Central pontine myelinolysis and the osmotic demyelination syndromes: an open and shut case?

Central pontine myelinolysis and extrapontine myelinolysis are collectively called the osmotic demyelination syndromes. Despite being described in 1959, there are several aspects of the disorder that remain an enigma. Animal models and neuroimaging techniques have allowed us to understand the condition better. From being a universally fatal disorder that was diagnosed post mortem, increased awareness, neuroimaging techniques and supportive care have enabled us to make the diagnosis ante-mortem. This has also led to a significant drop in associated mortality. The aim of this review is to highlight the clinical spectrum, neuroimaging findings, and recent developments.

Blood-brain barrier permeability towards small and large tracers in a mouse model of osmotic demyelination syndrome.

During osmotic demyelination syndrome (ODS), myelin and oligodendrocyte are lost according to specific patterns in centro- or extra-pontine regions. In both experimental model of ODS and human cases, brain lesions are locally correlated with the disruption of the blood brain-barrier (BBB). The initiation, the degree and the duration of blood-brain barrier (BBB) opening as well as its contribution to brain damages are still a matter of debate. Using a panel of intravascular tracers from low- to high- molecular weight (from 0.45 kDa 150 kDa), we have assessed the BBB permeability at different timings of ODS induced experimentally in mice. ODS was mimicked according to a protocol of rapid correction of a chronic hyponatremia. We demonstrated that BBB leakage towards smallest tracers Lucifer Yellow (0.45 kDa) and Texas Red-dextran (3 kDa) was delayed by 36 h compared to the first clues of oligodendrocyte loss (occurring 12 h post-correction of hyponatremia). At 48 h post-correction and concomitantly to myelin loss, BBB was massively disrupted as attested by accumulation of Evans Blue (69 kDa) and IgG (150 kDa) in brain parenchyma. Analysis of BBB ultrastructure verified that brain endothelial cells had minimal alterations during chronic hyponatremia and at 12 h post-correction of hyponatremia. However, brain endothelium yielded worsened alterations at 48 h, such as enlarged vesicular to tubular-like cytoplasmic profiles of pinocytosis and/or transcytosis, local basal laminae abnormalities and sub-endothelial cavities. The protein expressions of occludin and claudin-1, involved in inter-endothelial tight junctions, were also downregulated at 48 h post-correction of hyponatremia. Our results revealed that functional BBB opening occured late in pre-established ODS lesions, and therefore was not a primary event initiating oligodendrocyte damages in the mouse model of ODS.

Adrenomedullin Inhibits Osmotic Water Permeability in Rat Inner Medullary Collecting Ducts.

Adrenomedullin (ADM) is a vasodilator that causes natriuresis and diuresis. However, the direct effect of ADM on osmotic water permeability in the rat inner medullary collecting duct (IMCD) has not been tested. We investigated whether ADM and its ADM receptor components (CRLR, RAMP2, and 3) are expressed in rat inner medulla (IM) and whether ADM regulates osmotic water permeability in isolated perfused rat IMCDs. The mRNAs of ADM, CRLR, and RAMP2 and 3 were detected in rat IM. Abundant protein of CRLR and RAMP3 were also seen but RAMP2 protein level was extremely low. Adding ADM (100 nM) to the bath significantly decreased osmotic water permeability. ADM significantly decreased aquaporin-2 (AQP2) phosphorylation at Serine 256 (pS256) and increased it at Serine 261 (pS261). ADM significantly increased cAMP levels in IM. However, inhibition of cAMP by SQ22536 further decreased ADM-attenuated osmotic water permeability. Stimulation of cAMP by roflumilast increased ADM-attenuated osmotic water permeability. Previous studies show that ADM also stimulates phospholipase C (PLC) pathways including protein kinase C (PKC) and cGMP. We tested whether PLC pathways regulate ADM-attenuated osmotic water permeability. Blockade of either PLC by U73122 or PKC by rottlerin significantly augmented the ADM-attenuated osmotic water permeability and promoted pS256-AQP2 but did change pS261-AQP2. Inhibition of cGMP by L-NAME did not change AQP2 phosphorylation. In conclusion, ADM primarily binds to the CRLR-RAMP3 receptor to initiate signaling pathways in the IM. ADM reduced water reabsorption through a PLC-pathway involving PKC. ADM-attenuated water reabsorption may be related to decreased trafficking of AQP2 to the plasma membrane. cAMP is not involved in ADM-attenuated osmotic water permeability.

