Protective effect of melatonin on damage in the sperm parameters of mice exposed to diazinon / Efecto protector de la melatonina sobre el daño en los parámetros espermáticos de ratones expuestos a diazinón

Since normal sperm parameters can be altered by organophosphorous pesticides, this study intended to determine if melatonin is able to prevent the damage on sperm quality after an acute exposure to diazinon. Adult male mice were injected intraperitoneally with melatonin, diazinon (1/3 or 2/3 LD50) or both, and sperm parameters were evaluated on days 1 or 32 post injection. Groups treated with diazinon showed elevated lipid peroxidation levels on day 1 post treatment, while groups pretreated with melatonin before diazinon showed no difference compared to control. Sperm count showed a significant decrease in both diazinon-treated groups only on day 32 post injection; no differences were observed in groups pretreated with melatonin prior to diazinon compared to control. The percentage of abnormal sperm morphology increased in the diazinon-treated groups only on day 32 postinjection. The administration of melatonin prior to exposure to diazinon prevents the alteration of sperm parameters commonly caused by organophosphates, possibly due to its antioxidant properties.

Debido a que los parámetros normales de los espermatozoides pueden ser alterados por algunos contaminantes como los pesticidas organofosforados, este estudio pretende determinar si melatonina es capaz de prevenir o proteger del daño en la calidad espermática, después de una exposición aguda a diazinon. Ratones machos adultos fueron inyectados via intraperitoneal con diazinon 1/3 y 2/3 de la LD50 y otro grupo tratados con melatonina + 1/3 diazinon LD50 y melatonina + 2/3 LD50. Los parámetros espermáticos fueron evaluados al día 1 y al día 32 post tratamiento. Los grupos tratados con diazinon solo o conjugado con melatonina mostraron un incremento significativo en los niveles de lipoperoxidación en el tratamiento después de un día. Al día 32 no se observan diferencias significativas con el grupo control. El recuento espermático al día 1 no presenta diferencias entre los grupos tratados y el control. Sin embargo al día 32 los grupos tratados con diazinon solo, muestran una disminución significativa, solo el grupo de melatonina +1/3 diazinon, presenta valores similares al grupo control. La morfología espermática normal presenta una disminución significativa en grupos tratados con diazinon, pero un aumento significativo al día 32 en los grupos tratados con melatonina. Los mayores porcentajes de anormalidades se presentan en la cabeza y la cola de los espermatozoides. La administración de melatonina antes de la exposición al diazinon evita las alteraciones de los parámetros espermáticos, comúnmente causada por organofosforados, posiblemente debido a sus propiedades antioxidantes.

Melatonin prevents damage elicited by the organophosphorous pesticide diazinon on the mouse testis.

Organophosphates like O,O-diethyl O-2-isopropyl-6-methyl pyrimidinyl-4-g-1-phosphorothioate (diazinon) are pesticides used worldwide, which can affect both animals and man even after a single exposure. Whereas their toxicity is due to acetylcholinesterase inhibition, their secondary toxic effects have been related to free oxygen radicals. This study evaluates the effects of a single dose of diazinon and melatonin-a powerful antioxidant-on plasmatic acetylcholinesterase activity and testis histopathology in adult mice 1 and 32 days post-treatment. Diazinon diminished the plasma acetylcholinesterase activity on day 1 post-treatment, although testosterone levels remained unaffected. Morphometrical analysis showed a decrease in seminiferous epithelium height (days 1 and 32), whereas an increase in testicular superoxide dismutase (SOD) activity was detected (day 32). Melatonin pretreatment prevented every alteration induced by diazinon, except the diminution of acetylcholinesterase plasmatic activity. Testicular damage might be due to elevated concentrations of free oxygen radicals released upon diazinon exposure, inducing alterations in the DNA and promoting local apoptosis; however, antioxidant pretreatment with melatonin prevents or diminishes this damage.

Melatonin prevents damage elicited by the organophosphorous pesticide diazinon on mouse sperm DNA.

