RESUMEN
In rat cortical astrocytes, we investigated the occurrence of cross-talks between purinoceptor and endothelin (ET) receptor, or glutamate receptor. The treatments of adenosine triphosphate (ATP), ET-1, and glutamate induced the increase of intracellular calcium level in the astrocytes. In repetitive additions of ATP to astrocytes, the second application of ATP exhibited comparable amplitude of calcium response, but the stimulation with ATP completely blocked subsequent ET-1- or glutamate-evoked calcium responses showing complete heterologous desensitization. In contrast, ET-1 and glutamate failed to desensitize the response elicited by ATP. Preincubation with sphingosine, a protein kinase C (PKC) inhibitor, reversed the ATP-induced desensitization of ET-1- and glutamate-evoked calcium responses. Taken together, these results demonstrate the resistance of purinoceptor to homologous desensitization, and unidirectional desensitization between ATP and other receptors such as ET and glutamate receptors, suggesting a dominant role of purinoceptor in modulating calcium signal of astrocytes.
Asunto(s)
Adenosina Trifosfato/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Calcio/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Endotelina-1/farmacología , Ácido Glutámico/farmacología , Animales , Animales Recién Nacidos , Astrocitos/citología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Células Cultivadas , Corteza Cerebral/citología , Interacciones Farmacológicas/fisiología , Líquido Intracelular/efectos de los fármacos , Líquido Intracelular/metabolismo , Ratas , Receptores de Endotelina/efectos de los fármacos , Receptores de Endotelina/metabolismo , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismo , Receptores Purinérgicos/efectos de los fármacos , Receptores Purinérgicos/metabolismo , Factores de TiempoRESUMEN
The lethal toxin of Bacillus anthracis, which is composed of two separate proteinaceous exotoxins, namely protective antigen and lethal factor, is central to the pathogenesis of anthrax. Low levels of this toxin are known to induce release of cytokines such as tumor necrosis factor alpha (TNF-alpha). In the present study we investigated the effect of dehydroepiandrosterone (DHEA), melatonin (MLT), or DHEA + MLT on production of lethal toxin-induced TNF-alpha in mouse peritoneal macrophages. We found that treatment with DHEA significantly inhibited the TNF-alpha production caused by anthrax lethal toxin. Exposure of MLT to anthrax lethal toxin-treated macrophages also decreased the release of TNF-alpha to the extracellular medium as compared to the control. However, combined use of DHEA and MLT also inhibited TNF-alpha release, but not more than single therapies. These results suggest that DHEA and MLT may have a therapeutic role in reducing the increased cytokine production induced by anthrax lethal toxin.