In vitro assessment of the anti-sickling properties of Buchholzia coriacea and Mucuna pruriens seed extracts.

Sickle cell disease is a group of diseases inherited through the gene and it affects the haemoglobin in the red blood cell. This study investigated the methanol seed extract of Buchholzia coriacea for possible in vitro anti-sickling effects and also determined the effect of Mucuna pruriens seed extract on the solubility and oxygen-binding rate of sickle cell haemoglobin. Sickle cell blood was collected from sickle cell disease patients with subsequent addition of 2% sodium metabisulphite to cause more sickling. Varying concentrations of the seed extracts (50%, 25%, 12.5% and 6.25%) were added to the pre-treated blood for these in vitro assays. The results showed that the extract of Buchholzia coriacea significantly (P < 0.05) inhibited sickling at all concentrations with the highest percentage inhibition of 73.3 ± 5.8, reversed sickled erythrocytes at all concentrations with the highest percentage reversal of 83.3 ± 5.8 and significantly (P < 0.05) inhibited polymerisation at all concentrations used in comparison to the parallel control. The extract of Mucuna pruriens seed significantly (P < 0.05) increased the solubility of sickle haemoglobin at 50%, 25%, 12.5% and 6.25% concentrations, increased Fe2+/Fe3+ ratio from 1.7 (control) to 12.2 (50% concentration) and reduced osmotic fragility (at 12.5% and 6.25% concentrations) when compared with parallel control. The results indicate the feasibility of the seed extracts as promising agents in the management of sickle cell disease.

Counteraction of osmolytes on pH-induced unfolding of xylose reductase from Debaryomyces nepalensis NCYC 3413.

The stability of Debaryomyces nepalensis NCYC 3413 xylose reductase, a homodimeric enzyme recombinantly expressed and purified from E. coli Rosetta cells, was studied at different pH ranging from 5.0 to 10.0. Deactivation kinetics at different pH were studied by analyzing residual activity of the recombinant enzyme over time at 40 °C whereas conformational changes and stability dependence were investigated by using circular dichroism and differential scanning calorimetry. Four osmolytes viz. glycerol, sucrose, trehalose and sorbitol were explored for their effect on the deactivation and melting temperatures of the enzyme under neutral and extreme pH conditions. The enzyme was found to be catalytically and structurally stable at pH 7.0 with half-life of 250 min and a melting temperature of 50 °C. It was found that alteration in both secondary and tertiary structures caused enzyme deactivation in acidic pH while increased deactivation rates at alkaline pH was attributed to the variation of tertiary structure over time. Estimated thermodynamic parameters also showed that the enzyme stability was highest at neutral pH with ΔH of 348 kcal/mole and ΔG40 of 9.53 kcal/mole. All four osmolytes were effective in enhancing enzyme stability by several folds at extreme pH with sorbitol being the most efficient, which increased enzyme half-life by 11-fold at pH 10.0 and 8-fold at pH 5.0.

Development and optimization of osmotically controlled drug delivery system for poorly aqueous soluble diacerein to improve its bioavailability.

