Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cytoprotection”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed2004

The use of transgenic mice to study cytoprotection by the stress proteins.

Heat shock or stress proteins (HSPs) have been shown to be able to confer cytoprotection in a diversity of cell types and organisms. We were interested in assessing if HSPs, in particular HSP70, were protective against pathophysiological stresses such as myocardial ischemia. Our approach was to generate a transgenic mouse line that would constitutively express high levels of an inducible rat HSP70 isoform in the heart. The hearts of the transgenic mice were then used in an isolated perfused mouse heart model to assess whether increased expression of HSP70 alone was protective against ischemia-reperfusion injury. Our study showed that there was a significant improvement in contractile recovery, less cellular damage, and a reduction in infarct size in the hearts of transgenic mice as compared to non-transgenic mice following global ischemia in our isolated perfused mouse heart model. Additional studies have since shown that increased expression of HSP70 as well as other stress proteins in transgenic mice protects against different forms of pathological stresses. We present here the methods we used to generate HSP70 transgenic mice and assess their increased tolerance to ischemia-reperfusion injury.

Animals↗
PubMed2001

Iron complexes of deferiprone and dietary plant catechols as cytoprotective superoxide radical scavengers(1).

Superoxide radicals have been implicated in the pathogenesis of aging, cataract, ischemia-reperfusion, cancer and inflammatory diseases. In the present work, we found that deferiprone (L1), an iron-chelating drug, and dietary dihydroxycinnamic acids (catechols) were much more effective at protecting isolated rat hepatocytes against hypoxia-reoxygenation injury if complexed with Fe(3+). Furthermore, the 2:1 catechol-metal complexes with Cu(2+), Fe(2+), and Fe(3+) were also more effective than uncomplexed catechols in scavenging superoxide radicals generated enzymically (xanthine oxidase/hypoxanthine). The 2:1 deferiprone:Fe(3+) complex was less effective at scavenging enzymically generated superoxide radicals even though it was effective at preventing hepatocyte hypoxia-reoxygenation injury. On the other hand, the 1:1 deferoxamine:Fe(3+) complex, another iron-chelating drug, did not prevent hepatocyte hypoxia-reoxygenation injury and did not scavenge enzymically generated superoxide radicals. Furthermore, hepatocytes readily reduced the 2:1 deferiprone:Fe(3+) complex but not the deferoxamine:Fe(3+) complex. These results suggest that the initial step in superoxide radical scavenging (SRS) activity is the formation of a redox complex between Fe(3+) and deferiprone or catechols. The [deferiprone:Fe(3+)] complex was more cytoprotective than would be expected from its SRS activity. This suggests that [deferiprone:Fe(3+)] complex is reduced by a ferrireductase present on the hepatocyte membrane to form [deferiprone:Fe(2+)] complex, which then scavenges superoxide radicals. Therefore, the clinically used deferiprone (L1) may have therapeutic advantages over deferoxamine in having a double role therapeutically: (a) it chelates iron to alleviate iron overload pathology, and (b) the readily formed iron complex protects hepatocytes from superoxide radical-mediated hypoxia-reoxygenation injury.

Animals↗
PubMed1998

Antioxidant and cytoprotective activities of the calcium channel blocker mibefradil.

