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PubMed2004

Overexpression of HSP-72 confers cytoprotection in experimental peritoneal dialysis.

BACKGROUND: Peritoneal dialysis is complicated by mesothelial cell injury due to low biocompatibility of peritoneal dialysis fluid (PDF). We have previously demonstrated that heat shock protein (HSP)-72 is potently up-regulated in response to PDF exposure of mesothelial cells in in vitro and in vivo models of peritoneal dialysis. The aim of this study was to evaluate potential cytoprotective effects of overexpression of HSP-72. METHODS: Cytoprotection was assessed by comparing cellular viability between pretreated versus nonpretreated human mesothelial cells (Met 5a; ATCC, Manassas, VA, USA, and primary cell cultures) subjected to extended, usually lethal PDF exposure times (120 min, CAPD2; Fresenius, Bad Homburg, Germany). Pretreatment was performed with exposure to PDF (60 min, CAPD2; Fresenius) or heat (15 min, 41.5 degrees C), and by transient transfection with HSP-72. RESULTS: When mesothelial cells were pretreated by nonlethal exposure to PDF or heat, HSP-72 was markedly up-regulated (>5-fold, P < 0.01). Pretreated human mesothelial cells were significantly protected against subsequent "lethal" exposures to PDF, as assessed by dye exclusion (>50% reduction, P < 0.05) and lactate dehydrogenase (LDH) release (>30% reduction, P < 0.05). Comparable cytoprotection (50% reduction by dye exclusion) was indicated by overexpression of HSP-72 in cultered human mesothelial cells (>5-fold) after transient transfection with HSP-72. This cytoprotection was confirmed at a cellular basis by double staining techniques with HSP-72 and ApopTag (apoptosis detection kit). CONCLUSION: Our study therefore shows that the mesothelial stress response confers cytoprotection in experimental peritoneal dialysis, mediated by the induction of HSP-72, and that the stimulus of the pretreatment does not have to be identical to the subsequent injury. These data offer the basis for an attractive novel therapeutic approach against PDF toxicity.

Cell Line, Transformed↗
PubMed1988

Morphological characteristics of prostaglandin cytoprotection.

The term "cytoprotection" originally described the ability of prostaglandins, independent of their known antisecretory activity, to prevent macroscopic evidence of gastric injury induced in different animal models under various experimental conditions. Several recent reports have challenged this concept because the apparent macroscopic protection could not be confirmed microscopically. To determine whether prostaglandins do indeed possess cytoprotective properties, and if such effects are dependent on the dose and the route of prostaglandin administration, studies were performed using 16,16 dimethyl prostaglandin E2 (PGE2) and the known gastric damaging agent, ethanol. Fasted rats received either oral or subcutaneous PGE2 in doses of 10 or 20 micrograms/kg or equal volumes of saline. Thirty minutes later, animals were given a 1-ml oral bolus of 50% or 100% ethanol or an equal volume of saline. At 5 minutes to 24 hours following ethanol, animals were sacrificed, and tissues from the glandular portion of the stomach were removed for histologic quantification of injury. At 5 minutes following ethanol, PGE2 reduced the depth of injury, but had no protective effects against surface cell damage when compared with control animals. By 24 hours after ethanol, most of the PGE2-treated mucosa was repaired. Oral administration of 10 micrograms/kg PGE2 was more cytoprotective at 5 minutes after ethanol than when administered by subcutaneous injection. This relationship was not true for the 20 micrograms/kg dose. We conclude that cytoprotection can be confirmed histologically, but is limited primarily to the deep mucosa. The ability of PGE2 to enhance healing is probably related to the prevention of deep mucosal injury, which thereby allows epithelial reconstitution to occur. Lastly, the effectiveness of PGE2 as a cytoprotective agent is dose- and route-dependent.

Animals↗
PubMed1984

The studies on the role of gastric glycoproteins with reference to cytoprotection: protective effect of prostaglandin E2 and sofalcone on ethanol-induced necrosis.

