Cocaine has a short half-life of only about an hour but its effects, predominantly on the central nervous system (CNS), are fairly long-lasting. Of all cells within the CNS, astrocytes may be the first to display cocaine toxicity owing to their relative abundance in the brain. Cocaine entry could trigger several early response changes that adversely affect their survival, and inhibiting these changes could conversely increase their rate of survival. In order to identify these changes and the minimal concentrations of cocaine that can elicit them in vitro, rat C6 astroglia-like cells were treated with cocaine (2–4 mM for 1h) and assayed for alterations in gross cell morphology, cytoplasmic vacuolation, viability, reactive oxygen species (ROS) generation, glutathione (GSH) levels, cell membrane integrity, F-actin cytoskeleton, and histone methylation. We report here that all of the above identified features are significantly altered by cocaine, and may collectively represent the key pathology underlying acute toxicity-mediated death of astroglia-like cells. Pretreatment of the cells with the clinically available antioxidant N-acetyl cysteine (NAC, 5 mM for 30 min) inhibited these changes during subsequent application of cocaine and mitigated cocaine-induced toxicity. Despite repeated cocaine exposure, NAC pretreated cells remained highly viable and post NAC treatment also increased viability of cocaine treated cells to a smaller yet significant level. We show further that this alleviation by NAC is mediated through an increase in GSH levels in the cells. These findings, coupled with the fact that astrocytes maintain neuronal integrity, suggest that compounds which target and mitigate these early toxic changes in astrocytes could have a potentially broad therapeutic role in cocaine-induced CNS damage.

/pdf/n-acetyl-cysteine-mitigates-the-acute-effects-of-cocaine-1mb93zcj7e.pdf

N-Acetyl Cysteine Mitigates the Acute Effects of Cocaine-Induced Toxicity in Astroglia-Like Cells

Cocaine is one of the powerful addictive drugs, widely abused in most Western countries. Because of high lipophilic nature, cocaine easily reaches various domains of the central nervous system (CNS) and triggers different levels of cellular toxicity. The aim of this investigation was to reproduce cocaine toxicity in differentiated PC12 cells through quantitative knowledge on biochemical and cytotoxicity markers. We differentiated the cells with 0.1 μg/ml nerve growth factor (NGF) for 5 days, followed by treatment with cocaine for 48 h at in vivo and in vitro concentrations. Results indicated that cocaine at in vivo concentrations neither killed the cells nor altered the morphology, but decreased the mitochondrial membrane potential that paralleled with increased lactate and glutathione (GSH) levels. On the other hand, cocaine at in vitro concentrations damaged the neurites and caused cell death, which corresponded with increased reactive oxygen species (ROS) generation, plasma membrane damage, and GSH depletion with no detectable nitric oxide (NO) level. While direct understanding of cocaine and cell interaction under in vivo animal models is impeded due to high complexity, our present in vitro results assisted in understanding the onset of some key events of neurodegenerative diseases in cocaine treated neuronal cells.

/pdf/identification-of-biochemical-and-cytotoxic-markers-in-3il3w71a6k.pdf

Identification of biochemical and cytotoxic markers in cocaine treated PC12 cells.

The use of antiretroviral (ARV) medications has been linked to the emergence of severe adverse effects including mitochondrial toxicity. The liver also appears to be among the affected organs. Nevertheless different studies suggest that these patients mitochondrial alterations could be associated to other etiological factors. The goal of this study was to analyze hepatic mitochondria ultrastructural changes in HIV-infected patients under investigation for hepatopathy. Semiquantitative analysis of mitochondria was performed in liver biopsies from 10 patients divided into 2 groups: Group 1 consisted of 5 patients who had never used ARV medications; group 2 consisted of 5 patients who reported previous use of either zidovudine or didanosine. Significant mitochondrial alterations were found in both groups. The summation of the mitochondrial alterations was higher in group 1 (P < .05) when compared with those who had previously used ARV medications. Therefore the authors conclude that severe mitochondrial alterations occur in HIV-infected patients who have never been submitted to antiretroviral therapy.

Hepatic ultrastructural mitochondrial changes prior to antiretroviral therapy in HIV-infected patients in Brazil.

Se analizo la ultraestructura de embriones bovinos producidos in vitro durante su desarrollo temprano y tardio, mediante la tecnica de microscopia electronica de transmision (MET). Los complejos cumulus-ovocitos fueron aspirados de vacas sacrificadas en mataderos comerciales del estado Zulia y madurados, fecundados y cultivados in vitro. Luego de 24 horas (periodo temprano) y 48 horas (periodo tardio) de post inseminacion, los embriones resultantes se fijaron en glutaraldehido y se procesaron para MET. Se observo la presencia de estructuras celulares como el aparato de Golgi, el nucleo, microvellosidades, la zona pelucida y vacuolas citoplasmaticas de apariencia normal. Sin embargo, a nivel de las mitocondrias se encontro aumento en el porcentaje de mitocondrias vacuoladas y de mitocondrias edematizadas. Estas alteraciones mitocondriales se observaron mayormente en los embriones durante el periodo tardio. Estos hallazgos pudiesen tener relevancia en el retraso del desarrollo de los embriones obtenidos por el metodo in vitro durante el periodo tardio.

Estudio ultraestructural de embriones bovinos producidos in vitro durante las etapas del desarrollo temprano y tardío

This research studied the ultrastructure of in vitro produced bovine embryos at early and late development stages, using the transmission electron microscopy (TEM). Cumulus oocyte complexes were obtained by aspiration from cows sacrificed in local slaughterhouses and matured, fertilized and cultured in vitro. After 48 hours post insemination, resulting embryos were fixed in glutaraldehide and processed for TEM. Samples were analyzed and evaluated in order to determine the presence of ultrastructural alterations. Celullar estructures, such as Golgi apparatus, nucleus, micovilli, zona pellucida and citoplasmic vacuolae had a normal appearence. Nonetheless, at the mitochondrial level, an increase in the percentage of vacuolated and edematousos mitochondria in early and late developed embryos was observed. In vitro produced bovine embryos of late development had greater degrees of mitochondrial alterations than those of early development, which could indicate that mitochondrial alterations play a primordial deleterious role in the delayed development, normally observed in in vitro produced embryos. It is concluded that ultrastructural mitochondrial alterations are mostly found in in vitro produced bovine embryos with increased expression in embryos during late development.

Estudio ultraestructural de embriones bovinos producidos in vitro durante las etapas del desarrollo

The ultrastructural examination of liver biopsies from five male cocaine users showed hepatocytes presenting diverse alterations in rough and smooth endoplasmic reticulum, mitochondria, nuclei and microvilli Lipid deposition and an increase of autophagic vacuoles were also observed This study demonstrates that the hepatocyte is an important target cell for cocaine toxic effects in some patients

Hepatocyte ultrastructural alterations in cocaine users.

Liver Ultrastructural Pathology in Cocaine Users

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Hepatocyte ultrastructural alterations in cocaine users.

Liver Ultrastructural Pathology in Cocaine Users