Toxic effects of pesticides are commonly associated with DNA damage. To evaluate the effect of the organophosphate diazinon on sperm DNA and to test whether melatonin could prevent this damage, male mice were intraperitoneally treated with melatonin, diazinon (1/3 or 2/3 LD50) or both; cauda epididymal spermatozoa were obtained on days 1 and 32 postinjection and tested for DNA alterations. On day 1, sperm from diazinon-treated mice showed augmented DNA breakages and reduced chromatin packaging, whilst DNA damage increased only in the diazinon 2/3 LD50 group. Micronucleus test of bone marrow cells demonstrated somatic cell chromosomal damage in both diazinon-treated groups. Pretreatment with melatonin before diazinon acute administration improved all parameters studied on day 1 pi. The organophosphorous pesticide diazinon is a dose-dependent testicular toxicant that alters the sperm DNA structure; melatonin is able to prevent this damage.

Requestioning depression in patients with cancer: contribution of somatic and affective symptoms to Beck's Depression Inventory.

BACKGROUND: Depressive symptoms are a major complaint reported by cancer patients. Somatic and affective symptoms can contribute to depression. PATIENTS AND METHODS: We investigated the prevalence of somatic and affective depressive symptoms with the Beck Depression Inventory (BDI) in 213 hospitalized cancer patients prior to the start of chemotherapy. RESULTS: Seventeen of 213 patients (8%) were screened positive for major depression; 40 (19%) had mild to moderate depressive symptoms. The corresponding figures for somatic and affective symptoms were 33.3% and 2.8% in the patients with major depression and 23.0% and 8.0% in those with mild to moderate depressive symptoms. Female patients, patients with solid tumour and those with functional limitations had significantly higher mean scores. All differences were related to higher scores in somatic and not in affective items. CONCLUSIONS: Most alterations in the BDI in cancer patients are related to somatic and not to affective symptoms and may be attributed not to depression but to severity of the underlying disease.

Reboxetine and cytochrome P450--comparison with paroxetine treatment in humans.

OBJECTIVES: The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects. METHODS: Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel. RESULTS AND CONCLUSION: Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.

Función espermática post-hipoxia simulada en ratón / Simulated post-hypoxia spermatic fuction in mice

Se propone evaluar los cambios reproductivos en ratones sometidos a hipoxia-normoxia simulando condiciones laborales de la faena minera en el norte de Chile. Se estudió hipoxia hipobárica en cámara hipobárica, simulando 4.100 msnm, en tres grupos experimentales y un grupo control (500 msnm, altura promedio de Santiago), estando cada grupo integrado por seis animales. Ratones (Mus musculus) machos adultos fueron sometidos a regímenes de hipoxia (H)-normoxia (N) los siguientes días: 4H; 8H y 4H-4N-4H (4x4x4) y el grupo control en normoxia continua. Se evaluaron: hematocrito, peso testicular y epididimario, y recuento espermático total en testículo y cauda epididimaria. El peso testicular disminuye a los ocho días de exposición hipóxica hipobárica y se recupera con intervalos de cuatro días de normoxia, al igual que el recuento de espermatozoides en cauda; sin embargo, este valor permanece bajo ocho días post-hipoxia. La producción espermática permanece baja en todos los grupos experimentales. Dado que la alternancia 4x4x4 días se utiliza como régimen habitual de trabajo en las faenas mineras chilenas, es imprescindible estudiar los efectos de la altura sobre la fertilidad humana en estas condiciones.

Cell-mediated side effects of psychopharmacological treatment.