The gastric cytoprotective action of prostaglandin E2 (PGE2) and sofalcone was studied in rats. The in vitro incorporating activity of 3H-glucosamine into the gastric macromolecular glycoproteins was examined when PGE2 (0.1 mg/kg, p.o.) or sofalcone (100 mg/kg, i.p.) was administered 5, 15 or 30 min before the oral administration of absolute ethanol. The cytoprotective effect of PGE2 against gastric mucosal damage was demonstrated 5 min after PGE2 was given orally. The cytoprotective effect by sofalcone was seen after 15 min. However, during this period, the decrease in gastric macromolecular glycoprotein synthesis induced by the ethanol damage could not be restored by pretreatment with PGE2 or sofalcone. On the other hand, the reduction in the content of the gastric macromolecular glycoproteins by the ethanol damage was found to be prevented to a significant extent by pretreatment with PGE2. The same phenomenon was also observed in the administration of sofalcone. Accordingly, PGE2 has stimulating effect on the gastric glycoproteins biosynthesis, but this effect can not be considered as the mechanism responsible for cytoprotection, if indeed a single mechanism exists. Thus, it is suggested that the adhesion or maintenance of secreted macromolecular glycoproteins to the gastric tissue is closely related to cytoprotection.

Animals↗
PubMed1994

Cytoprotective effect of NC-1300-O-3 against gastric lesions induced by necrotizing agents in rats.

The cytoprotective effect of NC-1300-O-3 and its mechanism of action were investigated. NC-1300-O-3 at doses of 3 and 10 mg/kg, p.o. significantly prevented the formation of gastric lesions by HCl.ethanol in rats, and its efficacy was not influenced by repeated administration for up to 4 weeks. The interaction between NC-1300-O-3 and necrotizing agents in the stomach, which is considered to be related to the development of cytoprotection, was not observed. A preventive effect of NC-1300-O-3 against gastric lesions was observed at the same dose even when gastric secretion was completely inhibited by pretreatment with omeprazole. This suggests that the cytoprotective effect of NC-1300-O-3 is an action on the gastric mucosa independent of its antisecretory effect. The cytoprotective effect of NC-1300-O-3 was not affected by pretreatment with indomethacin but was partly decreased by N-ethylmaleimide pretreatment, suggesting the participation of endogenous sulfhydryl compounds in the action of NC-1300-O-3. This compound dose-dependently increased the hexosamine content in the gastric lumen in rats at a dose range of 3-30 mg/kg, p.o. and slightly inhibited a reduction in surface mucus and mucosal hexosamine content caused by necrotizing agents. Moreover, NC-1300-O-3 at doses of 10 and 30 mg/kg, p.o. significantly inhibited the increased gastric vascular permeability caused by alcohol treatment; and at 30 mg/kg, p.o., it inhibited the reduction in potential difference caused by aspirin in rats. These actions were suggested to contribute to the cytoprotective effect of NC-1300-O-3.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

Implication of sensory neurons in the diverse mechanisms of adaptive cytoprotection in the rat stomach.

Adaptive cytoprotection is mediated by diverse mediators and mechanisms. We investigated the implication of capsaicin-sensitive afferent neurons in the adaptive cytoprotection in the rat stomach, taking special notice of nitric oxide, prostaglandins and luminal dilution. Sensory deafferentation abolished the protective effect of capsaicin against 0.6 N HCl-induced gastric injury but not the indomethacin-resistant or NG-nitro-L-arginine-resistant adaptive cytoprotection conferred by 0.1 N NaOH. Nor did it attenuate the protection by 0.35 N HCl which accompanied luminal dilution. These findings suggest that certain mild irritants do not require sensory neurons to provide nitric oxide- and prostaglandins-mediated adaptive cytoprotection and, furthermore, that capsaicin-sensitive afferent neurons are not crucial, either, so long as there is a contribution of luminal dilution in the adaptive cytoprotection.

Animals↗
PubMed1987

Cytoprotective drugs. Focus on essential fatty acids and sucralfate.

Cytoprotection has been defined as an ability of prostaglandins to prevent gastric mucosal injury produced by a variety of ulcerogenic and necrotizing agents without inhibition of gastric acid secretion or without neutralizing intragastric acidity. Since the first demonstration of cytoprotection by prostaglandins many other agents have been claimed to be cytoprotective. Essential fatty acids: arachidonic and linoleic, licorice products, sucralfate, antacids and sulfhydryl compounds all possess cytoprotective properties. All of these compounds are able to prevent or reduce gastric mucosal necrosis produced by absolute ethanol, a necrotizing agent which injures mucosa independently of the luminal pH. Gastric mucosal protection by essential fatty acids is mediated by their conversion by the gastric mucosa to protective prostaglandins. Sucralfate and antacids are also cytoprotective compounds which stimulate release of endogenous prostaglandins from the gastric mucosa.

Animals↗
PubMed1999

The potential of amifostine: from cytoprotectant to therapeutic agent.