In an attempt to improve the low oral bioavailability of Diacerein (DCN), the combination of a ternary solid dispersion and an asymmetric osmotic pump system had been designed to enhance solubility and to control DCN delivery. Ternary DCN solid dispersion was prepared by melting fusion method using surfactant polymers, and carrier (Pluronic® PF127, Solutol® HS15, and PEG 35 K) and this DCN solid dispersion powder with the proper amount of excipients were compressed and coated with Opadry®CA to develop a Semi-Permeable and Asymmetric Osmotic Pump tablets. The ternary DCN solid dispersion by using surfactant polymers (Pluronic® F127 and Solutol® HS 15) with a ratio of 1:1 was displayed market significant improvement in saturated solubility (70.2 ± 4.14 µg/ml) and fast dissolution rate (Q60min = 79.28 ± 3.1% and IDR5 min = 5.25 ± 0.19 ml/min) in comparison to pure DCN. Moreover, the optimized asymmetric osmotic pump tablet with following parameters; 3% w/v Opadry® CA coat concentration, 1% w/w HPMC E15 gelling polymer and 35.8%w/w NaCl Osmogen concentration, was displayed control release of DCN at zero-order kinetic (R2 = 0.977) for up to 24 h(s). The in-vivo study conducted on rabbits was revealed a significant enhancement in the bioavailability of the optimized osmotic pump (28.84 ± 3.32 ng.hr/ml) compared to DCN dispersion (10.39 ± 1.45 ng.hr/ml). In conclusion, the approach of enhancing solubility and wet-ability in accompany with optimized asymmetric osmotic pump system could serve as a promising delivery system and a way to improve the bioavailability of poorly aqueous soluble drugs.

Reactive oxygen species scavenging mechanisms associated with polyethylene glycol mediated osmotic stress tolerance in Chinese potato.

Influence of polyethylene glycol (PEG) mediated osmotic stress on reactive oxygen species (ROS) scavenging machinery of Chinese potato (Solenostemon rotundifolius (Poir.) J. K. Morton) was investigated. Five genotypes of Chinese potato were raised in Murashige and Skoog (MS) basal medium containing 6-benzylaminopurine (BAP, 1 mg L-1) along with various concentrations of PEG-6000 mediated stress conditions (0, -0.2 and -0.5 MPa) and evaluated for osmotic stress tolerance in vitro. The medium containing PEG-6000 had a detrimental effect on plantlet growth and development while compared with the control. Accumulation of H2O2 was lower in Sreedhara and Subala and higher in Nidhi under PEG stress, which was evident by in situ detection in leaves. Lipid peroxidation product such as malondialdehyde (MDA) content was increased due to PEG stress which was more in susceptible genotype than that in tolerant ones. An enhanced ROS-scavenging antioxidant enzyme was observed under stress with respect to the control. The enzymes of ascorbate-glutathione cycle showed an important role in scavenging ROS. The imposition of PEG stress also increased the non-enzymatic antioxidants viz., the ascorbate and reduced glutathione content which was prominent in tolerant genotypes in comparison to susceptible. The present study indicated that, Sreedhara and Subala showed more tolerance to osmotic stress with better ROS scavenging machineries which would be the lines of interest for augmenting future breeding strategies in this climate resilient minor tuber crop.

Role of Stomatal Conductance in Modifying the Dose Response of Stress-Volatile Emissions in Methyl Jasmonate Treated Leaves of Cucumber (Cucumis sativa).

