in both resistance (mean=6 d.wk) and aerobic exercise (mean=2 d.wk) volunteered for the study. Both groups of subjects completed a ramp-protocol maximal treadmill exercise test to volitional fatigue. Several hemodynamic and metabolic measures were obtained before, during, and after testing. The results demonstrate for the first time that chronic administration of high doses of AAS (355.4+/-59.47 mg.wk) lead to hemodynamic and metabolic response impairment. In conclusion, the chronotropic significant incompetence in the current study was reflected by an exaggerated hemodynamic response to exercise. Furthermore, the findings suggest that nonusers of AAS showed increases in VO2max when compared to the AAS group. Therefore, this study provides a contraindication to AAS use, especially in those at increased risk of cardiovascular events.

Neurochemical, behavioral and architectural changes after chronic inactivation of NMDA receptors in mice

Schizophrenia is a psychotic illness characterized by problems in perception, learning, and memory. Post-mortem clinical data revealed abnormalities in neuronal organization, reduced soma and dendritic tree size. In rodents, reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. However, the dosage, treatment and species used in previous studies have not been consistent, leading to a lack of correlation between the findings reported in low-dose, long-term treatment models and the results in acute or chronic high dose administration. Thus, the present study investigates whether long-term, low-dose blockade of NMDA receptors with MK-801 in the early postnatal period results in molecular, cellular, morphological and behavioral changes in the mouse, alterations that have been singly described by using different drugs and dosages in either mice or rats. We found that early postnatal administration of 0.1mg/kg MK-801 for 15 days altered protein translation, synapse formation, hippocampus-dependent learning and neuronal development, resembling findings reported in schizophrenia. These results suggest that there are strong parallels between this animal model and schizophrenia, which validates it as an animal model for this condition and lends further strength of the NMDA receptor hypofunction as a useful model for the study of psychosis.

Quercetin Ameliorates Metabolic Syndrome and Improves the Inflammatory Status in Obese Zucker Rats

The aim of this study was to analyze the effects of chronic administration of high doses of quercetin on metabolic syndrome abnormalities, including obesity, dyslipidemia, hypertension, and insulin resistance. For this purpose, obese Zucker rats and their lean littermates were used. The rats received a daily dose of quercetin (2 or 10 mg/kg of body weight) or vehicle for 10 weeks. Body weight and systolic blood pressure (SBP) were recorded weekly. At the end of the treatment, plasma concentrations of triglycerides, total cholesterol, free-fatty acids (FFAs), glucose, insulin, adiponectin, and nitrate plus nitrite (NOx) were determined. Tumor necrosis factor-alpha (TNF-alpha) production, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) protein expression were analyzed in visceral adipose tissue (VAT). The raised SBP and high plasma concentrations of triglycerides, total cholesterol, FFA, and insulin found in obese Zucker rats were reduced in obese rats that received either of the doses of quercetin assayed. The higher dose also improved the inflammatory status peculiar to this model, as it increased the plasma concentration of adiponectin, reduced NOx levels in plasma, and lowered VAT TNF-alpha production in obese Zucker rats. Furthermore, chronic intake of the higher dose of quercetin enhanced VAT eNOS expression among obese Zucker rats, whereas it downregulated VAT iNOS expression. In conclusion, both doses of quercetin improved dyslipidemia, hypertension, and hyperinsulinemia in obese Zucker rats, but only the high dose produced antiinflammatory effects in VAT together with a reduction in body weight gain.

