piperidines and bis(1-hydroxy-2-2-6-6-tetramethyl-4-piperidinyl)decandioate

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate called IAC, is a new non-peptidyl low molecular weight radical scavenger able to give a fast reaction with the majority of radical species involved in the oxidative stress. This intrinsic property might be of particular interest in all the processes where it presents an over production of reactive oxygen/nitrogen species (ROS/RNS) such as inflammation. Indeed, it is well known that systemic inflammatory response is associated with the production of ROS, nitric oxide (NO), which in turn deplete the endogenous GSH, mediating cytotoxicity. It has been shown that IAC through its antioxidant activity, exerted a protective effect in vitro in islets isolated from type-2 diabetic patients, and in vivo in a non-obese diabetic mouse model and in DNBS-induced colitis in rats. The ability of IAC to protect brain from ischemia, suggests a possible use of the compound in broad range of inflammatory- related diseases. It is well known that the use of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of untoward side-effects such as gastrointestinal ulceration. The major pathogenetic element in the development of these effects is the depletion of prostaglandins (PGs) through inhibition of cyclooxygenase. The evidence that IAC protects gastric mucosa in an animal model of indomethacin-induced ulcer, through local increase of PGE2 levels and antioxidant activity, candidates this compound as a novel, promising, anti-inflammatory compound avoiding the major common untoward side-effects elicited by NSAID's.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Free Radical Scavengers; Free Radicals; Humans; Inflammation; Mice; Piperidines; Rats

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), is an innovative non- radical scavenger used with success in numerous disease models such as inflammation, neurological disorders, hepatitis and diabetes. The pharmacological treatments have been performed by the intraperitoneal route of administration, representing to date, the main limit for the drug use. The aim of this study was to develop a delivery system that allows the oral administration of IAC while maintaining its therapeutic efficacy. Solid Lipid Microparticles (SLMs) containing a theoretical 18% (w/w) of IAC have been produced by the spray congealing technology; three formulations have been tested (A, B and C) using different low melting point carriers (stearic acid, Compritol(®) HD5ATO and carnauba wax) alone or in combination. All IAC loaded SLMs exhibited a spherical shape, encapsulation efficiency higher than 94% and particle size suitable for the oral route. Administered per os at different dosages in an inflammation rat model, all SLMs demonstrated their efficacy in reducing oedema and alleviating pain, compared to the gold standards Indomethacin and Paracetamol. These results suggested that the SLMs are an efficacious delivery system for the oral administration of IAC, potentially useful for the treatment of others diseases related to an over production of free radicals.

Topics: Acetaminophen; Administration, Oral; Animals; Disease Models, Animal; Free Radical Scavengers; Glycerol; Indomethacin; Inflammation; Liposomes; Male; Particle Size; Piperidines; Polyethylene Glycols; Rats; Stearic Acids; Waxes

In this research we investigated the anti-inflammatory activity of a non-peptidyl low molecular weight radical scavenger (IAC) in an acute and chronic animal model of inflammation.. For this purpose the effect of IAC (10, 25, 50 mg/kg) was tested in rats on the associated behavioral responses to subsequent inflammatory and noxious challenges, such as hind paw oedema induced by intra-plantar injection of carrageenan and granuloma induced by subcutaneous implant of a cotton pellet, using indometacin (2.5 mg/kg) as reference drug. Moreover, the serum level of several cytokines was tested in the animal treated (or not) with IAC (50 mg/kg) both in the absence and presence of carrageenan-induced inflammation.. IAC showed a significant anti-inflammatory activity in both in acute and chronic models of inflammation. In addition IAC down regulated significantly the serum levels of interleukin (IL) 2 and IL6 whereas it increased the serum concentration of IL1α and glutathione.. Although it remains to be elucidated whether or not the antioxidant property of IAC is directly responsible for the modulation of the tested cytokines, these results suggest IAC to be a possible candidate for a novel anti-inflammatory compound.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Down-Regulation; Edema; Free Radical Scavengers; Glutathione; Granuloma, Foreign-Body; Interleukin-1alpha; Interleukin-2; Interleukin-6; Male; Molecular Weight; Piperidines; Rats; Rats, Sprague-Dawley