BACKGROUND AND OBJECTIVE: Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of free thiol that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs, and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. In fact, pretreatment with amifostine was well tolerated and reduced the cumulative hematologic, renal and neurological toxicity associated with cisplatin, cyclophosphamide and vinblastine therapy of advanced and metastatic solid tumors. The objective of this review is to focus the importance of amifostine as a myeloprotective and cytoprotective drug during treatment with chemotherapeutics, presenting the most recent results, and to discuss the application of amifostine in the therapy of myelodysplastic syndromes. EVIDENCE AND INFORMATION SOURCES: The material analyzed in this study includes data published or under publication by the authors as full papers or clinical protocols. Articles and abstracts published in Journals covered by Medline constitute the other source of information. STATE OF THE ART AND PERSPECTIVES: Amifostine, formerly known as WR-2721, is an organic thiophosphate that was developed to protect normal tissues selectively against the toxicities of chemotherapy and radiation. Amifostine is a pro-drug that is dephosphorylated at the tissue site to its active metabolite by alkaline phosphatase. Differences in the alkaline phosphatase concentrations of normal versus tumor tissues can result in greater conversion of amifostine in normal tissues. Once inside the cell the free thiol provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapies. Preclinical animal studies demonstrated that the administration of amifostine protected against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity, and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine was shown to protect a variety of animal species from lethal doses of radiation. Studies in tumor-bearing animals demonstrated that the administration of amifostine results in cytoprotection without loss of antitumor activity. Multiple phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose regimen, and 340 mg/m(2) in a multiple dose regimen. Amifostine afforded not only hematologic protection, but also other organ protection from cytotoxic agents such as nephrotoxicity, mucositis and peripheral neuropathy from cisplatin. Many studies have been performed to investigate cytoprotective efficacy of amifostine. In brief, amifostine gives hematologic protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin, and salivary gland from radiotherapy. In phase I/II studies these properties have been confirmed, together with a generally good tolerability of the drug, hypotension being the most common side effect. It has been observed that amifostine possibly enhances the anti-tumor effect of carboplatin, nitrogen mustard, melphalan, and cisplatin combined with 5-FU or vinblastine. For all these characteristics, amifostine is at present broadly used as supportive treatment during chemotherapy, in lymphomas and solid tumors, and its spec

Amifostine↗
PubMed1992

The mechanism of cytoprotective effect of CHINOIN-127.

According earlier, investigations nitrogen bridgehead compounds make a representative group of non-prostaglandin type gastroprotective agents. One member of this group is CHINOIN-127 (1,6-dimethyl-4-oxo-1, 6, 7, 8, 9, 9a-hexahydro-4H-pyrido-(1, 2a)-pyrimidine-3-carbox-amide). CHINOIN-127 is a potent non-narcotic analgesic and antiinflammatory agent and has a remarkable protective effect on indomethacin induced ulcer (ED50 = 25 mg/kg p.o.) and on acidified ethanol induced ulcer (ED50 = 26 mg/kg p.o.). In this study we examined the mechanism of action of cytoprotective effect of this drug and we made a comparison between the cytoprotective effect of 20% ethanol and 25 mg/kg CHINOIN-127. In the gastric mucosa of control rats we observed a balance between TxA2 and PGI2 (PGI2/TxA2 = 3.8) and between the cytoprotective prostaglandins (PGI2 and PGE2) and ulcerogen eicosanoids (TxA2 and leukotrienes) (PGI2 + PGE2/TxA2 + LTs = 3.9). 100% ethanol treatment causes disintegration of this balance, shifting the synthesis towards the ulcerogen eicosanoids production. CHINOIN-127 and 20% ethanol pretreatment improves the deranged balance between cytoprotective prostaglandins and ulcerogen eicosanoids. Our results demonstrate that CHINOIN-127 and 20% ethanol have a similar mechanism of cytoprotective action on ethanol induced ulcer in rats.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Gastric cytoprotection.

The term 'cytoprotection' means protection against gastric mucosal injury by a mechanism other than inhibition or neutralisation of gastric acid. Several mechanisms of gastric cytoprotection have been proposed like increased mucus and bicarbonate secretion, strengthening of gastric mucosal barrier, increased gastric mucosal blood flow, decreased gastric motility, increased formation of prostaglandins and sulfhydryls, scavenging of free radicals, stimulation of cellular growth and repair, decreased release of leukotrienes etc. Some of the drugs widely used in therapy of peptic ulcer are cytoprotective e.g. sucralfate, colloidal bismuth and aluminium containing antacids. As the concept of gastric cytoprotection is becoming widely accepted, the list of drugs which have shown a cytoprotective action in animal experiments is growing rapidly. This list includes zinc sulphate, meciadanol, propranolol, dipyridamole etc.

