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PubMed2004

Cytoprotective effect of glucosylceramide synthase inhibition against daunorubicin-induced apoptosis in human leukemic cell lines.

Several studies have shown that ceramide (CER) glucosylation contributes to drug resistance in multidrug-resistant cells and that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide synthase has not been studied in drug-sensitive cancer cells. We have demonstrated previously that the anthracycline daunorubicin (DNR) rapidly induces interphasic apoptosis through neutral sphingomyelinase-mediated CER generation in human leukemic cell lines. We now report that inhibition of glucosylceramide synthase using d,l-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) protected U937 and HL-60 cells from DNR-induced apoptosis. Moreover, blocking CER glucosylation did not lead to increased CER levels but to increased CER galactosylation. We also observed that pretreating cells with galactosylceramide (GalCER) significantly inhibited DNR-induced apoptosis. Finally, we show that GalCER-enriched lymphoblast cells (Krabbe's disease) were significantly more resistant to DNR- and cytosine arabinoside-induced apoptosis as compared with normal lymphoblasts, whereas glucosylceramide-enriched cells (Gaucher's disease) were more sensitive. In conclusion, this study suggests that sphingomyelin-derived CER in itself is not a second messenger but rather a precursor of both an apoptosis second messenger (GD3) and an apoptosis "protector" (GalCER).

Antineoplastic Agents↗
PubMed2005

Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL.

Humanin (HN) is a recently identified endogenous peptide that protects cells against cytotoxicity induced by various stimuli. Recently, we showed that HN binds to and inhibits Bax, a proapoptotic Bcl-2 family protein, suggesting a mechanism for HN action. In this study, we identified Bim, a Bcl-2 homology 3-only member of the Bcl-2/Bax family, as an additional HN target protein. Using in vitro protein binding, immunoprecipitation, and coimmunolocalization assays, we demonstrated that HN binds directly to the extra long isoform of Bim (BimEL) but not the long (BimL) or short (BimS) isoforms. HN also protects cells against apoptosis induced by BimEL but not BimL and BimS in gene transfection studies. In contrast, mutants of HN which failed to bind BimEL failed to protect from BimEL-induced cell death. Moreover, HN inhibited BimEL-induced release of SMAC and cytochrome c from mitochondria isolated from bax-/-cells, indicating that HN can suppress BimEL independently of its effect on Bax. Finally, we demonstrate that HN prevents BimEL-induced oligomerization of Bak using isolated mitochondria. Taken together, our results indicate that the inhibition of BimEL may contribute to the antiapoptotic properties of the HN peptide.

Adaptor Proteins, Signal Transducing↗
PubMed2000

p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system.

In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-kappaB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappaB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to activate p38 and NF-kappaB in other cell types. Thus, by stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.

Animals↗
PubMed2003

Proteomic analysis of oxidative stress-resistant cells: a specific role for aldose reductase overexpression in cytoprotection.

We are using a proteomic approach that combines two-dimensional electrophoresis and tandem mass spectrometry to detect and identify proteins that are differentially expressed in a cell line that is resistant to oxidative stress. The resistant cell line (OC14 cells) was developed previously through chronic exposure of a parent cell line (HA1 cells) to increasing hydrogen peroxide concentrations. Biochemical analyses of this system by other investigators have identified elevated content and activity of several classical antioxidant proteins that have established roles in oxidative stress resistance, but do not provide a complete explanation of this resistance. The proteomics studies described here have identified the enzyme aldose reductase (AR) as 4-fold more abundant in the resistant OC14 cells than in the HA1 controls. Based on this observation, the role of AR in the resistant phenotype was investigated by using a combination of AR induction with ethoxyquin and AR inhibition with Alrestatin to test the cytotoxicity of two oxidation-derived aldehydes: acrolein and glycolaldehyde. The results show that AR induction in HA1 cells provides protection against both acrolein- and glycolaldehyde-induced cytotoxicity. Furthermore, glutathione depletion sensitizes the cells to the acrolein-induced toxicity, but not the glycolaldehyde-induced toxicity, while AR inhibition sensitizes the cells to both acrolein- and glycolaldehyde-induced. These observations are consistent with a significant role for AR in the oxidative stress-resistant phenotype. These studies also illustrate the productive use of proteomic methods to investigate the molecular mechanisms of oxidative stress.