Mibefradil is a new calcium channel antagonist (CCA) that acts on both L- and T-type channels, with 10-fold selectivity for T-type channels. In this study, the structural interactions of mibefradil with cardiac membrane lipid bilayers were directly examined with small-angle x-ray diffraction approaches and correlated with lipid peroxidation and bovine aortic endothelial cell viability assays. Electron density profiles (A vs electrons/A3) calculated from the diffraction data (37 degrees C) demonstrated that mibefradil had an equilibrium location in the hydrocarbon core/headgroup region of the cardiac bilayer, 12-27 A from the center of the membrane. Mibefradil also effected a pronounced reduction in electron density 0-11 A from the center of the cardiac membrane concomitant with a 7.5% (3 A) decrease in membrane hydrocarbon core thickness; these changes in membrane structure were not observed with the phenylalkylamine verapamil, a CCA with some structural similarity to mibefradil. As a result of membrane physico-chemical interactions, mibefradil inhibited (10-500 nM) lipid peroxide formation in liposomes enriched in polyunsaturated fatty acids. In aortic endothelial cells, mibefradil also inhibited loss of cell viability (IC50 of 2 microM) following acute oxy-radical generation by dihydroxyfumarate and Fe-ADP; the order of potency was mibefradil > verapamil > diltiazem. These findings indicate that the chemical structure of mibefradil contributes to biophysical interactions with the cell membrane that underlie antioxidant and cytoprotective activities in models of oxidative stress.

Animals↗
PubMed2000

Ba(2+)-induced chromaffin cell death: cytoprotection by Ca(2+) channel antagonists.

Exposure of bovine adrenal medullary chromaffin cells to Ba(2+) ions (in the absence of Ca(2+) ions) caused their death, measured as lactate dehydrogenase (LDH) release. The concentration of Ba(2+) required to damage the cells by about 65% ranged between 1 and 10 mM (no Ca(2+) added); the required exposure time was rather brief (15 min-4 h). The simultaneous presence of Ca(2+), Mg(2+) or Zn(2+) together with Ba(2+) (2 mM, 4 h) afforded cyprotection (60-80%). Individual selective blockers of Ca(2+) channel subtypes afforded no protection. However, combined nifedipine (3 microM) plus omega-conotoxin MVIIC (3 microM) offered full protection. Substantial protection was also seen with the "wide-spectrum" Ca(2+) channel blockers penfluridol (0.3 microM), lubeluzole (3 microM), dotarizine (3 microM), flunarizine (3 microM), and mibefradil (3 microM). This protection was due to blockade of Ba(2+) entry through Ca(2+) channels because dotarizine (10 microM) inhibited the increase in cytosolic [Ba(2+)] seen in fura-2-loaded chromaffin cells. Once Ba(2+) accumulated in the cytosol, it was not extruded by the Na(+)/Ca(2+) exchanger, as shown by the prolonged and sustained elevation of the fura-2 signal. This contrasts with the fast dissipation of the fura-2 signal generated by [Ca(2+)](i) elevation. Thus, Ba(2+) overload can cause cell death by mechanisms similar to those reported for Ca(2+) overload and might be used as a novel and convenient tool to search for new cytoprotective compounds.

Animals↗
PubMed2003

Effects of dosmalfate, a new cytoprotective agent, on acute and chronic trinitrobenzene sulphonic acid-induced colitis in rats.

Activated neutrophils and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) are clearly involved in the pathogenesis of bowel disease. Increased expression of epidermal growth factor-receptor (EGF receptor) has been reported for the colon mucosa surrounding areas of ulceration, suggesting a pivotal role in mucosal defence and repair. In this study, we examined the effects of dosmalfate, a new flavonoid derivative compound (diosmin heptakis) with antioxidant and cytoprotective properties, on acute and chronic experimental trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. The inflammation response was assessed by neutrophil infiltration as evaluated by histology and myeloperoxidase activity. Mucosal TNF-alpha production and histological analysis of the lesions was also carried out. In addition, we studied the expression of the EGF receptor inmunohistochemically during the healing of TNBS-induced chronic colitis. A 2-day treatment with 400 or 800 mg/kg of dosmalfate ameliorated the colon damage score and the incidence of adhesions. It also significantly (P<0.05) decreased myeloperoxidase activity and colonic mucosal production of TNF-alpha. Chronic treatment (14 days) with 800 mg/kg/day of dosmalfate also had significant protective effects on TNBS-induced colitis which were reflected by significant attenuation (P<0.05) of the damage score while the inflammatory indicators were not improved. The chronic beneficial effect of dosmalfate was apparently related to the enhancement of EGF receptor expression. These findings confirm the protective effects of dosmalfate in acute and chronic experimental colitis.

