The N-Methyl-d-Aspartate Receptor Antagonist MK-801 Prevents Thallium-Induced Behavioral and Biochemical Alterations in the Rat Brain.

Thallium (Tl(+)) is a toxic heavy metal capable of increasing oxidative damage and disrupting antioxidant defense systems. Thallium invades the brain cells through potassium channels, increasing neuronal excitability, although until now the possible role of glutamatergic transmission in this event has not been investigated. Here, we explored the possible involvement of a glutamatergic component in the Tl(+)-induced toxicity through the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) in rats. The effects of MK-801 (1 mg/kg, intraperitoneally [ip]) on early (24 hours) motor alterations, lipid peroxidation, reduced glutathione (GSH) levels, and GSH peroxidase activity induced by Tl(+) acetate (32 mg/kg, ip) were evaluated in adult rats. MK-801 attenuated the Tl(+)-induced hyperactivity and lipid peroxidation in the rat striatum, hippocampus and midbrain, and produced mild effects on other end points. Our findings suggest that glutamatergic transmission via NMDA receptors might be involved in the Tl(+)-induced altered regional brain redox activity and motor performance in rats.

Thallium-induced DNA damage, genetic, and epigenetic alterations.

Thallium (Tl) is a toxic heavy metal responsible for noxious effects in living organisms. As a pollutant, Tl can be found in the environment at high concentrations, especially in industrial areas. Systemic toxicity induced by this toxic metal can affect cell metabolism, including redox alterations, mitochondrial dysfunction, and activation of apoptotic signaling pathways. Recent focus on Tl toxicity has been devoted to the characterization of its effects at the nuclear level, with emphasis on DNA, which, in turn, may be responsible for cytogenetic damage, mutations, and epigenetic changes. In this work, we review and discuss past and recent evidence on the toxic effects of Tl at the systemic level and its effects on DNA. We also address Tl's role in cancer and its control.

Human Health Risk Assessment of Arsenic and Other Metals in Herbal Products Containing St. John's Wort in the Metropolitan Area of Mexico City.

Consumption of St. John's wort plant is high worldwide due to its various medicinal properties. However, herbal products containing St. John's wort may be contaminated with toxic metals. This is often related to contamination of both water and the atmosphere, lack of proper cultivation methods, and inadequate plant storage conditions, as well as a lack of stricter sanitary supervision. A safety assessment of copper (Cu), lead (Pb), cadmium (Cd) and arsenic (As) content in 23 products containing St. John's wort (pharmaceutical herbal products, food supplements and traditional herbal remedies) sold in the metropolitan area of Mexico City was conducted. The analysis of metals was determined using a graphite-furnace atomic absorption spectrometer. All herbal products were contaminated with Cu, Pb, Cd and As. The pharmaceutical herbal items showed less contamination by metals. The daily human intake (DHI) values for Pb exceeded the permissible limits in the group of traditional herbal remedies. The DHI calculation for As exceeded the permitted intake values for all items in the group of traditional herbal remedies, five food supplements and one pharmaceutical herbal product. The hazard indicator calculation of the non-carcinogenic cumulative risk values for traditional herbal remedies was greater than 1, suggesting a risk to human health.

Autoradiography reveals selective changes in serotonin binding in neocortex of patients with temporal lobe epilepsy.

The main goal of the present study was to evaluate binding to serotonin in the neocortex surrounding the epileptic focus of patients with mesial temporal lobe epilepsy (MTLE). Binding to 5-HT, 5-HT(1A), 5-HT(4), 5-HT(7) receptors and serotonin transporter (5-HTT) in T1-T2 gyri of 15 patients with MTLE and their correlations with clinical data, neuronal count and volume were determined. Autopsy material acquired from subjects without epilepsy (n=6) was used as control. The neocortex from MTLE patients demonstrated decreased cell count in layers III-IV (21%). No significant changes were detected on the neuronal volume. Autoradiography experiments showed the following results: reduced 5-HT and 5-HT(1A) binding in layers I-II (24% and 92%, respectively); enhanced 5-HT(4) binding in layers V-VI (32%); no significant changes in 5-HT(7) binding; reduced 5-HTT binding in all layers (I-II, 90.3%; III-IV, 90.3%, V-VI, 86.9%). Significant correlations were found between binding to 5-HT(4) and 5-HT(7) receptors and age of seizure onset, duration of epilepsy and duration of antiepileptic treatment. The present results support an impaired serotoninergic transmission in the neocortex surrounding the epileptic focus of patients with MTLE, a situation that could be involved in the initiation and propagation of seizure activity.

Thallium Toxicity: General Issues, Neurological Symptoms, and Neurotoxic Mechanisms.

Thallium (Tl+) is a ubiquitous natural trace metal considered as the most toxic among heavy metals. The ionic ratio of Tl+ is similar to that of potassium (K+), therefore accounting for the replacement of the latter during enzymatic reactions. The principal organelle damaged after Tl+ exposure is mitochondria. Studies on the mechanisms of Tl+ include intrinsic pathways altered and changes in antiapoptotic and proapoptotic proteins, cytochrome c, and caspases. Oxidative damage pathways increase after Tl+ exposure to produce reactive oxygen species (ROS), changes in physical properties of the cell membrane caused by lipid peroxidation, and concomitant activation of antioxidant mechanisms. These processes are likely to account for the neurotoxic effects of the metal. In humans, Tl+ is absorbed through the skin and mucous membranes and then is widely distributed throughout the body to be accumulated in bones, renal medulla, liver, and the Central Nervous System. Given the growing relevance of Tl+ intoxication, in recent years there is a notorious increase in the number of reports attending Tl+ pollution in different countries. In this sense, the neurological symptoms produced by Tl+ and its neurotoxic effects are gaining attention as they represent a serious health problem all over the world. Through this review, we present an update to general information about Tl+ toxicity, making emphasis on some recent data about Tl+ neurotoxicity, as a field requiring attention at the clinical and preclinical levels.