Both antidepressants and neuroleptics are widely used in psychopharmacological treatment. In view of the often equal efficacy of substances belonging to the same class of drugs, potential side effects have become the most important criteria for the selection of a specific drug. The therapeutic effect of antidepressants is mediated by their inhibition of the reuptake of the neurotransmitters noradrenaline and of serotonin. Significant adverse effects may occur through the interaction of the antidepressants with other receptors believed not to be related to the therapeutic action, most importantly the muscarinic acetylcholine receptor (M), the histamine-1 (H1) receptor and the alpha-1 (alpha 1) adrenergic receptor. In contrast to the classical tricyclic antidepressants, the newly available selective serotonin reuptake inhibitors neither block the M1-, H1- nor the alpha 1 receptors. Although the rate of side effects is considerably lower compared to tricyclic antidepressants, adverse effects may, however, occur through the stimulation of different serotonin receptor subtypes (5-HT2A, 5-HT2B, and 5-HT3), leading to anxiety, sleep disturbances and nausea. Neuroleptics are often administered for years or even decades in the treatment of schizophrenia or schizoaffective disorder. The main adverse effects are extrapyramidal symptoms, including parkinsonism, akathisia, dystonic reactions, and tardive dyskinesias. With the introduction of the atypical neuroleptics (e.g. clozapine, risperidone, olanzapine) it became apparent that the antipsychotic effect and the extrapyramidal unwanted effect are not always and inextricably linked. The evidence for the hypotheses of the pathogenetic mechanisms leading to extrapyramidal side effects is reviewed. Both the dopamine receptor hypersensitivity hypothesis and the hypothesis of mitochondrial respiratory chain inhibition are as yet based on indirect evidence. However, if, as suggested by the analyses of mitochondrial energy metabolism, the antipsychotic effect and the adverse effects are unrelated properties of neuroleptics, new principles should be applied in the development of novel neuroleptics. Neuroleptics might then be developed that are effectively antipsychotic but are less likely to produce limiting extrapyramidal side effects.

Evidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia.

In-vivo imaging studies and post-mortem studies have demonstrated an impairment of energy metabolism in brains of patients with schizophrenia. Decreased oxidative metabolism has been consistently documented in the frontal lobes. However, the biochemical basis of these changes is unclear. The changes could be caused by reduced requirement of the cells for metabolic energy or an abnormality in energy generation. Neurons generate energy through the respiratory chain in the mitochondria. The respiratory chain consists of five enzyme complexes (I-V). The purpose of the present study was to assess mitochondrial function and test the hypothesis of an underlying oxidative phosphorylation defect in schizophrenia. We analysed spectrophotometrically post-mortem brain specimens of frontal cortex, temporal cortex, basal ganglia, and cerebellum of 12 patients who met the DSM-IV criteria for schizophrenia and of 13 healthy controls for the specific activities of respiratory chain enzymes in the mitochondria. The major finding was that the activity of complex IV was significantly reduced in the frontal cortex (40.9+/-6.7 vs. 87.3+/-12, P=0.003) and in the temporal cortex (39.5+/-6.8 vs. 78+/-10.8, P=0.006) of schizophrenics. In addition, the activity of complexes I+III was significantly reduced in the temporal cortex (2.2+/-0.6 vs. 4.4+/-0.5, P=0.01) and basal ganglia (1.6+/-0.5 vs. 3.4+/-0.3, P=0.015) in schizophrenia. All other enzyme activities showed no differences to healthy controls. The results confirm a defect of oxidative phosphorylation in brains from patients with schizophrenia, which may contribute to impaired energy generation.

A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients.

To assess mitochondrial function and test the hypothesis of an underlying oxidative phosphorylation defect in Alzheimer disease (AD), we evaluated the activities of mitochondrial respiratory chain enzyme complexes I+III, complexes II+III, complex IV (cytochrome c oxidase, COX), succinate dehydrogenase, and citrate synthase in the frontal cortex, temporal cortex, hippocampus, and cerebellum of 23 AD patients and 13 normal human brains. The major finding was a significant decrease in COX activity in AD temporal cortex and hippocampus, both whether activities were expressed per noncollagen protein content (49 +/-4.6 versus 78+/-10.8 nmol/min/mg NCP, P = 0.006; 23+/-1.9 versus 48.6+/-8.1 nmol/min/mg NCP, p = 0.003) or corrected for citrate synthase activity (1.6+/-0.2 versus 3+/-0.4, P = 0.001; 0.76+/-0.1 versus 1.76+/-0.26, P = 0.0009). There were no significant differences in the activities of complexes I+III, II+III, and of succinate dehydrogenase in any of the brain regions examined. Our results suggest a specific defect of COX in the AD brain versus the normal human brain, which may contribute to impaired energy generation. Biochemically, the defect is confined to selected brain regions, suggesting anatomic specificity.

Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a (31)P chemical shift spectroscopic-imaging study.

BACKGROUND: (31)Phosphorous magnetic resonance spectroscopy has been widely used to evaluate schizophrenic patients in comparison to control subjects, because it allows the investigation of both phospholipid and energy metabolism in vivo; however, the results achieved so far are inconsistent. Chemical shift imaging (CSI) has the advantage that instead of only one or a few preselected voxels the tissue of a whole brain slice can be examined. The aim of the present investigation was to determine whether the results of previous studies of our group, showing that phosphodiesters (PDE) are decreased in the frontal lobe of schizophrenic patients as compared to control subjects, might be confirmed in an independent unmedicated patient sample using the CSI technique. METHODS: A carefully selected new cohort including 11 neuroleptic-free schizophrenic patients and 11 age- and gender-matched healthy control subjects was recruited. CSI was applied and an innovative analysis method for CSI data based on a general linear model was used. RESULTS: PDE, phosphocreatine, and adenosine triphosphate (ATP) were found to be significantly decreased in the frontal lobe of patients with schizophrenia. CONCLUSIONS: Because PDE was decreased in schizophrenic patients, the membrane phospholipid hypothesis of schizophrenia could not be corroborated. Further results indicate decreased ATP production in the frontal lobe of patients with schizophrenia.

Gabapentin leads to remission of somatoform pain disorder with major depression.

Gabapentin, a novel antiepileptic drug, is effective in the treatment of partial seizures with and without secondary generalization. Evidence suggests that it may have mood-stabilizing and possibly antidepressant properties in bipolar depression. We report on a 48-year-old woman who had recurrent major depressive disorder. Following inguinal herniorrhaphy, she developed severe stabbing pain in the lower abdomen and inguinal area that progressed to constant pain in her whole body. She was depressive, hopeless, and had given up her social activities. A diagnosis of major depressive disorder and somatoform pain disorder was made. Antidepressants and carbamazepine were ineffective, and she had attempted suicide. Gabapentin resulted in remission of both the pain and the depressive mood at a dose of 1.800 mg/day.

Recurrent orbital myositis: report of a familial incidence.

BACKGROUND: In orbital myositis, painful diplopia develops owing to an enlargement of the extraocular muscles. Diagnosis is established based on history, clinical manifestations, and therapeutic response to steroids, with the findings of magnetic resonance imaging providing additional information. OBSERVATION: We observed a family in which 4 members had an ophthalmopathy suggestive of orbital myositis. The affected members are a sibling pair (female and male) and 2 children of the brothers of their father's father. CONCLUSION: The familial incidence suggests a potential genetic predisposition in the development of orbital myositis.

Increase of phosphodiesters during neuroleptic treatment of schizophrenics: a longitudinal 31P-magnetic resonance spectroscopic study.

BACKGROUND: Increased levels of phosphodiesters (PDE%) and reduced relative concentrations of phosphomonoesters (PME%) have been reported in unmedicated schizophrenics, whereas findings in brain of medicated patients were not consistent. METHODS: We determined in vivo the metabolism of phospholipids and high-energy phosphates in the left and right frontal lobes of 8 patients with schizophrenia using 31P-magnetic resonance spectroscopy (31P-MRS). Serial investigations were performed first after a neuroleptic-free period (mean 7.5 +/- 1.9 days) and second, after neuroleptic treatment (mean 20.6 +/- 11.1 days). RESULTS: PDE% increased significantly in the left frontal lobe (32.0 +/- 5.9% versus 36.9 +/- 5.6%, p = .009) after medication. All other parameters showed no significant differences. CONCLUSIONS: Our study suggests that neuroleptics do not decrease phospholipase A2 activity in schizophrenia. Individual neuroleptics may have different effects on phospholipase A2 activity as indicated by animal studies. An influence of neuroleptics on high-energy phosphates cannot be confirmed by our data.