Acute-Phase Reaction↗
PubMed1998

Cyclic GMP-dependent cytoprotection against ethanol-induced damage in rabbit isolated gastric parietal cells.

Prostaglandin E2 stimulates a nitric oxide/cyclic GMP (NO/cGMP) pathway which activates basolateral Cl- channels in rabbit gastric parietal cells. We examined whether the NO/cGMP pathway protects parietal cells from ethanol (EtOH)-induced cytotoxicity, using a parietal cell-rich suspension purified from rabbit gastric mucosa. Cytotoxicity was assayed by measuring the release of a fluorescent dye from the cells. N2,O2-dibutyryl guanosine 3',5'-cyclic monophosphate (DBcGMP) showed a concentration-dependent protective effect against EtOH-induced cytotoxicity. The half-maximal effect of DBcGMP was observed at 24 microM. DBcGMP in a concentration-dependent manner opened the basolateral Cl- channels of parietal cells, the EC50 value being 44 microM. The EtOH-induced cytotoxicity decreased as the Cl- concentration of medium decreased. A 30-s treatment with 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), an inhibitor of the Cl- channel, had a cytotoxic effect which was not prevented by pre-incubation with DBcGMP. The cytotoxic effects of EtOH and NPPB were additive and the NPPB effects did not depend on the medium Cl- concentration. The present study showed that cGMP protects the gastric parietal cell from EtOH-induced cytotoxicity, and this cytoprotection is related to basolateral Cl- channel activity in the plasma membrane via an unknown mechanism(s).

Animals↗
PubMed1998

Effects of renal cytoprotective agents on erythrocyte membrane stability.

To elucidate potential mechanisms of ischemic renal injury, investigators often use drugs that interfere with specific pathological pathways and study their protective efficacy in in vitro models of ischemia, such as isolated renal proximal tubules subjected to hypoxia. However, the protective effects of certain drugs may depend on non-specific membrane-stabilizing properties. We have studied the effects of several drugs on membrane integrity using osmotic lysis of erythrocytes as a model system. Freshly isolated rabbit erythrocytes were subjected to a hypotonic shock, and the protective effects of various calcium channel blockers, phospholipase inhibitors, free fatty acids, the NO-synthase inhibitor L-NAME, the amino acid glycine and its receptor-analogue strychnine, and two chloride channel blockers were examined. Most agents protected erythrocytes against hypotonic hemolysis when added to the medium in the same concentration range as used in suspensions of hypoxic proximal tubules. Only the protective agents that proposedly act via a blockade of chloride influx (glycine, strychnine and the chloride channel blockers), did not attenuate hypotonic hemolysis. The erythrocyte hemolysis assay may provide an easy and rapid method to screen for non-specific membrane-stabilizing effects of potentially cytoprotective agents.

Animals↗
PubMed2002

Ciclopirox prevents peroxynitrite toxicity in astrocytes by maintaining their mitochondrial function: a novel mechanism for cytoprotection by ciclopirox.

Previously we have reported that astrocytes deprived of glucose were highly vulnerable to peroxynitrite (Choi and Kim, J. Neurosci. Res. 54 (1998) 870; Neurosci. Lett. 256 (1988) 109; Ju et al., J. Neurochem. 74 (2000) 1989). Here we report that ciclopirox, which is clinically used as an anti-fungal agent, completely prevents the increased death in glucose-deprived astrocytes exposed to 3-morpholinosydnonimine (SIN-1, a peroxynitrite-releasing reagent). The increased vulnerability was in good correlation with the peroxynitrite-evoked decrease of mitochondrial transmembrane potential (MTP) in astrocytes. A simultaneous exposure to glucose deprivation and SIN-1 rapidly depolarized MTP and depleted ATP in astrocytes. Inclusion of ciclopirox initially increased the MTP, maintained it high, and blocked the ATP depletion in glucose-deprived SIN-1-treated astrocytes. However, ciclopirox did not prevent the depletion of reduced glutathione in glucose-deprived SIN-1-treated astrocytes. Consistently, ciclopirox did not scavenge various kinds of oxidants including peroxynitrite, nitric oxide, superoxide anion, hydrogen peroxide and hydroxyl radical. Ciclopirox has been experimentally used as a cell cycle G1/S phase transition blocker (Hoffman et al., Cytometry 12 (1991) 26). Flow cytometry analysis, however, showed that the cytoprotective effect of ciclopirox was not attributed to its inhibition of the cell cycle progression. The present results indicate that ciclopirox protects astrocytes from peroxynitrite cytotoxicity by attenuating peroxynitrite-induced mitochondrial dysfunction.

