Serum E-selectin and erythrocyte membrane Na+K+ ATPase levels in patients with rheumatoid arthritis

We conducted this study to assess serum soluble E-selectin (sE-selectin) levels and erythrocyte membrane Na(+)K(+) ATPase activity in patients with rheumatoid arthritis (RA) and correlate the levels with disease activity. Levels of sE-selectin were measured in the serum of 20 patients with RA and 20 control subjects by an enzyme-linked immunosorbant assay. Na(+)K(+) ATPase activity was determined by a colorimetric method in RA patients and healthy controls. There were no statistically significant differences between the two groups with respect to demographic data such as age and sex (p > 0.05). The serum levels of sE-selectin, ESR and C-reactive protein (CRP) in RA patients were significantly higher than in healthy controls (p < 0.001). Erythrocyte membrane Na(+)K(+) ATPase activity was significantly lower in the RA group than in the control group (p < 0.001). Correlation analysis revealed significant positive correlations between soluble E-selectin and ESR (r = 0.457; p < 0.05) and CRP (r = 0.682; p < 0.01) levels. There were statistically significant negative correlations between erythrocyte membrane Na(+)K(+) ATPase activity and ESR (r = -0.450; p < 0.05) and CRP (r = -0.446; p < 0.05) levels. Additionally, a significant negative correlations between sE-selectin and Na(+)K(+) ATPase activity was observed (r = -0.80; p < 0.001). These results show that decreases in erythrocyte membrane Na(+)K(+) ATPase activity and increases in sE-selectin are observed in RA, and that increased levels of sE-selectin may also reflect disease status or activity.     

Amomum tsaoko fruit extract exerts anticonvulsant effects through suppression of oxidative stress and neuroinflammation in a pentylenetetrazol kindling model of epilepsy in mice

BackgroundChronic epilepsy is a multifaceted common brain disorder with manifold underlying factors. Epilepsy affects around 70 million peoples worldwide. Amomum tsaoko is a perennial herbaceous plant that is extensively cultivated in many provinces of China reported to exert immense biological activities.ObjectiveThis research work was aimed to reveal the therapeutic actions of ethanolic extract of A.tsaoko fruits (EE-ATF) against the pentylenetetrazol (PTZ)-provoked convulsive seizures in the mice.MethodologyThe convulsive seizures were provoked to the animals via administering 70 mg/kg of PTZ through intraperitoneally to trigger the convulsive seizures then treated with the EE-ATF at 50, 75, and 100 mg/kg orally 30 min prior to PTZ challenge. After the 30 min of PTZ challenge, animals closely monitored for signs of convulsion, generalized clonic and tonic convulsion durations, and mortality. A sub-convulsive dose 35 mg/kg of PTZ was used to provoke the kindling and seizure stages were examined using standard method. The levels of dopamine, GABA, glutamate, and Na + K + ATPase and Ca + ATPase activities in the brain tissues were studied using marker specific assay kits. The oxidative stress and antioxidant markers studied using standard methods. The mRNA expressions of COX-2, TNF-α, NF-κB, TLR-4, and IL-1β in the brain tissues were studied using RT-PCR analysis. The brain tissues were examined histologically.ResultsEE-ATF treatment remarkably decreased the onset and duration of convulsion and suppressed the seizure severity and mortality in the PTZ animals. EE-ATF treatment appreciably ameliorated the PTZ triggered modifications in the GABA, glutamate, dopamine levels and Ca + 2ATPase and Na + K + ATPase activities in the brain tissues. EE-ATF suppressed the mRNA expressions of NF-κB, IL-1β, TLR-4, TNF-α, and COX-2. The status of antioxidants were elevated by the EE-ATF. Histological findings also demonstrated the curative actions of EE-ATF.ConclusionOur findings evidenced that the EE-ATF substantially ameliorated the PTZ-provoked convulsive seizures in the mice.     