Dapsone improves functional deficit and diminishes brain damage evaluated by 3-Tesla magnetic resonance image after transient cerebral ischemia and reperfusion in rats.

Stroke is a frequent cause of death and the first of disability in the world population. We have shown that dapsone acts as an antioxidant, antiinflammatory and antiapoptotic agent after brain Ischemia reperfusion (I/R) in rats; however, its therapeutic efficacy, measured by imaging has not been characterized. In this context, the aim of this study was to evaluate the neuroprotective effect of dapsone by magnetic resonance imaging (MRI) and to correlate imaging markers with motor function and oxidative stress after transient cerebral ischemia and reperfusion (I/R). We used male rats throughout the experiment. Functional deficit after I/R was assessed by using Longa scale. The area of brain tissue damage was measured by histology. The nuclear factor erythroid 2-related factor 2 (Nrf-2) and the amount of reactive oxygen species (ROS) were measured as biomarkers of oxidative stress. Finally, difussion tensor MRI was employed to measure the fractional anisotropy (FA), as a MRI marker of the pathophysiologic brain status. Results showed a better functional recovery and less damaged tissue in animals treated with dapsone vs control group. The values of FA were higher in animals receiving treatment, indicating a better preservation of brain structure. At early stages of the damage, dapsone was able to reduce both oxidative markers (Nrf-2 and ROS). Our findings provide new evidence for the efficacy of dapsone when administered during the acute phase after I/R and that quantitative sequences of MRI are useful for characterizing its potential therapeutic benefits after stroke.

Cas IIgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms.

In this work, we investigated the effects of Casiopeina II-gly (Cas IIgly)--a new copper compound exhibiting antineoplastic activity--on glioma C6 cells under both in vitro and in vivo conditions, as an approach to identify potential therapeutic agents against malignant glioma. The exposure of C6 cells to Cas IIgly significantly inhibited cell proliferation, increased reactive oxygen species (ROS) formation, and induced apoptosis in a dose-dependent manner. In cultured C6 cells, Cas IIgly caused mitochondrio-nuclear translocation of apoptosis induction factor (AIF) and endonuclease G at all concentrations tested; in contrast, fragmentation of nucleosomal DNA, cytochrome c release, and caspase-3 activation were observed at high concentrations. Administration of N-acetyl-L-cystein, an antioxidant, resulted in significant inhibition of AIF translocation, nucleosomal DNA fragmentation, and caspase-3 activation induced by Cas IIgly. These results suggest that caspase-dependent and caspase-independent pathways both participate in apoptotic events elicited by Cas IIgly. ROS formation induced by Cas IIgly might also be involved in the mitochondrio-nuclear translocation of AIF and apoptosis. In addition, treatment of glioma C6-positive rats with Cas IIgly reduced tumor volume and mitotic and cell proliferation indexes, and increased apoptotic index. Our findings support the use of Cas IIgly for the treatment of malignant gliomas.

Neuroprotective effect of thalidomide on MPTP-induced toxicity.

Thalidomide is a sedative with unique pharmacological properties; studies on epilepsy and brain ischemia have shown intense neuroprotective effects. We analyzed the effect of thalidomide treatment on the neurotoxicity caused by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahidropyridine (MPTP) in mice. Thalidomide was administered at two times; before and after the exposure to MPTP. In both circumstances thalidomide improved the neurotoxicity induced by MPTP as seen by a significant raise of the striatal contents of dopamine and simultaneous decrease of monoamine-oxidase-B (MAO-B). These results indicate that in the experimental model of Parkinson's disease the administration of thalidomide improves the functional damage on the nigrostriatal cell substratum as seen by the production of dopamine. This neuroprotective effect seems to be mediated by inhibition of excitotoxicity. Our results suggest that thalidomide could be investigated as potential adjuvant therapy for Parkinson's disease.

Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition.

Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

Changes in brain serotonin turnover, body and head shakes in kainic acid-treated rats.

Kainic acid induces seizures and neurotoxicity in rats, produces changes in brain serotonin (5-HT), dopamine and noradrenaline metabolites among other changes in neurotransmitters. In this work, we investigated the changes in 5-HT turnover in brain regions from 84 rats intraperitoneally injected with kainic acid and a specific behavioural change, the body and head shakes, exerted by this neurotoxin in the presence of 5-HT receptor antagonists. Kainic acid produced an increase in 5-hydroxyindoleacetic acid levels in frontal cortex (212%; 180%), striatum (177%; 116%), amygdala (202%; 337%) and hippocampus (43%; 70 %) at 2 and 24 hr as compared with controls, respectively. Serotonin turnover was increased in amygdala (157%) and frontal cortex (169%) at 2 hr; whereas 24 hr after kainic acid administration, increases were observed in amygdala (207%), and frontal cortex (178%). Kainic acid also produced an increase in the frequency of head and body shakes when administered alone or together with pargyline, a monoamine oxidase inhibitor; whereas the administration of 5-HT receptor antagonists such as ketanserin and methiothepin, decreased this behaviour 54% and 50% as compared with kainic acid alone, respectively. These results suggest an active participation of 5-HT neurotransmission on the excitotoxic action of kainic acid in the brain.