Adenosine Triphosphate↗
PubMed2005

Cytotoxic and cytoprotective actions of O2- and NO (ONOO-) are determined both by cellular GSH level and HO activity in macrophages.

Survival of macrophages, which serve as the first-line defense against invading pathogens by invoking the overproduction of highly toxic peroxynitrite (ONOO-), depends on their ability to maintain the intracellular GSH level and to induce the expression of heme oxygenase-1 (HO-1). The ONOO- is produced by macrophages stimulated by pathogens and is a powerful oxidant reacting directly with cellular GSH and proteins, killing both invading pathogens and macrophages themselves. However, macrophages can survive the toxicity of ONOO- by replenishing the depleted GSH level and by inducing HO-1 expression. In macrophages exposed to conditions overproducing O2-, NO, or ONOO-, the cellular level of GSH decreased rapidly, and when excessive, cells died. However, in cells surviving the toxicity caused by lower doses of O2-, NO, or ONOO-, the depleted intracellular GSH level was replenished, and HO-1 expression was increased, but not when they were coexposed to an inhibitor of HO-1 activity. Cells exposed to an inhibitor of GSH synthesis had greater induction of HO-1 expression and survived. However, cells exposed to an inhibitor of HO-1 activity died extensively and could not be revived by addition of N-acetylcysteine (NAC), a precursor of GSH synthesis. Thus, the dichotomous cytotoxic or cytoprotective effects of O2-, NO, or ONOO- in macrophages are determined both by cellular GSH level and by HO-1 activity.

Animals↗
PubMed2000

Bone marrow purging by photodynamic treatment in children with acute leukemia: cytoprotective action of amifostine.

In order to evaluate the combined effect of Amifostine and Merocyanine 540 during photoirradiation in neoplastic cells, bone marrow cells from children with acute leukemia (AL), age-matched controls as well as HL-60 cell line were studied. Cell suspensions were incubated with Amifostine, then with MC 540 and they were subsequently exposed to different irradiation doses by Argon Laser 514 nm. Cell survival was estimated by trypan blue supravital stain following a 24-h incubation. The leukemic cell line was studied in continuous liquid cell cultures for 4 weeks. The survival of normal bone marrow progenitors has been estimated by colony formation assay in methylcellulose cultures. Our results showed that Amifostine enhances the photokilling effect of MC 540 on leukemic cells and significantly protects bone marrow nucleated and committed progenitors (BFU-E and CFU-GM) from children with AL under chemotherapy. In conclusion, Amifostine seems to be a promising cytoprotective agent in the clinical use of purging with MC 540 mediated phototherapy.

Amifostine↗
PubMed2001

Cinnamophilin as a novel antiperoxidative cytoprotectant and free radical scavenger.