Early life stage salinity tolerance of wild and hatchery-reared juvenile pink salmon Oncorhynchus gorbuscha

Salinity tolerance in wild (Glendale) and hatchery (Quinsam) pink salmon Oncorhynchus gorbuscha (average mass 0·2 g) was assessed by measuring whole body [Na⁺] and [Cl^?] after 24 or 72 h exposures to fresh water (FW) and 33, 66 or 100% sea water (SW). Gill Na⁺, K⁺‐ATPase activity was measured following exposure to FW and 100% SW and increased significantly in both populations after a 24 h exposure to 100% SW. Whole body [Na⁺] and whole body [Cl^?] increased significantly in both populations after 24 h in 33, 66 and 100% SW, where whole body [Cl^?] differed significantly between Quinsam and Glendale populations. Extending the seawater exposure to 72 h resulted in no further increases in whole body [Na⁺] and whole body [Cl^?] at any salinity, but there was more variability among the responses of the two populations. Per cent whole body water (c. 81%) was maintained in all groups of fish regardless of salinity exposure or population, indicating that the increase in whole body ion levels may have been related to maintaining water balance as no mortality was observed in this study. Thus, both wild and hatchery juvenile O. gorbuscha tolerated abrupt salinity changes, which triggered an increase in gill Na⁺, K⁺‐ATPase within 24 h. These results are discussed in terms of the preparedness of emerging O. gorbuscha for the marine phase of their life cycle.     

Glutathione S‐transferase π complexes with and stimulates Na+,K+‐ATPase

Glutathione S‐transferase (GST) was found to complex with the Na⁺,K⁺‐ATPase as shown by binding assay using quartz crystal microbalance. The complexation was obstructed by the addition of antiserum to the α‐subunit of the Na⁺,K⁺‐ATPase, suggesting the specificity of complexation between GST and the Na⁺,K⁺‐ATPase. Co‐immunoprecipitation experiments, using the anti‐α‐subunit antiserum to precipitate the GST‐Na⁺,K⁺‐ATPase complex and then using antibodies specific to an isoform of GST to identify the co‐precipitated proteins, revealed that GSTπ was complexed with the Na⁺,K⁺‐ATPase. GST stimulated the Na⁺,K⁺‐ATPase activity up to 1.4‐fold. The level of stimulation exhibited a saturable dose–response relationship with the amount of GST added, although the level of stimulation varied depending on the content of GSTπ in the lots of GST received from supplier. The stimulation was also obtained when recombinant GSTπ was used, confirming the results. When GST was treated with reduced glutathione, GST activity was greatly stimulated, whereas the level of stimulation of the Na⁺,K⁺‐ATPase activity was similar to that when untreated GST was added. When GST was treated with H₂O₂, GST activity was greatly diminished while the stimulation of the Na⁺,K⁺‐ATPase activity was preserved. The results suggest that GSTπ complexes with the Na⁺,K⁺‐ATPase and stimulates the latter independent of its GST activity. Copyright © 2012 John Wiley & Sons, Ltd.     

Trade‐offs in osmoregulation and parallel shifts in molecular function follow ecological transitions to freshwater in the Alewife

Adaptation to freshwater may be expected to reduce performance in seawater because these environments represent opposing selective regimes. We tested for such a trade‐off in populations of the Alewife (Alosa pseudoharengus). Alewives are ancestrally anadromous, and multiple populations have been independently restricted to freshwater (landlocked). We conducted salinity challenge experiments, whereby juvenile Alewives from one anadromous and multiple landlocked populations were exposed to freshwater and seawater on acute and acclimation timescales. In response to acute salinity challenge trials, independently derived landlocked populations varied in the degree to which seawater tolerance has been lost. In laboratory‐acclimation experiments, landlocked Alewives exhibited improved freshwater tolerance, which was correlated with reductions in seawater tolerance and hypo‐osmotic balance, suggesting that trade‐offs in osmoregulation may be associated with local adaptation to freshwater. We detected differentiation between life‐history forms in the expression of an ion‐uptake gene (NHE3), and in gill Na⁺/K⁺‐ATPase activity. Trade‐offs in osmoregulation, therefore, may be mediated by differentiation in ion‐uptake and salt‐secreting pathways.     