Treatment by volatile plant hormone methyl jasmonate (MeJA) leads to release of methanol and volatiles of lipoxygenase pathway (LOX volatiles) in a dose-dependent manner, but how the dose dependence is affected by stomatal openness is poorly known. We studied the rapid (0-60 min after treatment) response of stomatal conductance (Gs), net assimilation rate (A), and LOX and methanol emissions to varying MeJA concentrations (0.2-50 mM) in cucumber (Cucumis sativus) leaves with partly open stomata and in leaves with reduced Gs due to drought and darkness. Exposure to MeJA led to initial opening of stomata due to an osmotic shock, followed by MeJA concentration-dependent reduction in Gs, whereas A initially decreased, followed by recovery for lower MeJA concentrations and time-dependent decline for higher MeJA concentrations. Methanol and LOX emissions were elicited in a MeJA concentration-dependent manner, whereas the peak methanol emissions (15-20 min after MeJA application) preceded LOX emissions (20-60 min after application). Furthermore, peak methanol emissions occurred earlier in treatments with higher MeJA concentration, while the opposite was observed for LOX emissions. This difference reflected the circumstance where the rise of methanol release partly coincided with MeJA-dependent stomatal opening, while stronger stomatal closure at higher MeJA concentrations progressively delayed peak LOX emissions. We further observed that drought-dependent reduction in Gs ameliorated MeJA effects on foliage physiological characteristics, underscoring that MeJA primarily penetrates through the stomata. However, despite reduced Gs, dark pretreatment amplified stress-volatile release upon MeJA treatment, suggesting that increased leaf oxidative status due to sudden illumination can potentiate the MeJA response. Taken together, these results collectively demonstrate that the MeJA dose response of volatile emission is controlled by stomata that alter MeJA uptake and volatile release kinetics and by leaf oxidative status in a complex manner.

Exogenous melatonin promotes seed germination and osmotic regulation under salt stress in cotton (Gossypium hirsutum L.).

Melatonin (MT; N-acetyI-5-methoxytryptamine) is an amine hormone involved in abiotic stress resistance. Previous studies have confirmed that melatonin can promote seed germination, mediate physiological regulation mechanisms, and stimulate crop growth under stress. However, the osmotic regulation mechanism by which exogenous melatonin mediates salt tolerance in cotton is still largely unknown. To investigate the effect of salt stress on melatonin concentration in germinating cotton seeds, we analyzed melatonin content over time during seed germination under different treatments. Melatonin content reached its minimum at day 6, while cotton germination rates peaked at day 6, indicating melatonin content and seed germination are correlated. Then we investigated the effects of 10-100 µM melatonin treatments on membrane lipid peroxides and osmotic adjustment substances during cotton seed germination under salt stress. Salt stress led to electrolyte leakage (EL) as well as accumulations of hydrogen peroxide (H2O2), malondialdehyde (MDA), organic osmotic substances (i.e., proline, soluble sugars), and inorganic osmotic substances (i.e., Na+, Cl-). Meanwhile, the contents of melatonin, soluble proteins, and K+ as well as the K+/Na+ balance decreased, indicating that salt stress inhibited melatonin synthesis and damaged cellular membranes, seriously affecting seed germination. However, melatonin pretreatment at different concentrations alleviated the adverse effects of salt stress on cotton seeds and reduced EL as well as the contents of H2O2, MDA, Na+, and Cl-. The exogenous application of melatonin also promoted melatonin, soluble sugar, soluble proteins, proline, and K+/Na+ contents under salt stress. These results demonstrate that supplemental melatonin can effectively ameliorate the repression of cotton seed germination by enhancing osmotic regulating substances and adjusting ion homeostasis under salt stress. Thus, melatonin may potentially be used to protect cotton seeds from salt stress, with the 20 µM melatonin treatment most effectively promoting cotton seed germination and improving salt stress tolerance.

Osmotic diuresis by SGLT2 inhibition stimulates vasopressin-induced water reabsorption to maintain body fluid volume.