The antioxidant properties of cinnamophilin were evaluated by studying its ability to react with relevant reactive oxygen species, and its protective effect on cultured cells and biomacromolecules under oxidative stress. Cinnamophilin concentration-dependently suppressed non-enzymatic iron-induced lipid peroxidation in rat brain homogenates with an IC50 value of 8.0+/-0.7 microM and iron ion/ADP/ascorbate-initiated rat liver mitochondrial lipid peroxidation with an IC50 value of 17.7+/-0.2 microM. It also exerted an inhibitory activity on NADPH-dependent microsomal lipid peroxidation with an IC50 value of 3.4+/-0.1 microM without affecting microsomal electron transport of NADPH-cytochrome P-450 reductase. Both 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azo-bis(2-amidinopropane) dihydrochloride-derived peroxyl radical tests demonstrated that cinnamophilin possessed marked free radical scavenging capacity. Cinnamophilin significantly protected cultured rat aortic smooth muscle cells (A7r5) against alloxan/iron ion/H2O2-induced damage resulting in cytoplasmic membranous disturbance and mitochondrial potential decay. By the way, cinnamophilin inhibited copper-catalyzed oxidation of human low-density lipoprotein, as measured by fluorescence intensity and thiobarbituric acid-reactive substance formation in a concentration-dependent manner. On the other hand, it was reactive toward superoxide anions generated by the xanthine/xanthine oxidase system and the aortic segment from aged spontaneously hypertensive rat. Furthermore, cinnamophilin exerted a divergent effect on the respiratory burst of human neutrophil by different stimulators. Our results show that cinnamophilin acts as a novel antioxidant and cytoprotectant against oxidative damage.

Animals↗
PubMed2002

Hypofractionated and accelerated radiotherapy with cytoprotection (HypoARC): a short, safe, and effective postoperative regimen for high-risk breast cancer patients.

PURPOSE: Although the role of radiotherapy (RT) after mastectomy in reducing the local relapse rate is well established, its impact on overall survival is strongly questioned. Up to 70% of patients will not benefit from additional RT, and a "wait and see" policy is often adopted. Establishment of short, still safe, and effective RT regimens would render adjunctive radiotherapy more appealing. We evaluated the toxicity and efficacy of a Hypofractionated and intensively Accelerated RT regimen supported with amifostine Cytoprotection (HypoARC) in a cohort of 72 high-risk breast cancer patients treated with modified mastectomy or conservative surgery and FEC (5-fluorouracil/epirubicin/cyclophosphamide) chemotherapy. PATIENTS AND METHODS: A high dose of amifostine, 1,000 mg, was given as a 5-min i.v. infusion before each of the 12 consecutive fractions of RT (4 x 3.5 Gy/fraction and 8 x 4 Gy/fraction, 1 fraction/day, 5 fractions/week). The breast or chest wall, as well as supraclavicular and axillary area, was included in the RT fields. The follow-up of patients ranged from 18 to 42 months (median, 28 months). Alkaline phosphatase (AF) expression was assessed immunohistochemically in normal and cancerous breast tissues. RESULTS: Ninety-two percent of patients successfully completed the regimen, the only side effects being mild nausea and asthenia. In 7% of patients, amifostine was interrupted because of a rash/fever reaction. A dramatic reduction in acute skin toxicity was noted (p < 0.0001). Acute pneumonitis, as well as late toxicity in breast, chest wall, axillary, and lung tissue, was lower with the HypoARC regimen, although not significantly, than with the standard fractionation regimen used to treat two matched control cohorts. Both HypoARC and standard RT significantly reduce the local relapse rate (p < 0.0001), although the local relapse-free and overall survival times were marginally better for the HypoARC group of patients (p > 0.09). AF showed a mixed nuclear/cytoplasmic pattern of expression in the epithelial, endothelial, and stromal component of the normal breast and benign lesions, whereas an impressive loss of AF expression was noted in in situ and invasive breast cancer and tumoral stroma. CONCLUSIONS: The HypoARC regimen is convenient for both patients and radiotherapy departments. The regimen is well tolerated and shows a significantly better profile in terms of early toxicity; a reduced rate of late sequel may be expected. The local relapse rate is as low as that expected from conventional RT. The absence of AF expression in cancer cells and tumoral stroma is probably a major reason for the selective protection of normal breast tissue by amifostine.