The purpose of this study was to evaluate the efficacy of the radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) in alleviating behavioral deficits and reducing amyloid-β (Aβ) accumulation in an Alzheimer's disease (AD) transgenic Tg2576 mouse model. Daily treatment with IAC (3-30 mg/kg, i.p.) was started at the age of 6 months and continued until the mice were 13 months old. At the age of 9 months and again at 12 months, the mice were tested in open field and water maze tests. At the age of 13 months, the mice were sacrificed and the brains processed for immunohistochemistry. Mortality was significantly reduced in all IAC-treated groups. In addition, IAC treatment improved the water maze hidden platform training performance but had no effect on motor activity in the open field or water maze swim speed in transgenic mice. Lastly, IAC treatment (10 mg/kg) significantly reduced the cortical Aβ plaque burden. In vitro, IAC is able to increase the number of neurites and neurite branches in cultured cortical primary neurons. In conclusion, IAC slowed down the development of the AD-like phenotype in Tg2576 mice and accelerated neurite growth in cultured neurons.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cell Survival; Cells, Cultured; Cognition; Cricetinae; Disease Models, Animal; Free Radical Scavengers; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Piperidines; Plaque, Amyloid; Rats; Rats, Wistar

It has been proposed that free radicals, reactive oxygen species (ROS) and reactive nitrogen species play a critical role in gastric mucosal damage. It is well known that the exposure of gastric mucosa to damaging factors such as stress and nonsteroidal anti-inflammatory drugs produces acute ulcers that are mainly mediated by ROS. The aim of the present study was to investigate the gastroprotective properties of bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC), a novel nonpeptidyl low-molecular-weight radical scavenger, in two different models of gastric ulcer in rats caused by ROS. IAC was orally administered at the doses of 50 and 100 mg/kg before gastric ulceration induced by indomethacin and water immersion and restraint stress. The number and severity of gastric lesions, following macroscopic inspection of the mucosa, were evaluated and expressed as an ulcer score. Oral administration of IAC dosed at 50 and 100 mg/kg was able to significantly prevent gastric ulceration induced by indomethacin and by stress. The gastroprotective effect of IAC on gastric mucosa could be attributed to its intrinsic antioxidant activity, suggesting it as a novel antiulcer agent.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Disease Models, Animal; Free Radical Scavengers; Indomethacin; Male; Piperidines; Rats; Rats, Sprague-Dawley; Restraint, Physical; Stomach Ulcer; Stress, Psychological

The removal of pathologically generated free radicals produced during ischemia, reperfusion and intracranical hemorrhage seems to be a viable approach to neuroprotection. However, at present, no neuroprotective agent has proven effective in focal ischemic stroke phase III trials, despite the encouraging data in animal models. This study aimed to explore the effect of the brain penetrant low molecular weight radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) in neurological damage subsequent to ischemia-reperfusion injury in Mongolian gerbils. We examined the intraperitoneal effects of IAC on temporary bilateral common carotid artery occlusion (BCCO) by means of morphological and histological analysis of the hippocampus. Significant dose-dependent protective effects of IAC (1 to 10mg/kg b.w.) against neuropathological and morphological brain changes were seen when administered i.p. 1h before temporary BCCO in Mongolian gerbils. When administered up to 6h after BCCO, IAC actually reverses the neurodegenerative processes (e.g. hippocampal cell viability) induced by ischemia in a dose-dependent fashion. Data show that IAC is highly effective in protecting and preventing oxidative brain damage associated with cerebral flow disturbances. It is also effective even in late treatment of the insult, emphasizing its potential role for the management of ischemic stroke patients.