Estrogen downregulates the number of caveolae and the level of caveolin in uterine smooth muscle

Estrogen and progesterone, while regulating uterine functions, also regulate the number of caveolae and the level of caveolin. Large numbers of caveolae, as well as elevated expression of caveolin-1 and caveolin-2 isoforms in the myometrium of ovariectomised (OVX) rats were detected. 17beta-estradiol (E2) has a downregulating effect: the treatment of OVX rats with E2 (5 microg/animal) reduced the formation of caveolae by approx. 90%. Western blots clearly demonstrated the reduction of membrane caveolin-1 and -2 content. Progesterone treatment (2.5 mg/animal) alone did not cause any substantial change, but prevented the effect of estrogen. Control experiments showed that the quantity of Na+/K+-ATPase, a plasma membrane protein excluded from caveolae, was not downregulated by E2. The administration of the pure estrogen receptor (ERalpha) antagonist ICI 182,780 (1 mg/animal) not only compensated for the inhibitory effect of E2, but further increased the level of caveolin-1 in the myometrium of OVX rats and facilitated the formation of caveolae by approximately 70%. In contrast, the partial antagonist tamoxifen (1 mg/animal) mimicked the effect of estrogen. The amount of caveolin also changed during pregnancy. During the first half of pregnancy the expression of caveolin was suppressed, but it gradually increased until delivery. Our results indicate that the formation and number of caveolae are influenced by the physiological state of the uterus in a hormone dependent manner.     

Ultrastructure and osmoregulatory function of the kidney in larvae of the Persian sturgeon Acipenser persicus

The localization of Na(+) , K(+) -ATPase (NKA) and the ultrastructural features of kidney were examined in larvae of the Persian sturgeon Acipenser persicus (L 31-41 mm total length and 182·3-417·3 mg). Investigations were conducted through light and electron microscopy and through immunofluorescence for NKA detection. The kidney nephrons consisted of a large glomerulus and tubules (neck, proximal, distal and collecting), which connected to the ureters. Posteriorly, ureters extended and joined together into a thin-walled ureter terminal sac. Ultrastructurally, the glomerular cells (podocytes) possessed distinctive pedicels that extended to the basal membrane. The proximal tubule (PT) showed two different cells. The cells lining the anterior part of PT possessed apical tall microvilli (c. 2·7 μm), a sub-apical tubular system, a basal nucleus and dense granules. Posteriorly in the cells, the sub-apical tubular system and granules were absent and round mitochondria associated with basolateral infoldings were found; the apical microvilli were reduced. Distal and collecting tubular cells showed the typical features of osmoregulatory cells, i.e. well-developed basolateral infoldings associated with numerous mitochondria. No immunofluorescence of NKA was detected in the glomeruli. A weak immunostaining was observed at the basolateral side of the cells lining the neck and PT. A strong immunostaining of NKA was observed in the entire cells of the distal tubules, collecting tubules and in some isolated cells of the ureters. In all immunostained cells, the basolateral region showed a much higher fluorescence and nuclei were immunonegative. In conclusion, the epithelial cells of kidney tubules had morphological and enzymatic features of ionocytes, particularly in the distal and collecting tubules. Thus, the kidney of A. persicus larvae possesses active ion exchange capabilities and, beside its implication in excretion, participates in osmoregulation.     