Most of the filtered glucose is reabsorbed in the early proximal tubule by the sodium-glucose cotransporter SGLT2. The glycosuric effect of the SGLT2 inhibitor ipragliflozin is linked to a diuretic and natriuretic effect that activates compensatory increases in fluid and food intake to stabilize body fluid volume (BFV). However, the compensatory mechanisms that are activated on the level of renal tubules remain unclear. Type 2 diabetic Goto-Kakizaki (GK) rats were treated with vehicle or 0.01% (in diet) ipragliflozin with free access to fluid and food. After 8 weeks, GK rats were placed in metabolic cages for 24-hr. Ipragliflozin decreased body weight, serum glucose and systolic blood pressure, and increased fluid and food intake, urinary glucose and Na+ excretion, urine volume, and renal osmolar clearance, as well as urine vasopressin and solute-free water reabsorption (TcH2O). BFV, measured by bioimpedance spectroscopy, and fluid balance were similar among the two groups. Urine vasopressin in ipragliflozin-treated rats was negatively and positively associated with fluid balance and TcH2O, respectively. Ipragliflozin increased the renal membrane protein expression of SGLT2, aquaporin (AQP) 2 phosphorylated at Ser269 and vasopressin V2 receptor. The expression of SGLT1, GLUT2, AQP1, and AQP2 was similar between the groups. In conclusion, the SGLT2 inhibitor ipragliflozin induced a sustained glucosuria, diuresis, and natriuresis, with compensatory increases in fluid intake and vasopressin-induced TcH2O in proportion to the reduced fluid balance to maintain BFV. These results indicate that the osmotic diuresis induced by SGLT2 inhibition stimulates compensatory fluid intake and renal water reabsorption to maintain BFV.

An atmospheric pollutant (inorganic nitrogen) alters the response of evergreen broad-leaved tree species to extreme drought.

Drought and nitrogen (N) deposition are important components of global climate and environmental change. In this greenhouse study, we investigated the ecophysiological responses of the seedlings of three subtropical forest plant species (Schima superba, Castanopsis fissa, and Michelia macclurei) to short-term experimental drought stress, N addition, and their interaction. The results showed that drought stress reduced the activities of antioxidant enzymes [superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT)] and total antioxidant capacity (T-AOC), but increased the malondialdehyde (MDA), abscisic acid (ABA), and proline (PRO) contents in plants. The PRO content, T-AOC, and antioxidant enzyme activities were increased, and ABA and MDA contents were decreased by N addition alone. Furthermore, N addition under drought stress increased antioxidant enzymes activities, PRO content, and T-AOC. The treatments, however, did not significantly affect the chlorophyll fluorescence parameters of the species. T-AOC was positively correlated with antioxidant enzyme activities in each species, indicating that antioxidant enzymes were important for plant resistance to oxidative stress. MDA content increased with the increase of ABA content, indicating that ABA may help regulate stomatal movement and drought-induced oxidative injury in plants. T-AOC was positively correlated with PRO content, probably because PRO participated in osmotic regulation of cells and increased osmotic stress resistance. These results indicate that N addition can reduce drought stress of subtropical forest plants and will help researchers predict how evergreen broad-leaved forests will respond to global change in the future.

Osmotic Treatment for Quantifying Cell Wall Elasticity in the Sepal of Arabidopsis thaliana.

Elastic properties of the cell wall play a key role in regulating plant growth and morphogenesis; however, measuring them in vivo remains a challenge. Although several new methods have recently become available, they all have substantial drawbacks. Here we describe a detailed protocol for osmotic treatments, which is based on the idea of releasing the turgor pressure within the cell and measuring the resulting deformation. When placed in hyperosmotic solution, cells lose water via osmosis and shrink. Confocal images of the tissue, taken before and after this treatment, are quantified using high-resolution surface projections in MorphoGraphX. The cell shrinkage observed can then be used to estimate cell wall elasticity. This allows qualitative comparisons of cell wall properties within organs or between genotypes and can be combined with mechanical simulations to give quantitative estimates of the cells' Young's moduli. We use the abaxial sepal of Arabidopsis thaliana as an easily accessible model system to present our approach, but it can potentially be used on many other plant organs. The main challenges of this technique are choosing the optimal concentration of the hyperosmotic solution and producing high-quality confocal images (with cell walls visualized) good enough for segmentation in MorphoGraphX.

Impact of Grafting, Salinity and Irrigation Water Composition on Eggplant Fruit Yield and Ion Relations.