Topics: Animals; Brain Damage, Chronic; Brain Infarction; Brain Ischemia; Carotid Stenosis; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Gerbillinae; Hippocampus; Infusions, Parenteral; Male; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Piperidines; Treatment Outcome

We previously reported that in a diabetes mouse model, characterised by moderate hyperglycaemia and reduced beta-cell mass, the radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate di-hydrochloride (IAC), a non-conventional cyclic hydroxylamine derivative, improves metabolic alterations by counteracting beta-cell dysfunction associated with oxidative stress. The aims of this study were to ascertain whether the beneficial effects of IAC treatment could be maintained after its discontinuation and further elucidate the underlying mechanisms. Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Diabetic mice were treated for 7 weeks with various doses of IAC (7.5, 15, or 30 mg/kg b.w./die i.p.) and monitored for additional 8 weeks after suspension of IAC. Then, pancreatic tissue was used for determination of beta-cell mass by immunohistochemistry and beta-cell ultrastructural analysis. STZ-NA mice showed moderate hyperglycaemia, glucose intolerance and reduced beta-cell mass (25% of controls). IAC-treated STZ-NA mice (at both doses of 15 and 30 mg/kg b.w.) showed long-term reduction of hyperglycaemia even after discontinuation of treatment, attenuation of glucose intolerance and partial preservation of beta-cell mass. The lowest IAC dose was much less effective. Plasma nitrotyrosine levels (an oxidative stress index) significantly increased in untreated diabetic mice and were lowered upon IAC treatment. At ultrastructural level, beta cells of IAC-treated diabetic mice were protected against degranulation and mitochondrial alterations. In the STZ-NA diabetic mouse model, the radical scavenger IAC induces a prolonged reduction of hyperglycaemia associated with partial restoration of beta-cell mass and function, likely dependent on blockade of oxidative stress-induced damaging mechanisms.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Free Radical Scavengers; Glucose Tolerance Test; Hyperglycemia; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Molecular Structure; Niacinamide; Piperidines; Streptozocin; Tyrosine

To investigate the effects of the free radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC) in the dextran sodium sulphate (DSS) experimental model of ulcerative colitis.. Colitis was induced in Sprague Dawley male rats by administration of 5% DSS in drinking water. IAC (30 mg/kg, lipophilic or hydrophilic form) was administered daily (orally or ip) for 6 d until sacrifice. Colonic damage was assessed by means of indirect (Disease Activity Index score) and direct measures (macroscopic and microscopic scores) and myeloperoxidase (MPO) activity. Neutrophil infiltration within the tissue and glutathione S-transferase activity were also investigated.. DSS-induced colitis impaired body weight gain and markedly increased all inflammatory parameters. Six-day treatment with lipophilic IAC significantly reduced intestinal damage caused by inflammation, induced a down-regulation in MPO activity (0.72 +/- 0.12 and 0.45 +/- 0.12 with lipophilic IAC po and ip, respectively, vs 1.10 +/- 0.27 in untreated DSS colitis animals) and minimized DSS-induced neutrophil infiltration, while hydrophilic IAC administered orally did not ameliorate DSS-induced damage.. These results support the hypothesis that reactive oxygen metabolites contribute to inflammation and that the radical scavenger IAC has therapeutic potential in inflammatory bowel disease.

Topics: Animals; Colitis; Dextran Sulfate; Free Radical Scavengers; Humans; Male; Molecular Structure; Molecular Weight; Piperidines; Rats; Rats, Sprague-Dawley