Gastric Mucosa↗
PubMed1989

Effect of atropine, PGF2 alpha and cimetidine on the beta-carotene induced cytoprotection in ethanol-treated rats.

The aim of the study was to evaluate the influence of atropine, PGF2 alpha and cimetidine on the gastric cytoprotective effect of beta-carotene. Mucosal damage was produced by intragastric (i.g.) addition of 96% ethanol in CFY-strain rats of both sexes weighing 180-220 g. Gastric cytoprotection caused by i. g. pretreatment with 1.0 mg/kg beta-carotene 30 minutes before ethanol administration, was observed after 1 hour. Atropine (0.5 mg/kg), cimetidine (50 mg/kg) and PGF2 alpha (200 micrograms/kg) were given intraperitoneally (i.p.) 30 minutes before ethanol administration with and without beta-carotene and the changes in the number and severity of the gastric ulcers were detected. PGF2 alpha did not influence the gastric cytoprotective effect of beta-carotene meanwhile it was inhibited by atropine and markedly by cimetidine. Deleterious effect of cimetidine on the beta-carotene-induced cytoprotection may be explained perhaps by the adverse effect of the two compounds on ATP-cAMP transformation hereby counteracting one another, but more data are needed to the better understanding of drug interactions relating to mucosal cytoprotection.

Animals↗
PubMed1989

Cytoprotective and antiulcer activities of the antacid magaldrate in the rat.

The cytoprotective and antiulcer activities of the antacid magaldrate (ES Riopan) as well as its effects on gastric mucosal blood flow and mucus secretions, were determined in the rat. Magaldrate afforded protection against gastric necrotic lesions induced by absolute ethanol (ED50, as magaldrate, 419 mg/kg); gastric ulcers induced by acidified acetylsalicylic acid (ED50 540 mg/kg), stress (cold restraint, ED50 388 mg/kg), indometacin (ED50 281 mg/kg), and pylorus ligation; and intestinal ulcers induced by cysteamine (ED50 243 mg/kg) and indometacin (ED50 184 mg/kg). At a dose of 8 ml/kg (1728 mg/kg magaldrate), the cytoprotective effect of magaldrate against ethanol was evident 1 min after oral administration and lasted more than 8 h. The cytoprotection induced by magaldrate was decreased by pretreatments with the depletor of endogenous thiols, n-ethylmaleimide, or with the cyclooxygenase inhibitor, indometacin. Magaldrate did not affect gastric mucosal blood flow, but it increased gastric mucus secretion. This later effect may be a factor responsible for the cytoprotective activity of the agent. The efficacy of magaldrate may be due not only to its antacid, bile sequestering, and antipeptic activities, but also to its cytoprotective activity. The present results suggest that magaldrate could be effective in preventing gastric damage caused by alcohol and antiinflammatory drugs.

Aluminum Hydroxide↗
PubMed1986

Cytoprotective properties of somatostatins.

Secretion of many hormones is inhibited by regular cyclic somatostatin-14. Since additional cytoprotective properties of this hormone have been described, the question arises of whether analogs of somatostatin with increased endocrine activity may also exert increased cytoprotective activity. It could be shown that the endocrine and the cytoprotective property of somatostatin-14 must have different modes of action. In analogs of somatostatin with increased endocrine activity the cytoprotective effect is also increased. A maximal increase in the cytoprotective effect of certain analogs of somatostatin is accompanied by a loss of endocrine activity.

Amino Acid Sequence↗
PubMed1986

Cytoprotection and prostaglandins.

Among substances producing gastrointestinal cytoprotection, prostaglandins are the most potent. They protect the mucosa after either exogenous administration or stimulation of endogenous release by the stomach. The first type is called "direct" cytoprotection, and the second "adaptive" cytoprotection. Certain agents are cytoprotective by a mechanism other than endogenous formation of prostaglandins. Depletion of the gastrointestinal tract of prostaglandins by administration of nonsteroidal antiinflammatory compounds or corticosteroids can lead to ulcer formation. The mechanism of cytoprotection is unknown. It may involve stimulation of bicarbonate and mucus secretion, protection of the gastric mucosal barrier, and increase in mucosal phospholipid surfactants, and maintenance in mucosal blood flow, increase in sulfhydryl agents or increase in cellular resistance.