Scarcity of fresh water in arid and semi-arid regions means that we must use more saline waters for irrigation and develop tools to improve crop salt tolerance. The objectives of our study were to (1) Evaluate fruit production, salt tolerance and ion composition of eggplant cv Angela, both nongrafted and when grafted on tomato cv Maxifort rootstock and (2) Evaluate eggplant specific toxicity effect of Cl- and Na+ ions under saline conditions. We salinized the irrigation water with either a Na+-Ca2+- Cl- composition typical of coastal Mediterranean ground waters as well as a mixed Na+-Ca2+-SO42- Cl- type water, a composition more typical of interior continental basin ground. For each water type we evaluated 5 different salinity (osmotic) levels of -0.003 (control), -0.15, -0.30, -0.45 and -0.60 MPa. There were no statistically significant differences in the fruit yield relative to the water type, indicating that Cl- ion toxicity is not a major factor in eggplant yield associated with salinity. This conclusion was confirmed by the determination that leaf Cl content was not correlated with relative yield. The electrical conductivity of the saturation extract (ECe) at which yield is predicted to be reduced by 50% was 4.6 dS m-1 for the grafted plants vs. 1.33 dS m-1 for the nongrafted plants. The relative yield was very well correlated to leaf Na concentrations regardless of grafting status, indicating that Na is the toxic ion responsible for eggplant yield loss under saline conditions. The increased salt tolerance of cv Angela eggplant when grafted onto tomato Maxifort rootstock is attributed to a reduced Na uptake and increased Ca and K uptake with Maxifort rootstock.

Metabolic responses of wheat seedlings to osmotic stress induced by various osmolytes under iso-osmotic conditions.

Many environmental stresses cause osmotic stress which induces several metabolic changes in plants. These changes often vary depending on the genotype, type and intensity of stress or the environmental conditions. In the current experiments, metabolic responses of wheat to osmotic stress induced by different kinds of osmolytes were studied under iso-osmotic stress conditions. A single wheat genotypes was treated with PEG-6000, mannitol, sorbitol or NaCl at such concentrations which reduce the osmotic potential of the culture media to the same level (-0.8MPa). The metabolic changes, including the accumulation of proline, glycine betaine (GB) and sugar metabolites (glucose, fructose, galactose, maltose and sucrose) were studied both in the leaves and roots together with monitoring the plant growth, changes in the photosynthetic activity and chlorophyll content of the leaves. In addition, the polyamine metabolism was also investigated. Although all osmolytes inhibited growth similarly, they induced different physiological and metabolic responses: the CO2 assimilation capacity, RWC content and the osmotic potential (ψπ) of the leaves decreased intensively, especially after mannitol and sorbitol treatments, followed by NaCl treatment, while PEG caused only a slight modification in these parameters. In the roots, the most pronounced decrease of ψπ was found after salt-treatments, followed by PEG treatment. Osmotic stress induced the accumulation of proline, glycine betaine and soluble sugars, such as fructose, glucose, sucrose and galactose in both the root and leaf sap. Specific metabolic response of roots and leaves under PEG included accumulation of glucose, fructose and GB (in the roots); sucrose, galactose and proline synthesis were dominant under NaCl stress while exposure to mannitol and sorbitol triggered polyamine metabolism and overproduction of maltose. The amount of those metabolites was time-dependent in the manner that longer exposure to iso-osmotic stress conditions stimulated the sugar metabolic routes. Our results showed that the various osmolytes activated different metabolic processes even under iso-osmotic stress conditions and these changes also differed in the leaves and roots.

Design and formulation of nano-porous controlled porosity osmotic pumps (CPOPs) containing a poorly water soluble drug, glibenclamide.