Lack of inhibition of vasopressin-stimulated NA+K+ATPase by atrial natriuretic factor in the rat renal medullary thick ascending limb of Henle's loop

The anti-diuretic hormone, arginine vasopressin (AVP) stimulates the activity of Na+K+ATPase in the rat renal medullary thick ascending limb of Henle's loop (mTAL). Atrial natriuretic factor (ANF) has been suggested to exert a tubular effect on the mammalian nephron, perhaps in part, by interacting with other hormones. In the present study, we investigated the effect of rat ANF with and without AVP upon mTAL Na+K+ATPase activity using cytochemical methods. ANF alone failed to inhibit or stimulate Na+K+ATPase activity in mTAL at any of the concentrations tested (10 nmol-0.1 pmol l-1). Unlike the rat hypothalamic digitalis-like factor, ANF (10 nmol-10 fmol l-1) did not inhibit Na+K+ATPase activity after stimulation with AVP (1 fmol l-1) for either 4 or 10 min. The results suggest that ANF does not exert an effect on mTAL, either alone or in conjunction with AVP.     

Immunohistological classification of ionocytes in the external gills of larval Japanese black salamander,Hynobius nigrescens Stejneger

In this cytological and immunohistological study, we clarified the localization of the membrane transporters Na⁺, K⁺‐ATPase (NKA), vacuolar‐type H⁺‐ATPase (VHA), and epithelial sodium channel (ENaC) and distinguished ionocyte subtypes in the gill of the Japanese salamander (Hynobius nigrescens). In larvae (IY stages 43–65), NKA immunoreactivity was observed on the basolateral plasma membrane in more than 60% cells and less than 20% cells in the primary filaments and secondary lamellae of the external gills, respectively. VHA immunoreactivity was observed on the apical membrane of some epithelial cells in the secondary lamellae of the external gills. High ENaCα immunoreactivity was widely observed on the apical cell membrane of a population of squamous cells, presumably pavement cells (PVCs), and mitochondria‐rich cells (MRCs), in the primary filaments and secondary lamellae of the external gills. Using double immunofluorescence microscopy, epithelial cell types involved in ionic regulation were characterized and divided into three ionocyte types: NKA‐, NKA‐ and ENaC‐, and VHA‐positive cells. VHA‐immunoreactive cells as well as NKA‐positive cells were observed during IY stages 43–65 of the salamander larvae. During late stages of metamorphosis, NKA, VHA, and ENaCα immunoreactivities in the external gills decreased and finally disappeared during the completion of metamorphosis (IY stage 68). PVCs and MRCs in the external gills are probably involved in acid–base balance regulation and osmoregulation in urodele amphibian larvae. The results are discussed in relation to the ionocytes previously reported in fish gills and the frog skin epithelium. J. Morphol., 2011. © 2011Wiley‐Liss, Inc.     

ATP-binding to P-type ATPases as revealed by biochemical, spectroscopic, and crystallographic experiments

P-type ATPases form a large family of cation translocating ATPases. Recent progress in crystallography yielded several high-resolution structures of Ca(2+)-ATPase from sarco(endo)plasmic reticulum (SERCA) in various conformations. They could elucidate the conformational changes of the enzyme, which are necessary for the translocation of cations, or the mechanism that explains how the nucleotide binding is coupled to the cation transport. However, crystals of proteins are usually obtained only under conditions that significantly differ from the physiological ones and with ligands that are incompatible with the enzyme function, and both of these factors can inevitably influence the enzyme structure. Biochemical (such as mutagenesis, cleavage, and labeling) or spectroscopic experiments can yield only limited structural information, but this information could be considered relevant, because measurement can be performed under physiological conditions and with true ligands. However, interpretation of some biochemical or spectroscopic data could be difficult without precise knowledge of the structure. Thus, only a combination of both these approaches can extract the relevant information and identify artifacts. Briefly, there is good agreement between crystallographic and other experimental data concerning the overall shape of the molecule and the movement of cytoplasmic domains. On the contrary, the E1-AMPPCP crystallographic structure is, in details, in severe conflict with numerous spectroscopic experiments and probably does not represent the physiological state. Notably, the E1-ADP-AlF(4) structure is almost identical to the E1-AMPPCP, again suggesting that the structure is primarily determined by the crystal-growth conditions. The physiological relevance of the E2 and E2-P structures is also questionable, because the crystals were prepared in the presence of thapsigargin, which is known to be a very efficient inhibitor of SERCA. Thus, probably only crystals of E1-2Ca conformation could reflect some physiological state. Combination of biochemical, spectroscopic, and crystallographic data revealed amino acids that are responsible for the interaction with the nucleotide. High sequence homology of the P-type ATPases in the cytoplasmic domains enables prediction of the ATP-interacting amino acids also for other P-type ATPases.     

