RESUMEN
Hyperglycemia exacerbates edema formation and worsens neurological outcome in ischemic stroke. Edema formation in the early hours of stroke involves transport of ions and water across an intact blood-brain barrier (BBB), and swelling of astrocytes. We showed previously that high glucose (HG) exposures of 24 hours to 7 days increase abundance and activity of BBB Na+-K+-2Cl- cotransport (NKCC) and Na+/H+ exchange 1 (NHE1). Further, bumetanide and HOE-642 inhibition of these transporters significantly reduces edema and infarct following middle cerebral artery occlusion in hyperglycemic rats, suggesting that NKCC and NHE1 are effective therapeutic targets for reducing edema in hyperglycemic stroke. The mechanisms underlying hyperglycemia effects on BBB NKCC and NHE1 are not known. In the present study we investigated whether serum-glucocorticoid regulated kinase 1 (SGK1) and protein kinase C beta II (PKCßII) are involved in HG effects on BBB NKCC and NHE1. We found transient increases in phosphorylated SGK1 and PKCßII within the first hour of HG exposure, after 5-60 min for SGK1 and 5 min for PKCßII. However, no changes were observed in cerebral microvascular endothelial cell SGK1 or PKCßII abundance or phosphorylation (activity) after 24 or 48 h HG exposures. Further, we found that HG-induced increases in NKCC and NHE1 abundance were abolished by inhibition of SGK1 but not PKCßII, whereas the increases in NKCC and NHE activity were abolished by inhibition of either kinase. Finally, we found evidence that STE20/SPS1-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 (SPAK/OSR1) participate in the HG-induced effects on BBB NKCC.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Glucosa/toxicidad , Proteínas Inmediatas-Precoces/metabolismo , Proteína Quinasa C beta/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Animales , Barrera Hematoencefálica/enzimología , Barrera Hematoencefálica/patología , Bovinos , Células Cultivadas , Células Endoteliales/enzimología , Células Endoteliales/patología , Activación Enzimática , Humanos , Fosforilación , Transducción de Señal , Factores de TiempoRESUMEN
The safety evaluation of oral exposure to substances, such as food ingredients, additives, and their constituents, relies primarily on a careful evaluation and analysis of data from oral toxicity studies. When relevant oral toxicity studies are unavailable or may have significant data gaps that make them inadequate for use in safety evaluations, data from non-oral toxicity studies in animals, such as studies on inhalation, dermal exposure, etc., might be used in support of or in place of oral toxicity studies through route-to-route (R-t-R) extrapolation. R-t-R extrapolation is applied on a case-by-case basis as it requires attention to and comparison of substance-specific toxicokinetic (TK) and toxicodynamic (TD) data for oral and non-oral exposure routes. This article provides a commentary on the utility of R-t-R extrapolation to assess the safety of oral exposure to substances, with an emphasis on the relevance of TK and systemic toxicity data.
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Administración por Inhalación , Seguridad , AnimalesRESUMEN
INTRODUCTION: Cognitive decline is common in patients with type 1 diabetes and has been attributed to the effects of chronic hyperglycemia and severe hypoglycemia. Diabetic ketoacidosis (DKA) has only recently been suspected to be involved in causing cognitive decline. We hypothesized that DKA triggers both acute and chronic neuroinflammation, contributing to brain injury. RESEARCH METHODS AND DESIGN: We measured concentrations of cytokines, chemokines and matrix metalloproteinases (MMP) in serum and brain tissue lysates in juvenile rats during and after DKA (during acute DKA, 24 hours and 7 days after DKA), and compared these to healthy controls and hyperglycemic controls. We also measured cytokine, chemokine and MMP concentrations in serum and brain tissue of adult rats (70 days) that had experienced DKA as juveniles and compared these measurements to those of adult diabetic rats without exposure to DKA. RESULTS: During acute DKA in the juvenile rats, serum concentrations of CCL3, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and MMP-9 were significantly increased. Serum concentrations of IL-2 and IL-17A increased 7 days after DKA recovery. In brain tissue lysates, concentrations of CCL3, CCL5, interferon (IFN)-γ and MMP-9 were significantly elevated during acute DKA. In adult rats that had DKA as juveniles (28 days previously), serum concentrations of IL-1ß and brain concentrations of IL-10 and IL-12p70 were elevated in comparison to diabetic rats without prior DKA. Composite scores for highly correlated cytokines and chemokines (mean z-scores for IL-10, IL-1ß, TNF-α, IL-17A, IFN-γ, CXCL-1 and CCL5) were also significantly elevated in adult rats with prior DKA. CONCLUSIONS: These data confirm that DKA causes acute systemic inflammation and neuroinflammation in a rat model. Importantly, the neuroinflammatory response triggered by DKA is long-lasting, suggesting the possibility that DKA-induced chronic neuroinflammation could contribute to long-term cognitive decline in individuals with diabetes.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética , Hiperglucemia , Animales , Citocinas , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Cetoacidosis Diabética/complicaciones , Humanos , RatasRESUMEN
Development of a femoral artery pseudoaneurysm occurs in 0.6% to 3.2% of interventional procedures. Nonsurgical treatment has consisted of ultrasound scan-directed compression and, more recently, direct thrombin injection into the pseudoaneurysm cavity to achieve thrombosis. Reported complications after thrombin injection are rare. We report two cases of femoral venous compression associated with pseudoaneurysm injection and review the literature. A 76-year-old man and an 86-year-old man both underwent thrombin injection of pseudoaneurysms compressing the ipsilateral common femoral vein. Both patients were diagnosed with deep venous thrombosis and subsequently needed surgical exploration for repair of the pseudoaneurysm and release of the venous compression. At exploration, both were found to have significant inflammation surrounding the femoral vessels, which made vessel exposure challenging. Because of the venous outflow obstruction involved in femoral pseudoaneurysms with secondary venous compression and the surgical difficulty caused by surrounding inflammation, avoidance of thrombin injection in favor of early surgical intervention is suggested.