The aim of this study was to design and develop controlled porosity osmotic pumps containing glibenclamide (as an insoluble agent) coated with nano-scale pore formers. Solubility enhancement methods including co-grinding with an anionic surfactant and pH adjustment in core formulation were employed and the prepared cores were coated with nano-suspension coating method. The prepared nano-porous osmotic pump (CPOP) system assessed by comparative parameters including D24h (cumulative release percentage after 24h), tL (lag time of the drug release from device), drug release rate from device and RSQzero. Solubility studies of glibenclamide co-ground with an anionic surfactant showed that by increasing the concentration of SLS to 83.33% (ratio of drug: SLS 1:5) in the presence of calcium carbonate, the solubility of glibenclamide was enhanced remarkably. Release study also displayed enhanced D24h and improved kinetic related parameter (RSQ zero) by increasing SLS and calcium carbonate in the core formulation via nano-porous CPOPs. It can be concluded that by employing both co-grinding technology and pH adjustment method in core formulation of glibenclamidenano-suspension coated CPOPs, enhanced D24h, drug release rate and improved kinetic related parameter (RSQ zero)) was achieved.

Current Opinion on Usage of L-Carnitine in End-Stage Renal Disease Patients on Peritoneal Dialysis.

The advantages of peritoneal dialysis (PD) over hemodialysis (HD) are well-documented. Notwithstanding, only a small proportion of patients with end-stage renal disease (ESRD) are managed with PD. This may be related to the high glucose load that PD solutions in current use have on the patient. The effects of such excess glucose include the relatively early limitation of the ultrafiltration capacity of the peritoneal membrane, and the metabolic effects associated with hyperglycemia, e.g., decreased insulin sensitivity. This article describes the advantages that may be realized by the glucose-sparing effects of substituting part of the glucose load with other osmotically active metabolites, particularly L-carnitine. The latter is anticipated to have metabolic advantages of its own, especially as in PD patients, high plasma concentrations can be achieved in the absence of renal clearance. Besides its better biocompatibility, L-carnitine demonstrates anti-anemia action due to its effects on erythropoiesis, and positive effects on the longevity and deformability of erythrocytes. Observations from our trials on the use of carnitine-enriched PD solutions have demonstrated the effectiveness of L-carnitine as an efficient osmolyte in PD, and its favorable effect on the insulin sensitivity of the patients. The significance of these findings for future developments in the use of PD in the management of patients with ESRD is discussed.

Vulnerability to stress consequences induced by repeated social defeat in rats: Contribution of the angiotensin II type 1 receptor in cardiovascular alterations associated to low brain derived neurotrophic factor.

After social stress, rats become vulnerable to depression, and this state is characterized by persistent low blood levels of brain-derived neurotrophic factor (BDNF). The aim of this study was to determine whether low BDNF levels are associated with long term autonomic changes. Defeated animals were subjected to four daily episodes of social defeats. Twenty five days later, defeated rats with low BDNF levels (Dlow) still displayed elevated sympathetic tone (as indicated by an elevated low frequency to high frequency ratio (LF/HF) in heart rate) and elevated blood pressure, as well as reduced baroreflex sensitivity (BRS). In contrast, those with higher BDNF levels (Dhigh) similar to controls, did not. Dlow animals persistent cardiovascular changes were abolished by acute inhibition of the dorsomedial nucleus of the hypothalamus (DMH). These cardiovascular changes were also prevented by chronic sub-cutaneous osmotic infusion of losartan, an angiotensin II type 1 receptor (AT1) receptor antagonist, started immediately after social defeat. In conclusion, the results show that greater vulnerability to stress consequences following a traumatic event is associated with an elevated LF/HF ratio, a persistent high blood pressure and a low BRS, all due to an AT1 receptor activation.

Differential effects of NaCl and Na2SO4 on the halophyte Prosopis strombulifera are explained by different responses of photosynthesis and metabolism.