Effects of gradual salinity increase on osmoregulation in Caspian roach Rutilus caspicus

This study was carried out to determine the effects of gradual salinity increase on osmoregulatory ability of the Caspian roach Rutilus caspicus, under conditions which mimic stocking conditions of hatchery-raised fish. Initially, 30 juvenile fish (mean ± S.D. 3.20 ± 0.34 g) were transferred to 20 l circular tanks, in which salinities were changed in a stepwise fashion, from 0 to 5, 10 or 15 at 48 h intervals. The fish at salinity 15 were held for an additional 48 h at this salinity. Forty-eight hours after salinity transfer, survival rate, haematocrit, plasma Cl(-) , Na(+) and K(+) concentrations, osmolality and gill Na(+) /K(+) -ATPase (NKA) activity were measured. The only effect of exposure to 5 was a significant reduction in haematocrit compared to the freshwater control group. Exposure to salinity 10 raised haematocrit, Cl(-) and Na(+) concentrations and osmolality. At 48 h exposure to salinity 15, haematocrit, Cl(-) and Na(+) concentrations and osmolality were significantly higher than freshwater controls, and gill NKA activity was significantly lower, but the effect on NKA was no longer evident at 96 h exposure. There were no effects on survival. These results indicate that R. caspicus juveniles experience an initial non-lethal iono-osmotic perturbation following salinity increase but can adapt to brackish water at salinity 15.     

Plasticity of smolting in spring chinook salmon: relation to growth and insulin-like growth factor-I

In two year classes of Willamette River spring chinook salmon, reared at the Willamette Hatchery, and two groups of Yakima River spring chinook salmon, one sampled from the Yakima River and the other reared in a hatchery, fish which had relatively high growth rates in the summer–autumn period smolted in the autumn as measured by increases in gill Na⁺ K⁺ AT Pase activity. In contrast, groups with relatively low growth rate did not smolt in the autumn. Plasma levels of insulin-like growth factor-I (IGF-I) showed discrete differences between groups, with high levels associated with increased gill Na⁺ K⁺ AT Pase activities. These results demonstrate that smolting is plastic in spring chinook salmon, occurring in the autumn or the spring. In addition, smolting appeared to be related to growth rate; however, the relationships shown were correlational and causal mechanisms were not elucidated. Yet, the results do indicate a relationship between growth, an endocrine growth factor and smolting, suggesting a mechanistic link between developmental plasticity and the environment mediated by the endocrine system.     

Enhanced protection against lipopolysaccharide‐induced acute lung injury by autologous transplantation of adipose‐derived stromal cells combined with low tidal volume ventilation in rats

