RESUMO
Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naïve animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems.
Assuntos
Dipeptidil Peptidase 4/genética , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Neuralgia/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Linhagem da Célula/genética , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Hiperalgesia/genética , Hiperalgesia/patologia , Inflamação/genética , Inflamação/patologia , Masculino , Neuralgia/genética , Neuralgia/patologia , Neuroglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores Opioides kappa/genética , Receptores Opioides mu , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologiaRESUMO
There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1), and monocarboxylate transporter 8 (MCT8). MRNA levels were studied by in situ hybridization and qPCR as well as protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9 hours after LPS injection, specifically in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48 hours after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24 hours whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation.
Assuntos
Barreira Hematoencefálica/metabolismo , Endotoxemia/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Astrócitos/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Transportadores de Ácidos Monocarboxílicos/genética , Neurônios/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Prosencéfalo/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , SimportadoresRESUMO
Iron is an essential element for all microorganisms. Bacteria and fungi produce versatile siderophores for binding and storing this essential transition metal when its availability is limited in the environment. The aim of the study was to optimize the fermentation medium of Aspergillus fumigatus for siderophore production. Triacetyl-fusarinine C and ferricrocin yields were dependent on glucose and glycine supplementations as well as the initial pH of the culture media. The optimal fermentation medium for triacetylfusarinine C production contained 8% glucose, 0.4% glycine and the initial pH was set to 5.9. Meanwhile, maximal ferricrocin yields were recorded in the presence of 10% glucose, 0.5% glycine and at an initial pH of 7.4. Under optimized fermentation conditions, the yields for triacetylfusarinine C and ferricrocin increased up to 2.9 g/l culture medium and 18.9 mg/g mycelium, respectively.