Prosopis strombulifera (Lam.) Benth. is a halophytic shrub found in highly saline soils in Argentina, with high tolerance against NaCl but strong growth inhibition by Na2SO4. In the present study, the differences in the physiological responses caused by these salts and an iso-osmotic combination thereof on photosynthesis, mineral composition and metabolism were analyzed. Na2SO4 treated plants were the most affected by salinity, showing a significant decrease in several photosynthetic parameters. Proline and cysteine accumulated significantly in the plants in response to salt stress. These results show by the first time that the SO42- anion is triggering damage in the photosynthetic apparatus and consequently affecting the photosynthetic process, which may explain the strong growth inhibition in these plants at high salinity. Moreover, the SO42- anion provoke challenges in the incorporation of nutrients, decreasing the levels of K, Ca, P and Mg, and inducing a strong antioxidant activity in P. strombulifera.

The spiking and secretory activity of oxytocin neurones in response to osmotic stimulation: a computational model.

KEY POINTS: A quantitative model of oxytocin neurones that combines a spiking model, a model of stimulus-secretion coupling and a model of plasma clearance of oxytocin was tested. To test the model, a variety of sources of published data were used that relate either the electrical activity of oxytocin cells or the secretion of oxytocin to experimentally induced changes in plasma osmotic pressure. To use these data to test the model, the experimental challenges involved were computationally simulated. The model predictions closely matched the reported outcomes of the different experiments. ABSTRACT: Magnocellular vasopressin and oxytocin neurones in the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. In rodents, both vasopressin and oxytocin magnocellular neurones are osmoresponsive, and their increased spiking activity is mainly a consequence of an increased synaptic input from osmoresponsive neurons in regions adjacent to the anterior wall of the third ventricle. Osmotically stimulated vasopressin secretion promotes antidiuresis while oxytocin secretion promotes natriuresis. In this work we tested a previously published computational model of the spiking and secretion activity of oxytocin cells against published evidence of changes in spiking activity and plasma oxytocin concentration in response to different osmotic challenges. We show that integrating this oxytocin model with a simple model of the osmoresponsive inputs to oxytocin cells achieves a strikingly close match to diverse sources of data. Comparing model predictions with published data using bicuculline to block inhibitory GABA inputs supports the conclusion that inhibitory inputs and excitatory inputs are co-activated by osmotic stimuli. Finally, we studied how the gain of osmotically stimulated oxytocin release changes in the presence of a hypovolaemic stimulus, showing that this is best explained by an inhibition of an osmotically regulated inhibitory drive to the magnocellular neurones.

[Technical characteristics of Alzheimer model based on organ technology (organoid)].

Alzheimer's disease (AD) is a serious neurodegenerative disorder that manifests itself as progressive damage to memory and knowledge and is the main cause of dementia in the elderly. AD is characterized by extracellular deposition of amyloid-ß plate (Aß) and by the formation of neurofibrillary tangles, composed of hyperphosphorylated Tau protein. These modifications lead to neuronal cell death, vascular dysfunction and inflammatory disorders. Described as "elderly disease", AD is an escalating threat to developed countries as life expectancy is increasing. Because of its severity, AD has been the subject of extensive studies that address the pathogenesis of the disease. However, its main cause remains unknown. Most research on neurological conditions has been applied to animal models. However, due to their high cost and the uncertain translation of their results to humans along with moral concerns, in recent years, there has been a growing need for in vitro modeling to mimic the brain. The creation of the aforementioned models aims at a better understanding of the factors contributing to the onset of the disease and the faster development of the treatment of diseases affecting the nervous system. Given this need, in this review, new approaches to study neurodegenerative disease were recorded. A three-dimensional (3D) neurosphere-based microfluid chip has been reported and this model imitates the in vivo microenvironment of the brain and provides a steady flow of fluid that is observed in the brain's space. Uniform neurospheres, with cell interactions and contacts in all directions, were formed in a hollow microfuge and a steady interstitial flow rate was maintained using a small pump osmotic system. In this model it was possible to control the toxic effects of amyloid-ß. At the end, it was observed that the deposition of amyloid-ß through an osmotic micro-pump significantly reduced the viability of the neurospheres and caused destruction of the neuronal networks. Therefore, this model was proposed as an in vitro brain model for neurodegenerative disease and high-throughput drugs.