Acrolein↗
PubMed2005

Human fibroblast growth factor 20 (FGF-20; CG53135-05): a novel cytoprotectant with radioprotective potential.

The aim was to evaluate the radioprotective properties of recombinant human fibroblast growth factor 20 (FGF-20; CG53135-05) in vitro and in vivo and to examine its effects on known cellular pathways of radioprotection. Relative transcript levels of the cyclooxygenase 2 (COX2), Mn-super oxide dismutase (SOD), CuZn-SOD, extracellular (EC)-SOD, nuclear respiratory factor 2 (Nrf2), glutathione peroxidase 1 (GPX1) and intestinal trefoil factor 3 (ITF3) genes, which are involved in radiation response pathways, were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) in NIH/3T3, IEC18, CCD-18Co, CCD-1070sk and human umbilical vein endothelial cells (HUVEC) cells exposed to FGF-20. Activation of the radioprotective signal transduction pathways initiating with the serine/threonine Akt kinase and the extracellular regulated kinase (ERK) were analysed. Levels of intracellular hydrogen peroxide and cytosolic redox potential were also measured in irradiated and unirradiated cells in the presence or absence of FGF-20. The effects of FGF-20 on cell survival in vitro following ionizing radiation were evaluated using clonogenic assays. To test the potential activity of FGF-20 as a radioprotectant in vivo, mice were administered a single dose of FGF-20 (4 mg kg(-1), intraperitoneally (i.p.) 1 day before lethal total-body irradiation and evaluated for survival. In vitro exposure to FGF-20 increased expression of the Nrf2 transcription factor and oxygen radical scavenging enzymes such as MnSOD, activated signal transduction pathways (ERK and Akt) and resulted in increased survival of irradiated cells in vitro. FGF-20 treatment also resulted in a concomitant reduction in intracellular levels of injurious reactive oxygen species (ROS) following acute ionizing irradiation. Finally, prophylactic administration of FGF-20 to mice before potentially lethal, whole-body X-irradiation led to significant increases in overall survival. FGF-20 reduced the lethal effects of acute ionizing radiation exposure in cells by up-regulating important signalling and free radical scavenging pathways. Survival-sparing effects of FGF-20 prophylaxis in acutely irradiated mice presumably are elicited by comparable mechanisms. These results indicate that FGF-20, has significant radioprotective attributes with potential applications in clinical and non-clinical exposure settings.

Animals↗
PubMed1988

Stress ulcer prophylaxis and ventilation pneumonia: prevention by antibacterial cytoprotective agents?

The gastric and tracheal flora of 142 consecutive patients receiving stress ulcer prophylaxis were investigated, identifying identical isolates by typing. Furthermore, the growth pattern of normal respiratory bacteria and organisms causing ventilation pneumonia at different pH values and the in vitro effect of sucralfate and bismuth subsalicylate on these bacteria in simulated gastric fluid were studied. The results obtained were as follows: (1) with rising gastric pH bacterial counts in gastric aspirates, especially gram-negatives, increased significantly; (2) in 45 (31.7%) of the patients identical organisms were first isolated in gastric samples and one to two days later in tracheal secretions; (3) ventilation pneumonia was significantly more frequent in patients with high gastric pH; (4) pathogens causing ventilation pneumonia grew well in simulated gastric fluid at higher pH values, unlike normal respiratory organisms; and (5) sucralfate and bismuth subsalicylate showed antibacterial activity against frequent causative organisms of ventilation pneumonia.

Anti-Bacterial Agents↗
PubMed2000

Induction of peroxiredoxins in transplanted livers and demonstration of their in vitro cytoprotection activity.

Peroxiredoxin (Prx)-I and -II belong to a new class of antioxidants. Here, we report that they are induced by ischemia/reperfusion (I/R) in transplanted livers. Hypothesizing that Prxs are induced to protect liver from oxidative damage, we transduced these human genes into murine NIH-3T3 cells. The overexpressed Prxs made the cells more resistant to t-butylhydroperoxide-induced apoptosis. These results indicate that Prx-I and Prx-II are induced by the transplantation process and can protect cells against oxidant damage in tissue culture. Thus, proper genetic manipulations of Prxs may be useful in increasing the success rate of organ transplantation.

3T3 Cells↗
PubMedDate not supplied

Redox mechanisms of cytoprotection by Bcl-2.