The impact of the opioids fentanyl and morphine on nociception and bone destruction in a murine model of bone cancer pain

Chronic pain resulting from metastasis into skeleton of certain neoplastic diseases remains poorly understood and relatively resistant to analgesic treatment. Opioids are the principal axis in drug therapy for this type of pain, especially at the end stage of cancer. Our aim was to examine whether, fentanyl as well as morphine, two potent analgesic opioids commonly used to treat cancer pain, would inhibit pain and bone lesion-related responses in a murine model of bone cancer pain. Repeated administration of equianalgesic doses of fentanyl (0.16 mg/kg s.c. once a day) and morphine (20 mg/kg s.c. once a day) initiated at day 1 (prophylactic treatment) or at day 7 (curative treatment) after tumor cell inoculation in the femoral cavity consistently decreased bone pain symptoms and tumor growth-induced bone destruction (micro-CT bone structure parameters). Both fentanyl and morphine treatments resulted in clear antinociceptive properties as well as reductions in cancer cell-induced bone lesions. The present results demonstrate that fentanyl, and to some lesser degree morphine, has potential benefits in the treatment and development of bone cancer pain. As such, chronic administration of high doses of certain opioids like fentanyl may have clinical utility in the management of bone cancer pain.

Adverse effects of gabapentin and lack of anti-allodynic efficacy of amitriptyline in the streptozotocin model of painful diabetic neuropathy.

Amitriptyline and gabapentin are the primary treatments for painful diabetic neuropathy (PDN), and it is clear that they produce beneficial effects, but there are questions about these treatments that have not been adequately addressed. For example, although there is a growing consensus that the therapeutic effects of amitriptyline in pain patients are independent of its effects on mood, it is not clear that amitriptyline has specific and direct effects on pain. There is also a fairly broad consensus that gabapentin is safe and well tolerated, but the side-effect profile of gabapentin has not been adequately assessed in pain populations. The rat streptozotocin (STZ) model of PDN was used (a) to assess the effects of amitriptyline on objective, quantitative measures of tactile allodynia, a common type of pain in PDN patients, and (b) to assess the side effects of gabapentin using measures of motor/ambulatory and cognitive function. Amitriptyline did not attenuate STZ-induced mechanical allodynia, even after chronic administration of high doses. Gabapentin produced robust anti-allodynic effects but also produced deficits in tests of motor/ambulatory and cognitive functions. The present experiments suggest that the beneficial effects of amitriptyline in PDN may not be a result of anti-allodynic efficacy and that gabapentin produces robust anti-allodynic effects but may also produce significant motor and cognitive deficits even at or near the lowest effective doses. These findings challenge the consensus opinions about these primary treatments for PDN and suggest that their therapeutic and adverse effects should be explored further in pain patients.

Neurochemical Correlates of Nicotine Neurotoxicity on Rat Habenulo-Interpeduncular Cholinergic Neurons

Chronic administration of high doses of nicotine results in axonal degeneration in the central core of the fasciculus retroflexus, a fiber tract connecting the habenulae (Hb) to the interpeduncular nucleus (IPN). An important part of this connection is cholinergic and neurons of origin are located in the medial Hb. We have undertaken the present investigation in order to ascertain whether the cholinergic Hb–IPN neurons are the actual target of nicotine toxicity and to begin studying molecular correlates of this action. In the present report, we demonstrate that 7-day-long continuous administration of nicotine through osmotic minipumps, results in a significant (−13%) decrease in the volume of the medial Hb, where cholinergic neurons projecting to the IPN are located, and in a drop of a specific marker for cholinergic neurons, choline acetyltransferase (ChAT), in Hb (−36%) and IPN (−28%). At various intervals (2–6 days) during continuous nicotine administration, some apoptotic neurons were visualized in the medial Hb by the TUNEL technique. The chronic nicotine treatment also resulted, after 2 days of continuous administration in significant activation of the transcription factor CREB and the ERK/MAPK survival kinase in the Hb, suggesting that these alterations in expression are in some way related to the neurodegenerative/neuroreparative process. The present observations demonstrate that the cholinergic Hb–IPN neurons are a target for nicotine neurotoxicity and confirm the usefulness of the experimental model used here not only to study the consequences of chronic stimulant abuse, but also to study the neurochemistry of the affected neural systems and the role of signaling factors in neurodegenerative and repair mechanisms. Medical relevance of the data on unique vulnerability of the Hb–IPN connection to nicotine in relation to heavy smoking habits, is briefly discussed.