Validating a computational framework for ionic electrodiffusion with cortical spreading depression as a case study

Cortical spreading depression (CSD) is a wave of pronounced depolarization of brain tissue accompanied by substantial shifts in ionic concentrations and cellular swelling. Here, we validate a computational framework for modelling electrical potentials, ionic movement, and cellular swelling in brain tissue during CSD. We consider different model variations representing wild type or knock-out/knock-down mice and systematically compare the numerical results with reports from a selection of experimental studies. We find that the data for several CSD hallmarks obtained computationally, including wave propagation speed, direct current shift duration, peak in extracellular K + concentration as well as a pronounced shrinkage of extracellular space, are well in line with what has previously been observed experimentally. Further, we assess how key model parameters including cellular diffusivity, structural ratios, membrane water and/or K + permeabilities affect the set of CSD characteristics.

Activation of Neutrophil Granulocytes by Platelet-Activating Factor Is Impaired During Experimental Sepsis

Platelet-activating factor (PAF) is an important mediator of the systemic inflammatory response. In the case of sepsis, proper activation and function of neutrophils as the first line of cellular defense are based on a well-balanced physiological response. However, little is known about the role of PAF in cellular changes of neutrophils during sepsis. Therefore, this study investigates the reaction patterns of neutrophils induced by PAF with a focus on membrane potential (MP), intracellular pH, and cellular swelling under physiological and pathophysiological conditions and hypothesizes that the PAF-mediated response of granulocytes is altered during sepsis. The cellular response of granulocytes including MP, intracellular pH, cellular swelling, and other activation markers were analyzed by multiparametric flow cytometry. In addition, the chemotactic activity and the formation of platelet–neutrophil complexes after exposure to PAF were investigated. The changes of the (electro-)physiological response features were translationally verified in a humanex vivowhole blood model of endotoxemia as well as during polymicrobial porcine sepsis. In neutrophils from healthy human donors, PAF elicited a rapid depolarization, an intracellular alkalization, and an increase in cell size in a time- and dose-dependent manner. Mechanistically, the alkalization was dependent on sodium-proton exchanger 1 (NHE1) activity, while the change in cellular shape was sodium flux- but only partially NHE1-dependent. In a pathophysiological altered environment, the PAF-induced response of neutrophils was modulated. Acidifying the extracellular pHin vitroenhanced PAF-mediated depolarization, whereas the increases in cell size and intracellular pH were largely unaffected.Ex vivoexposure of human whole blood to lipopolysaccharide diminished the PAF-induced intracellular alkalization and the change in neutrophil size. During experimental porcine sepsis, depolarization of the MP was significantly impaired. Additionally, there was a trend for increased cellular swelling, whereas intracellular alkalization remained stable. Overall, an impaired (electro-)physiological response of neutrophils to PAF stimulation represents a cellular hallmark of those cells challenged during systemic inflammation. Furthermore, this altered response may be indicative of and causative for the development of neutrophil dysfunction during sepsis.

Effect of the Indomethacin drug on kidney histology in Male Albino Rats.

The kidneys are major organs that clear the drugs. Urine is one of the primary elimination routes for drugs and metabolites to be excreted outside of the body. Most drugs are predominantly excreted via the kidneys as their metabolized products. The histopathological change of kidney in the rats that treated with indomethacin at dose (20mg/kg)show abnormal structure of glomerulus is more damage and bowmanand#39;s space is very swelling ,distortion glomerulus and the compound inside it is shrinkage with presence of inflammation cell and bleeding fibrosis, when compared with control. While the change of kidney in the rats that treated with indomethacin at dose (50mg/kg) Showed abnormal structure of glomerulus is shrinkage with tubular cellular swelling and necrosis and presence of interstitial inflammation and swelling tubular. when used hesperidin show protective effect of antioxidant normal structure of glomerulus and renal tubule also no necrosis or swelling ,the Bowman’s space and capsule is normal.

Bursting at the Seams: Molecular Mechanisms Mediating Astrocyte Swelling

Brain swelling is one of the most robust predictors of outcome following brain injury, including ischemic, traumatic, hemorrhagic, metabolic or other injury. Depending on the specific type of insult, brain swelling can arise from the combined space-occupying effects of extravasated blood, extracellular edema fluid, cellular swelling, vascular engorgement and hydrocephalus. Of these, arguably the least well appreciated is cellular swelling. Here, we explore current knowledge regarding swelling of astrocytes, the most abundant cell type in the brain, and the one most likely to contribute to pathological brain swelling. We review the major molecular mechanisms identified to date that contribute to or mitigate astrocyte swelling via ion transport, and we touch upon the implications of astrocyte swelling in health and disease.

Control of Spreading Depression with Electrical Fields

Spreading depression or depolarization is a large-scale pathological brain phenomenon related to migraine, stroke, hemorrhage and traumatic brain injury. Once initiated, spreading depression propagates across gray matter extruding potassium and other active molecules, collapsing the resting membrane electro-chemical gradient of cells leading to spike inactivation and cellular swelling, and propagates independently of synaptic transmission. We demonstrate the modulation, suppression and prevention of spreading depression utilizing applied transcortical DC electric fields in brain slices, measured with intrinsic optical imaging and potassium dye epifluorescence. We experimentally observe a surface-positive electric field induced forcing of spreading depression propagation to locations in cortex deeper than the unmodulated propagation path, whereby further propagation is confined and arrested even after field termination. The opposite surface-negative electric field polarity produces an increase in propagation velocity and a confinement of the wave to more superficial layers of cortex than the unmodulated propagation path. These field polarities are of opposite sign to the polarity that blocks neuronal spiking and seizures, and are consistent with biophysical models of spreading depression. The results demonstrate the potential feasibility of electrical control and prevention of spreading depression.

Artemia salina lethality and histopathological studies onBacopa monnieri leaf extract

Bacopa monnieri leaf aqueous and methanolic extractions at 1, 3, 5 and 24 hours were determined for the highest amount of total phenolic compound and used for evaluating the toxicity test against Artemia salina at varied concentrations as 0, 5, 50, 100, 500, 1000, 2,500 and 5,000 ppm, by determining the median and 90% lethal concentration, LC50 and LC90, respectively, within 24 hours. The result revealed that the total phenolic compound measurements in 1, 3, 5 and 24 hours were 70.58+2.74, 70.52+1.63, 67.11+2.51 and 79.01+2.87 mg of gallic acid equivalent per gram of aqueous extractions, and 37.88+1.57, 43.08+2.74, 45.86+2.68 and 55.31+3.60 mg of gallic acid equivalent per gram of methanolic extractions, respectively. Due to the highest amount of total phenolic compound, the 24-hour aqueous extract of B. monnieri leaf expressed the 24-h LC50 and LC90 values in A. salina and they were 3,577.90 and 6,440.22 ppm, respectively. Under histological analysis, pathological lesions like cellular swelling, and elongation of the epithelial cells and edema were observed. More additional, cells protruding into the lumen and absence of microvilli were also found.