Bcl-2 is a multifunctional protein that protects against cell death induced by a wide variety of stimuli. The best characterized antiapoptotic Bcl-2 mechanism of action involves direct binding to proapoptotic proteins, e.g., Bax, inhibiting their ability to oligomerize and form pores in the mitochondrial outer membrane, through which soluble mitochondrial proapoptotic proteins, e.g., cytochrome c, are released into the cytosol. Bcl-2 also exerts antiapoptotic and antinecrotic effects that are mediated by its influence on cellular redox state and apparently independent of its interaction with proapoptotic proteins. Bcl-2 expression increases cell resistance to oxidants, augments the expression of intracellular defenses against reactive oxygen species, and may affect mitochondrial generation of superoxide radicals and hydrogen peroxide. This review focuses on the protective effects of Bcl-2 related to changes in mitochondrial redox capacity.

Animals↗
PubMed2003

Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients.

BACKGROUND: A phase III multicenter randomized trial has been designed in order to address whether amifostine (WR-2721, Ethyol), an organic thiophosphate cytoprotector, can protect ovarian cancer patients from toxicity induced by carboplatin-paclitaxel chemotherapy. PATIENTS AND METHODS: Patients were randomly assigned to receive carboplatin [area under the curve (AUC) 5 mg.min/ml] and paclitaxel (175 mg/m(2)) with (arm A) or without (arm B) amifostine (910 mg/m(2)) every 21 days for six cycles. RESULTS: One-hundred and eighty-seven patients were accrued: 93 patients in arm A and 94 patients in arm B. There was no difference in terms of erythrocytopenia between the two arms; grade 3-4 thrombocytopenia was higher in arm A (3.3% versus 0.6%; P = 0.0010). There was no significant reduction of grade 3-4 leukopenia in arm A (11.8% versus 13.8%). The incidence of grade 3-4 neutropenia was lower in arm A (31.3% versus 37.9%; P = 0.03), as was the incidence of severe mucositis (4.7% versus 15.4% in arm A versus arm B, respectively; P <0.0001). Finally, amifostine appears to be protective against neurotoxicity (grade 3-4 neurotoxicity 3.7% versus 7.2%; P = 0.02). With a median follow-up of 24 months (range 2-41), time to progression was similar between the two groups. CONCLUSIONS: We showed that amifostine can exert some protection from the cumulative toxicity associated with this regimen. The results need to be confirmed in other randomized trials with this combination.

Adult↗
PubMed1993

Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle.

Ca2+ overload is known to play a major role in cell dysfunctioning in ischaemia/reperfusion and in cardiac glycoside intoxication. Suppression of Ca2+ overload or its consequences may therefore improve cellular function in these pathological conditions. Recent evidence suggests that Ca2+ overload occurs secondary to Na+ overload. Both depressed efflux and increased influx mechanisms have been mentioned as factors contributing to Na+ load. Prevention of this initial Na+ overload, without interfering with the normal Na+ current during the action potential, may therefore represent a novel pharmacological approach in the management of Ca2+ overload. The new cardioprotective drug R 56865 potently protects the heart against Ca2+ overload: ischaemia induced and ouabain induced arrhythmias and cell death are prevented in the absence of negative inotropism (no L-type Ca2+ channel blockade). At least three interactions at the cellular level may be held responsible for protection in these conditions. First, excessive Na+ entry into myocardial cells due to non-inactivating Na+ channels in depolarised cells is inhibited at concentrations that do not affect action potential configuration or contractile force. This leads to prevention of Na+ overload and subsequent Ca2+ overload and cell death. Second, R 56865 inhibits the transient inward current in Ca(2+)-(over)loaded cells, thus effectively preventing after-depolarisations and triggered propagated contractions. It has been proposed that R 56865, independent of its action on Na+ loading, might reduce oscillatory Ca2+ release from the intracellular Ca2+ stores, without interfering with the normal release mechanisms. Third, the drug attenuates K+ efflux in Na+ and Ca2+ loaded cells. In this way, R 56865 may contribute to prevention of action potential shortening and inhomogeneous repolarisation.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzothiazoles↗
PubMed1993

Myocardial cytoprotection during percutaneous transluminal coronary angioplasty.

