Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Neurônios/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologiaRESUMO
Lanthionine ketimine ethyl ester (LKE) is a synthetic derivative of the naturally occurring amino acid lanthionine ketimine. We previously showed that LKE reduced clinical signs in a mouse model of multiple sclerosis (MS) associated with reductions in axonal damage; however, whether LKE has direct beneficial actions on mammalian neuronal cells was not examined. In the current study, we tested the effects of LKE in SH-SY5Y human neuronal cells and in primary mouse cerebellar granule neurons. In both cell types, LKE dose-dependently reduced the cell death that occurred spontaneously followed a change in media. LKE also reduced cell death due to glutamate excitoxicity, accompanied by a reduction in production of reactive oxygen species. LKE induced neuritogenesis in both undifferentiated SH-SY5Y cells and in primary neuron, increasing process numbers and lengths. These results demonstrate that direct neuroprotective and neurotrophic effects of LKE likely contribute to its beneficial actions in vivo.
Assuntos
Aminoácidos Sulfúricos/farmacologia , Fatores de Crescimento Neural/farmacologia , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Linhagem Celular Tumoral , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Camundongos , Neurônios/fisiologia , Neuroproteção/fisiologiaRESUMO
Superwarfarins are very long-lasting rodenticides effective in warfarin-resistant rodents at extremely low doses. The consequences of chronic superwarfarin levels in tissues, due to biological half-lives on the order of 20 days, have not been examined. We now characterized the neurological effects of brodifacoum (BDF), one of the most widely used superwarfarins, in adult male Sprague Dawley rats. Dosing curves established the acute oral lethal dose for BDF as 221 ± 14 µg/kg. Measurement of tissue BDF levels showed accumulation throughout the body, including the central nervous system, with levels diminishing over several days. Immunocytochemical staining showed that both astrocyte and microglial activation was increased 4 days after BDF administration, as were levels of carbonylated proteins, and neuronal damage assessed by fluorojade B staining. Direct toxic effects of BDF on neurons and glia were observed using enriched cultures of cerebellar neurons and cortical astrocytes. Proteomic analysis of cerebellar lysates revealed that BDF altered expression of 667 proteins in adult rats. Gene ontology and pathway analysis identified changes in several functional pathways including cell metabolism, mitochondria function, and RNA handling with ribosomal proteins comprising the largest group. In vitro studies using primary astrocytes showed that BDF suppressed de novo protein synthesis. These findings demonstrate that superwarfarin accumulation increases indices of neuroinflammation and neuropathology in adult rodents, suggesting that methods which minimize BDF toxicity may not address delayed neurological sequelae.
Assuntos
4-Hidroxicumarinas/toxicidade , Sistema Nervoso/efeitos dos fármacos , Rodenticidas/toxicidade , 4-Hidroxicumarinas/administração & dosagem , 4-Hidroxicumarinas/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Dose Letal Mediana , Masculino , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Proteômica , Ratos , Ratos Sprague-Dawley , Rodenticidas/administração & dosagem , Rodenticidas/farmacocinética , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
Superwarfarins were developed following the emergence of warfarin resistance in rodents. Compared to warfarin, superwarfarins have much longer half-lives and stronger affinity to vitamin K epoxide reductase and therefore can cause death in warfarin-resistant rodents. By the mid-1970s, the superwarfarins brodifacoum and difenacoum were the most widely used rodenticides throughout the world. Unfortunately, increased use was accompanied by a rise in accidental poisonings, reaching >16,000 per year in the United States. Risk of exposure has become a concern since large quantities, up to hundreds of kilograms of rodent bait, are applied by aerial dispersion over regions with rodent infestations. Reports of intentional use of superwarfarins in civilian and military scenarios raise the specter of larger incidents or mass casualties. Unlike warfarin overdose, for which 1-2 days of treatment with vitamin K is effective, treatment of superwarfarin poisoning with vitamin K is limited by extremely high cost and can require daily treatment for a year or longer. Furthermore, superwarfarins have actions that are independent of their anticoagulant effects, including both vitamin K-dependent and -independent effects, which are not mitigated by vitamin K therapy. In this review, we summarize superwarfarin development, biology and pathophysiology, their threat as weapons, and possible therapeutic approaches.
Assuntos
Varfarina/efeitos adversos , Varfarina/análise , Animais , Anticoagulantes/efeitos adversos , Anticoagulantes/análise , Anticoagulantes/química , Biomarcadores/análise , Exposição Ambiental/análise , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/patologia , Varfarina/química , Varfarina/intoxicaçãoRESUMO
The hallmark microscopic lesion in canine visceral leishmaniosis is the accumulation of lymphocytes and macrophages parasitized by amastigotes of Leishmania in the lymphoid organs. Matrix metalloproteinase (MMP)-2 and MMP-9 are important for leukocyte migration as they degrade the type IV collagen in the basal lamina. Sera from 65 dogs, 53 with serological diagnosis of visceral leishmaniosis and 12 healthy ones, were analysed by gelatin-zymography to detect MMP-2 and MMP-9 activity. The infected dogs presented higher levels of serum mature MMP-9, proMMP-9 and proMMP-2 than control dogs. No mature MMP-2 activity was observed. The levels of mature and proMMP-9 were highly correlated. These findings suggest that the multi-systemic inflammatory lesions observed in visceral leishmaniosis are associated with an increase in serum MMPs, especially MMP-9. In concert with other clinical data, quantification of serum MMP-9 in infected dogs may lead to a better understanding of the pathogenesis of visceral leishmaniosis.