Animals↗
PubMed1983

Membrane-bound ATP-dependent energy systems and gastric cytoprotection by prostacyclin, atropine and cimetidine in the rat.

The effects were studied of different doses of prostacyclin (PG12), atropine and cimetidine on the gastric secretory responses of four-hour pylorus-ligated rats and on the gastric mucosal damage produced by intragastric administration of 0.6 M HCl, to determine the cytoprotective doses of PG12, atropine and cimetidine. In another series of observations, gastric mucosal damage was produced by intragastric administration of 0.6 M HCl and the effects were studied of cytoprotective doses of PG12, atropine and cimetidine on the number and severity of gastric lesions, in connection with the biochemical changes of the rat gastric fundic mucosa. The drugs were given intraperitoneally 30 min before the application of the necrotizing agent, and the animals were killed one hour later. During the experiments, the tissue levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and lactate were measured enzymatically, and the tissue content of cyclic adenosine monophosphate (cAMP) was determined by radioimmunoassay. The specimens were taken from the gastric fundic mucosa of groups of animals treated with saline solution (absolute control), with 0.6 M HCl (pathological control) and with 0.6 M HCl plus PG12, atropine and cimetidine (given in cytoprotective doses). The ratio of ATP.ADP-1, adenylate pool (ATP + ADP + AMP) and energy charge (ATP + 0.5 ADP.ATP + ADP + AMP-1) were calculated in all groups of animals. It was found that: (i) PG12 (in a dose of 5 micrograms.kg-1) atropine (in a dose of 0.025 mg.kg-1) and cimetidine (in a dose of 2.5 micrograms.kg-1) have cytoprotective effects; (ii) the gastric fundic mucosal damage produced by intragastric administration of 0.6 M HCl appears as a result of a positive metabolic adaptation of the gastric fundic mucosa; (iii) the development of gastric cytoprotection by PG12, atropine and cimetidine give rise to very different changes in the tissue levels of ATP, ADP, AMP and cAMP.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1984

PGF2 alpha mediated cytoprotection: a reassessment.

UNLABELLED: The demonstration of gastrointestinal ctyoprotection by PGF2 alpha (a supposed vasoconstrictor) has been cited as evidence against alteration of mucosal blood flow as a mechanism for the cytoprotection phenomenon. However, cytoprotection by PGF2 alpha has never been demonstrated in a model having concomitant documentation of gastrointestinal blood flow. This experiment was designed to accomplish two objectives. First, the effect of intravenous PGF2 alpha (0.1, 1.0, 10.0 mcg/kg/minute) on blood flow throughout the gastrointestinal tract was documented in a chloralose anesthetized miniature swine model (n = 7). Second, the effect of intravenous PGF2 alpha (1.0 mcg/kg/minute) on both gastric mucosal blood flow and stress ulceration was assessed during a 3-hour period of hemorrhagic shock in the same model (six controls, six PGF2 alpha). The radiolabeled microsphere technique of blood flow determination was employed. RESULTS: Intravenous PGF2 alpha significantly decreased myocardial blood flow at all doses employed. Although blood flow in the gastrointestinal tract tended to decrease with the largest dose of PGF2 alpha, this did not reach statistical significance. During shock PGF2 alpha had no effect on gastrointestinal blood flow. Furthermore, there was no evidence of gastric mucosal cytoprotection compared to controls. These results suggest that PGF2 alpha is neither vasoconstrictive nor cytoprotective when sub maximal doses are used. Dismissal of mucosal blood flow as a possible mechanism of prostaglandin-mediated cytoprotection is premature.

Animals↗
PubMed1983

[Anti-ulcerogenic and cytoprotective effects of trimoprostil (Ro 21-6937), a trimethylprostaglandin E2 derivative].