Transluminal coronary angioplasty (PTCA) is a well defined controlled model inducing regional myocardial ischaemia in man. Direct cardiac anti-ischaemic effects of anti-anginal drugs can be assessed by intracoronary injection of small doses which do not affect systemic parameters. Trimetazidine (TMZ) has recently been shown to improve anginal symptoms without modifying haemodynamic variables. A randomized, double-blind, placebo-controlled trial was conducted in 20 patients to study the effects of TMZ on the severity of myocardial ischaemia during PTCA of the left anterior descending coronary artery. Five minutes after a first successful dilation (D0), a control balloon inflation (D1) was performed until onset of ischaemic signs on both the intracoronary (i.c.) and precordial ECG. Two minutes later, patients received either trimetazidine 6 mg or placebo i.c. Another inflation (D2) was performed 5 min after D1. No differences were found between the two groups regarding responses in heart rate, systemic and i.c. pressures during the study. TMZ decreased maximum ST segment shift at D2 as compared to D1 (0.8 +/- 0.1 vs 1.4 +/- 0.3 mV, P = 0.023) and delayed its onset (46 +/- 4 vs 36 +/- 5 s, P = 0.024). TMZ also decreased maximum T wave changes (1.06 +/- 0.24 vs 2.19 +/- 0.3 mV, P = 0.001), and significantly reduced the area under the curve (AUC:mV.s-1) of the i.c. ST segment and T wave changes during balloon inflation (P = 0.002 and P < 0.001 respectively). Placebo had no effect on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1996

Bactericidal effect of plaunotol, a cytoprotective antiulcer agent, against Helicobacter pylori.

In order to investigate the bactericidal effect of plaunotol, an oily antiulcer agent, against Helicobacter pylori, comparative studies were conducted using its derivatives, M-4, M-5, and M-6, whose hydrophobicity decreased in the order of plaunotol > M-6 > M-5 > M-4 by log P determination. Plaunotol rapidly reduced the viability of H. pylori in vitro, and cell death was associated with cell lysis. In addition, plaunotol showed eightfold stronger bactericidal activity against H. pylori than M-6 and M-5, while the compound with the lowest hydrophobicity, M-4, showed no bactericidal activity. The bactericidal activities of plaunotol and its derivatives were related to the hydrophobicity of these compounds. To investigate a possible interaction between these compounds and the cell membrane of H. pylori, their effects on liposomal membranes prepared from phosphatidylethanolamine and cardiolipin, which are known to be present in the membrane of H. pylori, were determined by detection of glucose release from the liposomes. Plaunotol showed eight-fold higher activity than M-6 and M-5, while M-4 showed no activity. The effects of plaunotol and its derivatives on liposomal membrane were therefore related to their bactericidal activities. In addition, it was confirmed that the bactericidal effect of plaunotol against H. pylori was neutralized by the liposomal membrane, and that plaunotol led to an increase in permeability of the membrane, as evidenced by measurement of the leakage of 260 nm absorbing-material from H. pylori. These results suggest that the bactericidal effect of plaunotol against H. pylori is due to the interaction between this compound and the bacterial cell membrane.

Anti-Bacterial Agents↗
PubMed2006

Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury.

Tissue reoxygenation following hypoxia is associated with ischemia-reperfusion injury (IRI) and may signal the development of ischemic preconditioning, an adaptive state that is protective against subsequent IRI. Here we used microarray RNA analysis of in vivo and in vitro models of IRI to delineate the underlying molecular mechanisms. Microarray analysis of renal tissue after ischemia-reperfusion revealed a number of highly up-regulated antioxidant genes including aldehyde dehydrogenases (ALDH1A1 and ALDH1A7), glutathione S-transferases (GSTM5, GSTA2 and GSTP1), and NAD(P)H quinone oxidoreductase (NQO1). The transcription factor NF-E2-related factor-2 (Nrf2), a master regulator of this antioxidant response, is also elevated in IRI. Furthermore, microarray analysis of renal epithelial cells exposed to hypoxia/reoxygenation identified Nrf2 to be up-regulated on reoxygenation. We also reveal a reoxygenation-specific nuclear accumulation of Nrf2 protein and subsequent activation of a NQO1 promoter reporter construct. Attenuating reactive oxygen species (ROS) in reoxygenation using the antioxidant N-acetyl cysteine results in inhibition of Nrf-2 activation. mRNA levels for Nrf2-dependent genes were detected in human liver biopsy 1 h after transplantation. These results indicate that reoxygenation-dependent Nrf-2 activity facilitates ischemic preconditioning through the induction of antioxidant gene expression and that ROS may be critical in signaling this event.