Adult↗
PubMed1999

Cytoprotection and iron mobilization in rat hepatocyte cultures by a new synthetic dihydroxamate chelator.

The cytoprotection and iron mobilization effect of a new dihydroxamate chelator 1,1 bis [(11-N-hydroxy)-2,5,11-triaza-1,6,10-trioxo dodecanyl] ethane or KD was studied in primary rat hepatocyte cultures exposed to iron-citrate. Lactate dehydrogenase (LDH) release and malondialdehyde (MDA) production were measured as indexes of cytotoxicity. Cell viability was evaluated using the [3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyl tetrazolium bromide] (MTT) reduction test. To demonstrate that this chelator was able to decrease iron uptake or increase iron release from the hepatocytes, labelled cells were obtained by maintaining the cultures in the presence of 0.02 microM 55Fe-citrate. The efficacy of KD was compared to desferrioxamine B (DFO) at stoechiometry concentrations. After 24 h of exposure to 50 microM of iron-citrate, a significant release of LDH and MDA was observed. Cell viability was also significantly decreased. When 100 microM of KD were added at the same time as iron, LDH and MDA release was decreased and cell viability was improved. In the presence of the same chelator concentration, a net decrease of iron uptake by the cells was observed as attested by the low intracellular 55Fe level. Moreover, in the 55Fe loaded hepatocytes, the chelator increased the iron extracellular level indicating its iron release effect from the cells. In all tested experimental conditions, the efficacy of 100 microM of the dihydroxamate chelator KD was close to that of 50 microM of the trihydroxamate chelator DFO. In conclusion, KD is effective at a level comparable to DFO in protecting rat hepatocytes against the toxic effect of iron-citrate by decreasing the uptake of the metal and increasing its release from the cells. This synthetic compound appears to have some potential therapeutical interest and the results obtained encourage the synthesis of new hydroxamate ligands.

Animals↗
PubMed2002

Ammonia aggravates stress-induced gastric mucosal oxidative injury through the cancellation of cytoprotective heat shock protein 70.

The relationship between Helicobacter pylori colonization and the formation of stress-induced gastric mucosal injury remains unknown. Since ammonia (NH(3)) is known as one of the injurious factors in H. pylori-colonized gastric mucosa, the present study is designed to investigate the level of stress-induced gastric mucosal oxidative injury with or without intragastric NH(3) overloading. To apply emotional stress, the communication box paradigm was used in the mouse model. Mice (C57BL/6, male) were pretreated with distilled water (responder-H(2)O) or 0.01% NH(3) (responder-NH(3)) through a gastric tube once a day for a week. Emotional stress was then applied to the responder mice for 3 h per day for 3 d by watching and hearing the behavior of the sender mice subjected to electric shocks to the feet (2 mA, 10 s, 50 s interval). After the communication box protocol, the tissue MPO activity, the contents of TBA-reactive substances (TBARS), and the level of gastric mucosal HSP70 were examined. Responder-NH(3) mice developed more severe gastric lesions than the responder-H(2)O subjects. MPO activity and TBARS contents were enhanced significantly in the responder-NH(3) group compared with the responder-H(2)O subjects. Although the contents of HSP70 in the gastric mucosa increased in the responder-H(2)O group compared with the control-H(2)O animals, they were significantly attenuated in the responder-NH(3) mice. Excess intragastric NH(3) was able to enhance the formation of emotional stress-induced gastric mucosal lesions. This injury may be associated with the enhanced production of oxygen free radicals from accumulated neutrophils under the NH(3)-mediated cancellation of gastric mucosal cytoprotective HSP70.

Ammonia↗
PubMed1996

The need for cytoprotection.

The toxicity associated with chemotherapy is significant and dose limiting. Multiple organ systems can be affected, with both acute and chronic side effects producing adverse effects. The concept of cytoprotection, or the selective protection of normal tissues is a strategy now being investigated in preclinical and clinical models. Systemic approaches have included the use of compounds such as sodium thiosulphate, diethyldithiocarbamate and amifostine. The most promising results have been obtained with the organic thiophosphate compound amifostine (Ethyol, WR-2721).