Adipose‐derived stromal cells (ADSCs) showed excellent capacity in regeneration and tissue protection. Low tidal volume ventilation (LVT) strategy demonstrates a therapeutic benefit on the treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). This study, therefore, aimed to undertaken determine whether the combined LVT and ADSCs treatment exerts additional protection against lipopolysaccharide (LPS)‐induced ALI in rats. The animals were randomized into seven groups: Group I (control), Group II (instillation of LPS at 10 mg/kg intratracheally), Group III (LPS+LVT 6 ml/kg), Group IV (LPS+intravenous autologous 5 × 10⁶ ADSCs which were pretreated with a scrambled small interfering RNA [siRNA] of keratinocyte growth factor [KGF] negative control), Group V (LPS+ADSCs which were pretreated with a scrambled siRNA of KGF, Group VI (LPS+LVT and ADSCs as in the Group IV), and Group VII (LPS+LVT and ADSCs as in the Group V). We found that levels of tumor necrosis factor‐α, transforming growth factor‐β1, and interleukin (IL)‐1β and IL‐6, the proinflammatory cytokines, were remarkably increased in LPS rats. Moreover, the expressions of ENaC, activity of Na, K‐ATPase, and alveolar fluid clearance (AFC) were obviously reduced by LPS‐induced ALI. The rats treated by ADSCs showed improved effects in all these changes of ALI and further enhanced by ADSCs combined with LVT treatment. Importantly, the treatment of ADSCs with siRNA‐mediated knockdown of KGF partially eliminated the therapeutic effects. In conclusion, combined treatment with ADSCs and LVT not only is superior to either ADSCs or LVT therapy alone in the prevention of ALI. Evidence of the beneficial effect may be partly due to improving AFC by paracrine or systemic production of KGF and anti‐inflammatory properties.     

In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models

The principal active constituent of the botanical drug candidate PBI-05204, a supercritical CO(2) extract of Nerium oleander, is the cardiac glycoside oleandrin. PBI-05204 shows potent anticancer activity and is currently in phase I clinical trial as a treatment for patients with solid tumors. We have previously shown that neriifolin, which is structurally related to oleandrin, provides robust neuroprotection in brain slice and whole animal models of ischemic injury. However, neriifolin itself is not a suitable drug development candidate and the FDA-approved cardiac glycoside digoxin does not cross the blood-brain barrier. We report here that both oleandrin as well as the full PBI-05204 extract can also provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we show that the neuroprotective activity of PBI-05204 is maintained for several hours of delay of administration after oxygen and glucose deprivation treatment. We provide evidence that the neuroprotective activity of PBI-05204 is mediated through oleandrin and/or other cardiac glycoside constituents, but that additional, non-cardiac glycoside components of PBI-05204 may also contribute to the observed neuroprotective activity. Finally, we show directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clinical potential for PBI-05204 in the treatment of ischemic stroke and prevention of associated neuronal death.     

Na+/K+ATPase immunoreactivity in olfactory epithelium of small-spotted catshark Scyliorhinus canicula (L.): possible presence of ion exchanging cells?

Na⁺/K⁺ATPase immunoreactivity in olfactory epithelium of Scyliorhinus canicula was localized in well featured light large cells. It was distributed in the basolateral membranes as reported in the literature for typical ion exchanging cells.     

Erythrocyte sodium pump stimulation by ouabain and an endogenous ouabain-like factor

Cardiac glycosides inhibit the sodium pump. However, some studies suggest that nanomolar ouabain concentrations can stimulate the activity of the sodium pump. In this study, using the Na(+)/K(+)-ATPase of human erythrocytes, we compared the effect of digoxin, ouabain and an ouabain like-factor (OLF), on (86)Rb uptake. Ouabain concentrations below 10(-9) M significantly stimulate Rb(+) uptake, and the maximal increase above base-line values is 18 +/- 5% at 10(-10) M ouabain. No stimulation is observed in the same conditions by digoxin. OLF behaved like ouabain, producing an activation of Rb(+) flux at concentrations lower than 10(-9) M ouabain equivalents (14 +/- 3% at 10(-10) M). Western blot analysis revealed the presence of both alpha(1) and alpha(3) pump isoforms in human erythrocytes. Our data confirm the analogies between OLF and ouabain and suggest that Na(+)/K(+)-ATPase activation may be related to the alpha(3) isoform. In addition, we investigated whether ouabain at different concentrations was effective in altering the intracellular calcium concentration of erythrocytes. We found that ouabain at concentration lower than 10(-9) M did not affect this homeostasis.     