Carnitine acyltransferases are not changed in Alzheimer disease.

We evaluated the activities of carnitine palmitoyltransferase (CPT), carnitine octanoyltransferase (COT), and carnitine acetyltransferase (CAT) in the frontal cortex, temporal cortex, parietal cortex, hippocampus, and cerebellum of Alzheimer disease (AD) patients and normal human brains. There were no significant differences in total CPT activity, its inhibition by malonyl-CoA, the effect of the detergent Triton X-100 on CPT activity, COT activity, and CAT activity in any of the brain regions examined whether activities were expressed as grams of wet weight or corrected for noncollagen protein content. The addition of Triton X-100 increased CAT activity by 50%. Our results suggest that there is no defect of fatty acid transport within the AD brain cell. Total CPT activity, COT activity, and CAT activity are not affected in AD nor is the ratio of CPT I to CPT II altered in the AD versus the normal human brain.

Inhibition of complex I by neuroleptics in normal human brain cortex parallels the extrapyramidal toxicity of neuroleptics.

There is increasing evidence that a defect of the mitochondrial respiratory chain is implicated in the development of Parkinson disease. Decreased complex I activity of the mitochondrial respiratory chain has been reported in platelets, muscle, and brain of patients with Parkinson disease. Extrapyramidal symptoms (e.g. parkinsonism and dystonic reactions) are major limiting side effects of neuroleptics. Experimental evidence suggests that neuroleptics inhibit complex I in rat brain. There has not been a study of the effects of neuroleptics in human tissue, however. We therefore analyzed the activities of complexes I + III, complexes II + III, succinate dehydrogenase, complex IV (cytochrome c oxidase), and of citrate synthase in normal human brain cortex after the addition of haloperidol and chlorpromazine and the atypical neuroleptics risperidone, zotepine, and clozapine. Activity of complex I was progressively inhibited by all neuroleptics. Half-maximal inhibition (IC50) was 0.1 mM for haloperidol, 0.4 mM for chlorpromazine, and 0.5 mM for risperidone and zotepine. Clozapine had no effect on enzyme activity at concentrations up to 0.5 mM, followed by a slow decline with a maximum inhibition of 70% at 10 mM. IC50 was at about 2.5 mM. Thus, the concentration of clozapine needed to cause 50% inhibition of the activity of complexes I and III was about 5 times that of zotepine and risperidone, about 6 times that of chlorpromazine, and 25 times that of haloperidol. The inhibition thus paralleled the incidence of extrapyramidal effects caused by the different neuroleptics as they are known from numerous clinical studies. Our data support the hypothesis that neuroleptic-induced extrapyramidal side effects may be due to inhibition of the mitochondrial respiratory chain.

Carnitine palmitoyltransferase in patients with cardiac ischemia due to atherosclerotic coronary artery disease and in patients with idiopathic dilated cardiomyopathy.

Cardiac ischemia is associated with an impairment in long-chain fatty acid metabolism. We studied carnitine palmitoyltransferase (CPT) in left ventricular biopsies of 6 transplant recipients with ischemia due to atherosclerosis, 4 patients with dilated cardiomyopathy, and 5 donor hearts. Total CPT activity was not significantly different between the three groups (7.9 +/- 3; 6.7 +/- 2, and 8 +/- 3 nmol/min/mg noncollagenous protein). Residual CPT activity after inhibition by malonyl-CoA (0.4 mM) was 38 +/- 11, 36 +/- 5 and 38 +/- 7%. There were no difference in IC50 values. Residual CPT activity after the addition of the detergent Triton X-100 (0.5%) was 58 +/- 17, 54 +/- 2 and 50 +/- 8% (nonsignificant). Our results suggest that (i) total CPT activity and (ii) the sensitivity of the interaction of CPT I with its regulator malonyl-CoA are not affected by cardiac ischemia, and (iii) the ratio of CPT I to CPT II is not altered in cardiac ischemia.