Animals↗
PubMed2000

Pilot trial of cytoprotection with amifostine given with high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

In an attempt to limit toxicities associated with dose-intensive therapy used for transplant regimens, we performed a pilot study using amifostine with high-dose busulfan (12 mg/kg), melphalan (100 mg/m2), and thiotepa (500 mg/m2) in 21 patients with a variety of malignancies. After 3 days of oral busulfan, amifostine was given at 910 mg/m2 IV for 10 minutes, preceding the infusion of each of 2 doses of melphalan and thiotepa given for 4 days. Antiemetic premedication for amifostine was given to all patients. The median patient age was 50 years (range: 32-65 years). Twenty-one patients received 82 separate amifostine infusions. One patient discontinued amifostine after the second dose because of severe nausea and emesis, and two infusions were temporarily held secondary to hypotension. Of these 82 cycles, there was a total of 37 episodes of nausea/vomiting, 28 episodes of sneezing, 11 episodes of flushing, and 1 episode of oral paresthesia. Systolic blood pressure and mean arterial pressure decreased by a mean of 8.4 mm Hg and 5.0 mm Hg, respectively. In general, the infusion was well tolerated. Patients were observed until discharge home (N = 15), until initiation of an additional tandem transplant procedure (N = 4), or until death (N = 2). All twenty-one patients experienced nonhematologic toxicities grade II or greater. Grade II toxicities included mucositis (N = 21), gastrointestinal (N = 3), skin (N = 1), and liver (N = 1), and grade III toxicities included liver (N = 1). Mucositis was also scored according to a detailed toxicity assessment. Mucositis did not appear to be improved with amifostine when compared with a control group of patients not receiving amifostine. Renal dysfunction after transplantation was decreased in the amifostine group, whereas there was no significant effect on posttransplant hepatic dysfunction. Although these data demonstrate the feasibility of delivering parenteral amifostine in conjunction with dose-intensive chemotherapy and autologous peripheral blood stem cell transplantation, there was no evidence of a significant reduction in nonmarrow toxicities.

Adult↗
PubMed2001

Pharmacologic study of paclitaxel administered with or without the cytoprotective agent amifostine, and given as a single agent or in combination with epirubicin and cisplatin in patients with advanced solid tumors.

The main purpose of this study was to investigate whether the coadministration of amifostine alters the pharmacokinetic behavior of paclitaxel. Eight patients were included in the study: six received paclitaxel in combination with epirubicin and cisplatin, and two received paclitaxel as a single agent. Doses of paclitaxel in these protocols were 135, 150, 175, and 200 mg/m(2) and two patients were treated at each dose level. Pharmacokinetic sampling for paclitaxel analysis was performed in each patient during two consecutive cycles, one with and one without amifostine (750 mg/m(2) as a 15-minute intravenous infusion 30 minutes before paclitaxel administration). At each dose level, the pharmacokinetic data of paclitaxel were compared per patient for a cycle without amifostine versus a cycle with amifostine. Amifostine did not seem to interact pharmacokinetically with paclitaxel, given either alone or in combination chemotherapy. This is in line with the clinical findings that amifostine has no negative effects on the antitumor activity of various antineoplastic agents. Also, amifostine may reduce toxic effects of combination chemotherapy regimens that include paclitaxel.

Amifostine↗
PubMed1991

Gastric mucosal cytoprotection in the rat by scavenging oxygen-derived free radicals.