Anti-ulcerogenic effects of trimoprostil, a prostaglandin E2 (PGE2) derivative, were studied in comparison with those of PGE2, cimetidine and sulpiride. Trimoprostil and PGE2 given p.o. prevented the formation of gastric lesions produced by absolute ethanol, 0.2N NaOH, 0.6N HCI and hypertonic NaCl solutions in rats and aspirin-induced fecal occult bleeding in dogs. Although both prostaglandins did not alter the gastric mucus content, they equivalently prevented the stress-induced decrease in the mucus content in rats. The duration of these effects of trimoprostil was longer than those of PGE2. Cimetidine and sulpiride did not exert such cytoprotective effects. Trimoprostil inhibited stress-induced gastric ulcer formation in rats more markedly than PGE2, cimetidine and sulpiride. Trimoprostil and PGE2 at the cytoprotective dose (30 micrograms/kg, p.o.) did not change the gastric blood flow in conscious rats. In Shay rats, trimoprostil at doses larger than the cytoprotective doses inhibited the gastric acid secretion when given p.o., but was not effective when given i.d. PGE2 exerted the similar action, but the potency was clearly weaker than that of trimoprostil. In Heidenhain-pouch dogs, trimoprostil also inhibited the gastric acid secretion stimulated by pentagastrin more markedly than did cimetidine. In conclusion, trimoprostil at doses smaller than the antisecretory doses exerted gastric cytoprotective action with a longer duration than that of PGE2, probably through the preservation of the mucus barrier. Such cytoprotection was not found with cimetidine and sulpiride.

Animals↗
PubMed2003

Relative levels of cytoprotection produced by analogs of choline and the role of alpha7-nicotinic acetylcholine receptors.

Several analogs of the acetylcholine precursor molecule choline have been widely studied as potential false cholinergic neurotransmitters with the therapeutic goal of using them to limit cholinergic neurotransmission. More recently, choline itself has been shown to act as a full, if low potency, agonist at the alpha7 subtype of the nicotinic acetylcholine receptor. This pharmacological property has been associated with the ability of nicotine and other related alpha7 receptor agonists to offer neuroprotection in a variety of experimental models. We confirm here that choline offers a significant degree of protection against the cytotoxicity induced by growth factor deprivation in differentiated PC-12 cells. Choline-induced cytoprotection ( approximately 1 mM) was about 3 orders of magnitude less potent than that for nicotine (EC(50) = 0.7 microM). Choline also exhibited only about 40% of the full cytoprotective effect of nicotine. Ethyl substitution for choline's N-methyl groups did not result in a significant improvement over choline as a cytoprotective agent. In contrast, pyrrolidinecholine exhibited much greater potency (EC(50) = 20 microM) and increased efficacy (about 55% of nicotine's effect) than choline. Like choline and nicotine, pyrrolidinecholine fully displaced [(125)I]alpha-bungarotoxin binding (K(i) = 33 microM) and chronic exposure to the analog increased cell surface binding sites. The cytoprotective effects of the analog were completely inhibited by coincubation with methyllycaconitine (MLA), a selective alpha7-nicotinic receptor antagonist. These findings are consistent with the possibility that the choline structure may serve as a template for the development of novel agents with both alpha7-nicotinic agonist activity and potential neuroprotective ability, as many of these compounds, including pyrrolidinecholine, are transported along with choline into the central nervous system.

Animals↗
PubMed2005

Cytoprotection of PEG-modified adult porcine pancreatic islets for improved xenotransplantation.

Functional poly(ethylene glycol) (PEG) derivatives, including monosuccinimidyl PEG (MSPEG) with molecular weight (MW) of 2000 (2 kDa) as well as 5 kDa and disuccinimidyl PEG (DSPEG) with MW of 3 and 6 kDa, were synthesized and characterized. They were used to modify the surface of adult porcine islets for cytoprotection. The islets were isolated, purified and modified with functional PEG. Untreated porcine islets were used as control. An in vitro human antibody/complement-mediated cytotoxicity test based on the release of intracellular lactate dehydrogenase was used to evaluate cytotoxicity of human serum to the modified islets. In vitro cell viability was assessed using membrane-integrity straining and islet metabolism in culture. In vitro islet functionality was evaluated by glucose-stimulated insulin release of islets in static incubation with human serum. In vivo islet functionality was evaluated by monitoring non-fasting blood glucose level in streptozotocin-induced diabetic (SCID) immunocompromized mice after intraportal transplantation of porcine islets. Results show that all the PEG derivatives used in the study showed significant in vitro and in vivo cytoprotections against cytotoxic effects elicited by human serum and diabetic SCID mice, respectively, to porcine islets. DSPEG derivatives combined with human albumin exhibited a better cytoprotection, as compared to MSPEG ones, due to the capacity of the succinimidyl groups to selectively react with amino groups of the albumin under physiological conditions. The effects of both MW and concentration of the PEG derivatives on cytoprotection were significant. It appears that this novel biotechnology will be an attractive approach for improved xenotransplantation of islets.

Animals↗