Brain Na+ K+ ATPase and cholesterol in acute experimental trypanosomiasis.

Brain Na+ K+ ATPase activity has been found to decrease in experimental trypanosomiasis in rats infected with Trypanosoma congolense. Some physical features that affect membrane fluidity were also observed to be altered. The levels of cholesterol in the brain and free fatty acids in the serum were found to increase in the infected animals. These findings might be relevant to the development of brain lesions.     

The effects of the caffeic acid phenethyl ester (CAPE) on erythrocyte membrane damage after hind limb ischaemia-reperfusion

Reactive oxygen species have been implicated in pathogenesis injury after ischaemia-reperfusion (I/R). Caffeic Acid Phenethyl Ester (CAPE), an active component of honeybee propolis extract, exhibits antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of CAPE on erythrocyte membrane damage after hind limb I/R. Rats were divided into two groups: I/R and I/R with CAPE pre-treatment. They were anaesthetized with intramuscular ketamine 100 mg kg(-1). A 4-h I/R period was performed on the right hind limb of all animals. In the CAPE-treated group, animals received CAPE 10 microm by intraperitoneal injection 1 h before the reperfusion. At the end of the reperfusion period, a midsternotomy was performed. A 5-ml blood sample was withdrawn from the ascending aorta for biochemical assays. Serum and erythrocyte membrane MDA levels were significantly lower in the CAPE-treated group when compared to the I/R group ( p = 0.001 and p<0.001, respectively). Erythrocyte membrane Na(+)-K(+) ATPases activity in the CAPE-treated group was significantly higher than the I/R group ( p<0.001). In conclusion, CAPE seems to be effective in protecting against oxidative stress. Therefore, we suggest that in order to decrease I/R injury, pre-administration of CAPE may be a promising agent for a variety of conditions associated with I/R.     

Decreased neuronal Na+, K+ -ATPase activity in Atp1a3 heterozygous mice increases susceptibility to depression-like endophenotypes by chronic variable stress

Unipolar depression and bipolar depression are prevalent and debilitating diseases in need of effective novel treatments. It is becoming increasingly evident that depressive disorders manifest from a combination of inherited susceptibility genes and environmental stress. Genetic mutations resulting in decreased neuronal Na(+) ,K(+) -ATPase (sodium-potassium adenosine triphosphatase) activity may put individuals at risk for depression given that decreased Na(+) ,K(+) -ATPase activity is observed in depressive disorders and animal models of depression. Here, we show that Na(+) ,K(+) -ATPase α3 heterozygous mice (Atp1a3(+/-) ), with 15% reduced neuronal Na(+) ,K(+) -ATPase activity, are vulnerable to develop increased depression-like endophenotypes in a chronic variable stress (CVS) paradigm compared to wild-type littermates (Atp1a3(+/+) ). In Atp1a3(+/+) mice CVS did not decrease Na(+) ,K(+) -ATPase activity, however led to despair-like behavior in the tail suspension test (TST), anhedonia in a sucrose preference test and a minimal decrease in sociability, whereas in Atp1a3(+/-) mice CVS decreased neuronal Na(+) ,K(+) -ATPase activity to 33% of wild-type levels, induced despair-like behavior in the TST, anhedonia in a sucrose preference test, anxiety in the elevated plus maze, a memory deficit in a novel object recognition task and sociability deficits in a social interaction test. We found that a mutation that decreases neuronal Na(+) ,K(+) -ATPase activity interacts with stress to exacerbate depression. Furthermore, we observed an interesting correlation between Na(+) ,K(+) -ATPase activity and mood that may relate to both unipolar depression and bipolar disorder. Pharmaceuticals that increase Na(+) ,K(+) -ATPase activity or block endogenous Na(+) , K(+) -ATPase inhibition may provide effective treatment for depressive disorders and preclude depression in susceptible individuals.