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2.
Toxicol In Vitro ; 29(7): 1941-51, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26255146

ABSTRACT

Cannabinoid receptor (CBs) agonists affect the growth of tumor cells via activation of deadly cascades. The spectrum of action of these agents and the precise role of the endocannabinoid system (ECS) on oncogenic processes remain elusive. Herein we compared the effects of synthetic (CP 55-940 and WIN 55,212-2) and endogenous (anandamide or AEA) CBs agonists (10-20 µM) on morphological changes, cell viability, and induction of apoptosis in primary astrocytes and in two glioblastoma cell lines (C6 and U373 cells) in order to characterize their possible differential actions on brain tumor cells. None of the CBs agonist tested induced changes in cell viability or morphology in primary astrocytes. In contrast, CP 55-940 significantly decreased cell viability in C6 and U373 cells at 5 days of treatment, whereas AEA and WIN 55,212-2 moderately decreased cell viability in both cell lines. Treatment of U373 and C6 for 3 and 5 days with AEA or WIN 55,212-2 produced discrete morphological changes in cell bodies, whereas the exposure to CP 55-940 induced soma degradation. CP 55-940 also induced apoptosis in both C6 and U373 cell lines. Our results support a more effective action of CP 55-940 to produce cell death of both cell lines through apoptotic mechanisms. Comparative aspects between cannabinoids with different profiles are necessary for the design of potential treatments against glial tumors.


Subject(s)
Cannabinoid Receptor Agonists/pharmacology , Cannabinoids/pharmacology , Animals , Apoptosis/drug effects , Arachidonic Acids/pharmacology , Astrocytes/cytology , Astrocytes/drug effects , Benzoxazines/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cells, Cultured , Cyclohexanols/pharmacology , DNA , Endocannabinoids/pharmacology , Humans , Morpholines/pharmacology , Naphthalenes/pharmacology , Polyunsaturated Alkamides/pharmacology , Rats , Rats, Wistar
3.
Neuroscience ; 285: 97-106, 2015 Jan 29.
Article in English | MEDLINE | ID: mdl-25446347

ABSTRACT

The endocannabinoid system (ECS) is involved in a considerable number of physiological processes in the Central Nervous System. Recently, a modulatory role of cannabinoid receptors (CBr) and CBr agonists on the reduction of the N-methyl-d-aspartate receptor (NMDAr) activation has been demonstrated. Quinolinic acid (QUIN), an endogenous analog of glutamate and excitotoxic metabolite produced in the kynurenine pathway (KP), selectively activates NMDAr and has been shown to participate in different neurodegenerative disorders. Since the early pattern of toxicity exerted by this metabolite is relevant to explain the extent of damage that it can produce in the brain, in this work we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) and other agonists (anandamide or AEA, and CP 55,940 or CP) on early markers of QUIN-induced toxicity in rat striatal cultured cells and rat brain synaptosomes. WIN, AEA and CP exerted protective effects on the QUIN-induced loss of cell viability. WIN also preserved the immunofluorescent signals for neurons and CBr labeling that were decreased by QUIN. The QUIN-induced early mitochondrial dysfunction, lipid peroxidation and reactive oxygen species (ROS) formation were also partially or completely prevented by WIN pretreatment, but not when this CBr agonist was added simultaneously with QUIN to brain synaptosomes. These findings support a neuroprotective and modulatory role of cannabinoids in the early toxic events elicited by agents inducing excitotoxic processes.