Amifostine↗
PubMed2003

Hydrophilic bile salts have a cytoprotective effect against cyclosporine A-induced cholestasis through enhanced canalicular membrane fluidity and transporter activity.

Cyclosporine A (CsA) reduces liver canalicular membrane (CM) fluidity to cause a disproportionate reduction of biliary lipid secretion (the uncoupling phenomenon) without affecting adenosine triphosphate-dependent (ABC) transporters except for Mdr1. This study investigated whether hydrophilic bile salts inhibit CsA-induced cholestasis, focusing on CM fluidity and ABC transporter expression. Male Sprague-Dawley rats were infused with taurocholate (TC) (200 nmol/min/100 g body weight) for 2 h, flowed by infusion with tauroursodeoxycholate (TUDC), tauroalphamuricholate, or taurobetamuricholate (100 nmol/min/100 g body weight plus TC at 100 nmol/min/100 g body weight). Thereafter, CsA (20 mg/kg body weight) was injected as a bolus and bile was collected for 2 h. Canalicular membrane vesicles were prepared for analysis of cholesterol (CH), phospholipid (PL), CM fluidity, and expression of ABC transporters (Mdr1, Bsep, Mdr2, and Mrp2). CsA administration reduced biliary lipid secretion along with a disproportionately smaller decline of bile salt secretion. Hydrophilic bile salts significantly inhibited cholestasis after CsA injection by increasing CM fluidity and by increasing the expression of Mrp2 and Bsep, whereas Mdr1 and Mdr2 were unaltered. (1) Hydrophilic bile salts inhibit CsA-induced cholestasis, presumably by increasing CM fluidity, and this action was greatest with TUDC. (2) The fact that ABC transporters, except for Mdr1 and Mdr2, were overexpressed in the CM after infusion of these bile salts suggests that cytoprotective bile salts functions may increase transporter mass as well as enhancing transporter activity.

Journal Article↗
PubMed2001

Mood stabilizers regulate cytoprotective and mRNA-binding proteins in the brain: long-term effects on cell survival and transcript stability.

Manic depressive illness (MDI) is a common, severe, chronic and often life-threatening illness. Despite well-established genetic diatheses and extensive research, the biochemical abnormalities underlying the predisposition to, and the pathophysiology of, these disorders remain to be clearly established. Despite formidable obstacles in our attempts to understand the underlying neurobiology of this illness, there is currently considerable excitement about the progress that is being made using novel strategies to identify changes in gene expression that may have therapeutic relevance in the long-term treatment of MDI. In this paper, we describe our recent research endeavours utilizing newer technologies, including a concerted series of mRNA RT-PCR studies, which has led to the identification of novel, hitherto completely unexpected targets for the long-term actions of mood stabilizers - the major cytoprotective protein bcl-2, a human mRNA binding (and stabilizing) protein, AUH, and a Rho kinase. These results add to the growing body of data suggesting that mood stabilizers may bring about some of their long-term benefits by enhancing neuroplasticity and cellular resilience. These results are noteworthy since recent morphometric brain imaging and post-mortem studies have demonstrated that MDI is associated with the atrophy and/or loss of neurons and glia. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.

Animals↗
PubMed1985

Antiulcer agents. 1. Gastric antisecretory and cytoprotective properties of substituted imidazo[1,2-a]pyridines.

A novel class of antiulcer agents, the substituted imidazo[1,2-a]pyridines, is described. The present compounds are not histamine (H2) receptor antagonists nor are they prostaglandin analogues, yet they exhibit both gastric antisecretory and cytoprotective properties. The mechanism of gastric antisecretory activity may involve inhibition of the H+/K+-ATPase enzyme. Structure-activity studies led to the identification of 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, SCH 28080 (27), which was selected for further development and clinical evaluation.

Animals↗