Oxygen-derived free radicals are cytotoxic and promote tissue damage. Dimethyl sulfoxide (DMSO) and allopurinol scavenge hydroxyl radicals, and the latter agent also inhibits the enzyme xanthine oxidase, which is responsible for the formation of superoxide anions. These agents were given daily by gavage (1 ml/d). After 2 days of administration as 1, 2, or 5% solutions, the H+ output of the rat with or without pyloric ligation was not significantly affected. After six hours reserpine (5 mg/kg i.p.) or serotonin (50 mg/kg i.p.) produced ischemic mucosal injury in all stomachs (39 +/- 5.2 mm2 and 25.9 +/- 2.8 mm2, mean +/- standard error of the mean [SEM], n = 10). Pretreatment for 2 days with 1 ml/d of 1% allopurinol or DMSO significantly (p less than 0.001) protected the rat against the reserpine (23 +/- 2.1 mm2 and 24 +/- 1.9 mm2, respectively, vs 39 +/- 5.2 mm2, n = 10) and serotonin injury (10 +/- 1.5 mm2 and 11 +/- 1.8 mm2, respectively, vs 25.9 +/- 2.8 mm2, n = 10). However, 2 days pretreatment with 1 ml/d of 2% allopurinol or DMSO was more effective (p less than 0.001) in this respect, and injury only developed in 40% of the rats given reserpine (8 +/- 1.2 mm2 and 9 +/- 1.6 mm2) and in 20% of those given serotonin (2.4 +/- 0.4 mm2 and 1.9 +/- 0.5 mm2). Similar pretreatment with 5% solutions completely protected the rat stomach against the reserpine and serotonin injuries without significantly influencing the H+ output.(ABSTRACT TRUNCATED AT 250 WORDS)

Allopurinol↗
PubMed1985

Cytoprotective effect of pentagastrin and epidermal growth factor on stress ulcer formation. Possible role of somatostatin.

This study was designed to test the effects of pentagastrin and epidermal growth factor (EGF) on stress-induced ulceration and on the antral content of gastrin and somatostatin (SLI) in rats. Four groups of 14 to 15 rats had been prepared for 7 days by one of the following methods: saline injection (control); injection of pentagastrin (250 micrograms/kg, 3 times/day); injection of EGF (10 micrograms/kg, 3 times/day); or injection of EGF plus pentagastrin. At the end of the treatment period, half of each group of rats were sacrificed (nonstress group). There were no ulcers in the nonstress control groups of rats. Stress was applied by water immersion in the remaining half of the rats. The injections of pentagastrin and/or EGF resulted in substantial increase in antral content of SLI. After 20 hours of stress, the ulcer index was 40.5 +/- 3.3 in the controls, compared to 6.4 +/- 1.2 and 16.2 +/- 2.3 in rats that received pentagastrin or EGF, respectively. Injections of both pentagastrin and EGF resulted in an ulcer index of 26.2 +/- 2.0, which was significantly lower than that in controls, but higher than that in rats treated with either peptide alone. The stress resulted in significant decrease in antral SLI in all groups of rats, whereas SLI content in rats treated with pentagastrin and/or EGF remained significantly higher than that of controls. Antral content of gastrin did not differ significantly in the four groups tested. The ulcer index was inversely correlated with antral SLI content. We confirm and extend previous observations that pentagastrin and EGF prevent stress ulcer formation, and suggest that endogenous SLI may account, at least in part, for their antiulcer activity.

Animals↗
PubMed1995

Potential treatment of Alzheimer disease using cholinergic channel activators (ChCAs) with cognitive enhancement, anxiolytic-like, and cytoprotective properties.

Compounds that activate neuronal nicotinic acetylcholine receptors (nAChRs) may have potential benefit in the treatment of dementia, especially Alzheimer disease (AD). This article summarizes the preclinical pharmacology of ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole], a novel analog of (-)-nicotine that is being clinically evaluated for the treatment of AD. ABT-418 is a cholinergic channel activator (ChCA) with cognitive enhancement and anxiolytic-like activity possessing a substantially reduced side-effect profile compared to (-)-nicotine [Arneric SP, Sullivan JP, Briggs CA, et al. (S)-3-Methyl-5-(1-Methyl-2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with cognition enhancing and anxiolytic activity. I. In vitro activity. J Pharmacol Exp Ther 1994 ;270:310-318; Decker MW, Brioni JD, Sullivan JP, et al. (S)-3-Methyl-5-( 1-Methyl-2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther 1994a;270:319-328; Decker MW, Curzon P, B rioni JD, Arne ric SP. Effects of ABT-418, a novel cholinergic channel ligand, on place learning in septal-lesioned rats. Eur J Pharmacol 1994;261:217-222; Garvey DS, Wasicak JT, Decker MW, et al. Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities. J Med Chem 1994;37:1055-1059]. ABT-418 may be the first agonist of nAChRs to be developed and evaluated specifically for the treatment of AD. Some brief speculation will be given on the potential benefits that this or other ChCAs may have in treating neurodegenerative disorders as compared with (-)-nicotine, and how this differs from other potential treatment approaches.

Alzheimer Disease↗