Inhibitors of the mammalian target of rapamycin (mTOR) have been shown to protect against neuronal injury, but the mechanisms underlying this effect are not fully understood. The present study aimed to examine the effects of rapamycin, an inhibitor of the mTOR pathway, on inflammation and capillary degeneration in a rat model of N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity. Inflammation and capillary degeneration were evaluated by counting the numbers of CD45-positive leukocytes and Iba1-positive microglia, and by measuring the length of empty basement membrane sleeves, respectively. Marked increases in the numbers of leukocytes and microglia were observed 1 d after intravitreal injection of NMDA (200 nmol), and significant capillary degeneration was observed after 7 d. These NMDA-induced changes were significantly reduced by the simultaneous injection of rapamycin (20 nmol) with NMDA. These results suggest that rapamycin has preventive effects on inflammation and capillary degeneration during retinal injury.Key words endothelial cell; excitotoxicity; leukocyte; mammalian target of rapamycin; microglia Glutamate is a major excitatory neurotransmitter, and excessive extracellular levels of glutamate cause neuronal cell death. The neurotoxicity induced by elevated glutamate levels is implicated in some ocular diseases, including diabetic retinopathy and glaucoma. 1,2) In many cases, glutamate-induced neurotoxicity has been predominantly attributed to overstimulation of N-methyl-D-aspartate (NMDA) receptors. 3,4) In addition to direct effects on neurons, indirect effects, such as upregulation of pro-inflammatory cytokines and recruitment of leukocytes into the retina, are involved in NMDA-induced retinal neuronal damage. 5,6) Recent studies have shown that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), exerts neuroprotective and axon growth-promoting effects during neuronal injury. 7,8) The mTOR is a serine/threonine kinase that regulates a wide array of cellular functions, including cell proliferation and cell-cycle control. 9) There are two distinct functional mTOR complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin inhibits mTORC1, which prevents phosphorylation of at least 2 well-characterized effectors: the p70S6 kinases (S6K1 and S6K2) and eIF4E-binding proteins (4E-BP1). 10) Inactivation of mTORC1 can cause autophagy, which has an important role in cellular homeostasis. 11) A role for autophagy has been suggested as a neuroprotective mechanism, whereby it enhances the clearance of harmful protein aggregates. 12,13) In addition, rapamycin could prevent inflammatory responses during brain injury, including activation of microglia. 14) Thus, multiple mechanisms might be involved in the neuroprotective effects of rapamycin.In the present study, we examined the effects of rapamycin on inflammation and capillary degeneration in a rat model of retinal neurotoxicity induced by overstimulation of NMDA receptors. MATERIALS AND METHODSAnimals Male Sprague-Dawley rats weighi...

We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-D-aspartic acid (NMDA)-induced retinal neurotoxicity, but the mechanism underlying this protection is not fully understood. The present study aimed to examine the effects of everolimus, another inhibitor of mTOR, on neuronal cell loss and inflammation in a rat model of NMDAinduced retinal neurotoxicity, and to determine whether the extracellular signal-regulated kinase (ERK) pathway contributes to the protective effect of everolimus. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer, (2) increase in the numbers of CD45-positive leukocytes and Iba1-positive microglia, and (3) phosphorylation of ribosomal protein S6 (pS6), a downstream indicator of mTOR activity. Simultaneous injection of everolimus with NMDA significantly attenuated these NMDA-induced responses. The neuroprotective effect of everolimus was almost completely prevented by the mitogen-activated protein kinase/ERK kinase inhibitor U0126 (1 nmol). NMDA increased the level of phosphorylated ERK (pERK) in Müller cells, and increase in pERK levels was also observed after co-injection of NMDA and everolimus. These results suggest that everolimus has a neuroprotective effect against NMDA-induced retinal neurotoxicity, an effect that seems to be mediated partly by activation of the ERK pathway in Müller cells.

No abstract

No abstract

Simple hepatic cysts are typically saccular, thin-walled masses with fluid-filled epithelial lined cavities that arise from aberrant bile duct cells during embryonic development. With the development of diagnostic modalities such as ultrasonography, computed tomography and magnetic resonance imaging, simple hepatic cysts are seen with relative frequency in daily clinical examination. US is the most useful and noninvasive tool for the diagnosis of simple hepatic cysts, and can generally differentiate simple hepatic cysts from abscesses, hemangiomas and malignancies. Cysts with irregular walls, septations, calcifications or daughter cysts on US should be evaluated with enhanced CT or MRI to differentiate simple hepatic cysts from cystic neoplasms or hydatid cysts.Growth and compression of hepatic cysts cause abdominal discomfort, pain, distension and dietary symptoms such as nausea, vomiting, a feeling of fullness and early satiety. Complications of simple hepatic cysts include infection, spontaneous hemorrhage, rupture, and external compression of biliary tree or major vessels.Asymptomatic simple hepatic cysts should be observed. Treatment for symptomatic simple hepatic cysts includes percutaneous aspiration, aspiration followed by sclerotherapy, and surgery. The American College of Gastroenterology clinical guidelines recommend laparoscopic fenestration based on its high success rate and low invasiveness. Percutaneous procedures for treatment of simple hepatic cysts are particularly effective for the immediate palliation of patient symptoms; however, they are not generally recommended because of the high rate of recurrence. Management of simple hepatic cysts requires correct differentiation from neoplasms and infections, and the selection of a reliable treatment.