Subject(s)
Brain/drug effects , Cannabinoid Receptor Agonists/pharmacology , Excitatory Amino Acid Agents/toxicity , Mitochondria/drug effects , Oxidative Stress/drug effects , Quinolinic Acid/toxicity , Animals , Arachidonic Acids/pharmacology , Benzoxazines/pharmacology , Brain/physiopathology , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Cyclohexanols/pharmacology , Endocannabinoids/pharmacology , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Male , Mitochondria/metabolism , Morpholines/pharmacology , Naphthalenes/pharmacology , Neurons/drug effects , Neurons/physiology , Oxidative Stress/physiology , Polyunsaturated Alkamides/pharmacology , Rats, Wistar , Reactive Oxygen Species/metabolism , Receptors, Cannabinoid/metabolism , Synaptosomes/drug effects , Synaptosomes/physiology
4.
Neuroscience ; 231: 91-101, 2013 Feb 12.
Article in English | MEDLINE | ID: mdl-23201824

ABSTRACT

Quinolinic acid (QA)-induced overactivation of N-methyl-d-aspartate receptors yields excitotoxicity, oxidative stress and mitochondrial dysfunction, which altogether contribute to trigger a wide variety of toxic pathways with biochemical, behavioral and neuropathological alterations similar to those observed in Huntington's disease. Noteworthy, in the brains of these patients, increased expression of heme oxygenase-1 (HO-1) levels can be found. It has been proposed that this enzyme can exert a dual role, as it can be either protective or deleterious to the CNS. While some evidence indicates that its overexpression affords cellular anti-oxidant protection due to decreased concentrations of its pro-oxidative substrate heme group, and increased bilirubin levels, other reports established that high HO-1 expression and activity may result in a pro-oxidizing atmosphere due to a release of Fe(2+). In this work, we examined the temporal evolution of oxidative damage to proteins, HO-1 expression, immunoreactivity, total activity, and cell death after 1, 3, 5 and 7 days of an intrastriatal QA infusion (240 nmol/µl). QA was found to induce cellular degeneration, increasing carbonylated proteins and generating a transitory response in HO-1 mRNA, protein content, and immunoreactivity and activity in nerve cells. In order to study the role of HO-1 in the QA-induced cellular death, the tin protoporphyrin IX (SnPP), a well-known HO inhibitor, was administered to rats (30 µmol/kg, i.p.). The administration of SnPP to animals treated with QA inhibited the HO activation, and exacerbated the striatal cell damage induced by QA. Our findings reveal a potential modulatory role of HO-1 in the toxic paradigm evoked by QA in rats. This evidence provides a valuable tool for further approaches on HO-1 regulation in neurotoxic paradigms.


Subject(s)
Corpus Striatum/metabolism , Heme Oxygenase-1/antagonists & inhibitors , Nerve Degeneration/metabolism , Oxidative Stress/physiology , Up-Regulation/physiology , Animals , Corpus Striatum/drug effects , Corpus Striatum/pathology , Heme Oxygenase-1/metabolism , Male , Metalloporphyrins/pharmacology , Nerve Degeneration/chemically induced , Nerve Degeneration/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Protoporphyrins/pharmacology , Quinolinic Acid , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Up-Regulation/drug effects
5.
Trans R Soc Trop Med Hyg ; 86(2): 170-2, 1992.
Article in English | MEDLINE | ID: mdl-1440779

ABSTRACT

High rates of erythrophagocytosis and collagenolysis in vitro have been regarded as indicative of virulence in vivo of Entamoeba histolytica trophozoites. In the present study, the erythrophagocytic index and the collagenolytic activity of 3 axenic lines of E. histolytica, strain HM1:IMSS, were measured. The 3 lines shared the same pathogenic zymodeme but showed clear-cut differences in the extent of liver damage induced in hamsters. A direct correlation between collagenolysis in vitro and the size of liver abscesses produced by each line of E. histolytica trophozoites was found. In contrast, the line with the highest erythrophagocytic index produced small amoebic abscesses in hamsters, whereas the line with a relatively low erythrophagocytic index produced the largest liver lesions. It is concluded that the extent of collagenolytic activity is a better marker of virulence of E. histolytica cultured under axenic conditions than is erythrophagocytosis.


Subject(s)
Collagen/metabolism , Entamoeba histolytica/pathogenicity , Liver Abscess, Amebic/parasitology , Phagocytosis , Animals , Entamoeba histolytica/metabolism , Erythrocytes , Guinea Pigs , Virulence
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