SWAT ungauged: Water quality modeling in the Upper Mississippi River Basin.

Improving model performance in ungauged basins has been a chronic challenge in watershed model application to understand and assess water quality impacts of agricultural conservation practices, land use change, and climate adaptation measures in large river basins. Here, we evaluate a modified version of SWAT2012 (referred to as SWAT-EC hereafter), which integrates an energy balanced soil temperature module (STM) and the CENTRUY-based soil organic matter algorithm, for simulating water quality parameters in the Upper Mississippi River Basin (UMRB), and compare it against the original SWAT2012. Model evaluation was performed for simulating streamflow, sediment, and nitrate-N (NO3-N) and total nitrogen (TN) loadings at three stations near the outlets of UMRB. The model comparison was conducted without parameter calibration in order to assess their performance under ungauged conditions. The results indicate that SWAT-EC outperformed SWAT2012 for stream flow and NO3-N and TN loading simulation on both monthly and annual scales. For sediment, SWAT-EC performed better than SWAT2012 on a monthly time step basis, but no noticeable improvement was found at the annual scale. In addition, the performance of the uncalibrated SWAT-EC was comparable to other calibrated SWAT models reported in previous publications with respect to sediment and NO3-N loadings. These findings highlight the importance of advancing process representation in physically-based models to improve model credibility, particularly in ungauged basins.

Platelet activating factor induces transient blood-brain barrier opening to facilitate edaravone penetration into the brain.

The blood-brain barrier (BBB) greatly limits the efficacy of many neuroprotective drugs' delivery to the brain, so improving drug penetration through the BBB has been an important focus of research. Here we report that platelet activating factor (PAF) transiently opened BBB and facilitated neuroprotectant edaravone penetration into the brain. Intravenous infusion with PAF induced a transient BBB opening in rats, reflected by increased Evans blue leakage and mild edema formation, which ceased within 6 h. Furthermore, rat regional cerebral blood flow (rCBF) declined acutely during PAF infusion, but recovered slowly. More importantly, this transient BBB opening significantly increased the penetration of edaravone into the brain, evidenced by increased edaravone concentrations in tissue interstitial fluid collected by microdialysis and analyzed by Ultra-performance liquid chromatograph combined with a hybrid quadrupole time-of-flight mass spectrometer (UPLC-MS/MS). Similarly, incubation of rat brain microvessel endothelial cells monolayer with 1 µM PAF for 1 h significantly increased monolayer permeability to (125)I-albumin, which recovered 1 h after PAF elimination. However, PAF incubation with rat brain microvessel endothelial cells for 1 h did not cause detectable cytotoxicity, and did not regulate intercellular adhesion molecule-1, matrix-metalloproteinase-9 and P-glycoprotein expression. In conclusion, PAF could induce transient and reversible BBB opening through abrupt rCBF decline, which significantly improved edaravone penetration into the brain. Platelet activating factor (PAF) transiently induces BBB dysfunction and increases BBB permeability, which may be due to vessel contraction and a temporary decline of regional cerebral blood flow (rCBF) triggered by PAF. More importantly, the PAF induced transient BBB opening facilitates neuroprotectant edaravone penetration into brain. The results of this study may provide a new approach to improve drug delivery into the brain.

Therapeutic neuroprotective effects of XQ-1H in a rat model of permanent focal cerebral ischemia.

Cerebral ischemia is one of the leading causes for death and severe disabilities in the world. XQ-1H exerts neuroprotective effects under various neurotoxic conditions in vitro. In vivo, it reduces brain damage after transient focal cerebral ischemia. The present study evaluated the dose effectiveness and therapeutic time window of neuroprotection of XQ-1H by behavioral and histological measures in rats subjected to permanent middle cerebral artery occlusion (pMCAO). Neurological deficits, TTC stain, brain water content, necrosis neuron counts, and Evans-Blue extravasation were used to quantify brain damage and blood-brain barrier dysfunction. Our results demonstrated that postischemic treatment with XQ-1H at a dose of 31.2 mg/kg produced a significant reduction in neurological scores when treatment was initiated within 2 h of pMCAO. A similar improvement was also observed in infarct volume, brain water content, Evans-Blue extravasation, and neuronal necrosis when treatment was initiated within 1 h of pMCAO. Treatment with XQ-1H at the dose of 15.6 mg/kg within 1 h also produced significant improvement in ischemia deficit. In conclusion, the therapeutic time window of XQ-1H extends for up to 1 h after pMCAO, and treatment with XQ-1H exhibits potent neuroprotection that may be of value for the design of stroke therapies.

Penetration of verapamil across blood brain barrier following cerebral ischemia depending on both paracellular pathway and P-glycoprotein transportation.

BACKGROUND: Blood brain barrier (BBB) dysfunction is a common facet of cerebral ischemia, and the alteration of drug transporter, P-glycoprotein (P-gp), has been documented. AIMS: This study explores influence of damaged BBB and elevated P-gp on cerebral verapamil penetration after ischemia both in vivo and in vitro. METHODS: Middle cerebral artery occlusion (MCAO) induced ischemia/reperfusion (I/R) of rats, and Na(2)S(2)O(4) induced hypoxia/reoxygenation (H/R) damage of rat brain mirovessel endothelial cells (RBMECs) respectively, served as BBB breakdown model in vivo and in vitro. Evans-Blue (EB) extravagation and (125)I-albumin were used to quantify BBB dysfunction; UPLC-MS/MS analytical method was performed to determine accurately the concentration of verapamil in brain tissue and cell. Flow cytometry, immunohistochemistry and western blotting were applied to evaluate transport function and protein expression of P-gp. RESULTS: Overexpressed ICAM-1 and MMP-9 mediated BBB dysfunction after ischemia, which induced EB leakage and (125)I-albumin uptake increase. Enhanced accumulation of verapamil in brain tissue, but intracellular concentration reduced evidently after H/R injury. Transcellular transportation of verapamil elevated when P-gp function or expression was inhibited after H/R injury. CONCLUSION: These data indicated that BBB penetration of verapamil under ischemia condition was not only depending on BBB breakdown, but also regulated by P-gp.

Therapeutic neuroprotective effects of ginkgolide B on cortex and basal ganglia in a rat model of transient focal ischemia.

Cerebral ischemia and reperfusion is one of the leading causes for death and severe disabilities in the world and often lead to irreversible brain damage over later lifespan. The aim of this study was to investigate the evolution of pathological damage in cerebral cortex and basal ganglia following ischemia and to evaluate the therapeutic neuroprotective effect of ginkgolide B in a rat model of stroke induced by middle cerebral artery occlusion (MCAO). TTC stain, brain water content and Evans-Blue extravasation were used to quantify brain damage. Our results demonstrated that basal ganglia undergo progressive pathological damage earlier following MCAO, and injury was stable and irreversible after 5 h following ischemia. However, onset of ischemia injury in cerebral cortex appeared later than basal ganglia and became evident about 3 h following MCAO, and injury was stable and irreversible after 6 h following ischemia. Blood brain barrier opened progressively, and it seemed to be significantly destroyed after 4 h following MCAO comparing with 0 h. Post-ischemic treatment with ginkgolide B improved neurological function and reduced infarct size in basal ganglia within 3 h and cerebral cortex within 5 h following MCAO. The therapeutic effect of ginkgolide B on extenuate brain edema and decrease blood brain barrier permeability were extended for 5h after ischemia, and more evident reversal effect were observed when administrated at earlier time.