We investigated the ability of a novel low-molecular-weight free-radical scavenger, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), to protect the gastric mucosa from indometacin-induced ulceration.. The pharmacological effects of IAC, administered orally or by intraperitoneal injection, on the gastric mucosa were assessed in a rat model of gastric ulceration induced by indometacin. The effect of IAC on the level of prostaglandin PGE2 in the gastric mucosa was also investigated.. IAC, which has no ulcerative activity per se, had a preventive and protective activity against indometacin-induced gastric ulceration. This effect could be only partially attributed to a modulatory effect of IAC on PGE2 levels; it is more likely to be due to the antioxidant activity of the compound.. Taking into account the properties of IAC and the mechanisms underlying gastric inflammation elicited by non-steroidal anti-inflammatory drugs, IAC may represent a novel anti-ulcer agent.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Antioxidants; Dinoprostone; Disease Models, Animal; Esters; Free Radical Scavengers; Gastric Mucosa; Indomethacin; Injections, Intraperitoneal; Male; Piperidines; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Intestinal inflammation is accompanied by excessive production of reactive oxygen and nitrogen radical species because of the massive infiltration of polymorphonuclear and mononuclear leukocytes. Antioxidant compounds seem to protect against experimental colitis. Here we investigated the effects of the innovative non-peptidyl, low molecular weight radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC), which is highly reactive with most oxygen, nitrogen and carbon centred radicals and is easily distributed in cell membranes and intra-extra cellular compartments, in the DNBS model of colitis. Colitis was induced in male SD rats by intrarectal administration of DNBS (15 mg/rat). IAC (30 mg/kg b.w., hydrophilic or lipophilic form) was administered daily (orally or i.p.) starting from the day before the induction of colitis for 7 days (n=6-8 per group). Colonic damage was assessed by means of macroscopic and histological scores, myeloperoxidase activity (MPO) and TNF-alpha tissue levels. Colitis impaired body weight gain and markedly increased all inflammatory parameters. IAC significantly counteracted the reduction in body weight gain, decreased colonic damage and inflammation and TNF-alpha levels in DNBS-colitis. The antioxidant IAC significantly ameliorates experimental colitis in rats. This strengthens the notion that antioxidant compounds may have therapeutic potential in inflammatory bowel disease.

Topics: Animals; Colitis; Dinitrofluorobenzene; Fluorescent Antibody Technique; Free Radical Scavengers; Hydrophobic and Hydrophilic Interactions; Male; Molecular Weight; Peptides; Piperidines; Protons; Rats; Rats, Sprague-Dawley

Chronic exposure to high free fatty acids (FFA) can lead to irreversible damage of beta-cell accounting for impaired insulin secretion. Multiple mechanisms concur in generating the damage, but activation of oxidative stress may contribute to the final toxic effect. To better understand the phenomenon of lipotoxicity in human beta-cells, we evaluated the effects of 24-h pre-culture with 1.0 mmol/l FFA on the function, survival and mRNA expression of several enzymes involved in the generation and scavenging of reactive oxygen species (ROS).. Human islets, prepared by collagenase digestion and density gradient purification from 9 pancreases of multiorgan donors, were incubated for 24-h in the presence 1.0 mmol/l long-chain mixture (oleate:palmitate, 2:1) FFA, with or without 100 micromol/l IAC, a non-peptidyl low molecular weight radical scavenger. At the end of incubation period, insulin secretion was measured by static incubation, and mRNA expression of insulin, Cu/Zn-SOD, Mn-SOD, Catalase, Glutathione peroxidase (GSH-px) and HO-1 by quantitative Real-Time RT-PCR. Nitrotyrosine levels were determined by an ELISA technique.. As compared to control incubation (Ctrl, no FFA), exposure to FFA was associated with impaired insulin release and reduced insulin mRNA expression. The presence of IAC in the incubation medium increased insulin release significantly and prevented changes in mRNA expression. Exposure to FFA was associated with oxidative stress as indicated by a significant accumulation of nitrotyrosine and IAC restrained such an increase. mRNA expression of Cu/Zn-SOD, Mn-SOD, Catalase, GSH-Px, and HO-1 were all modified after FFA exposure. These changes were partially prevented in the presence of IAC.. In human islets 24-h exposure to high FFA causes oxidative stress associated with changes of several enzymes involved in ROS scavenging. These effects were prevented by the use of an antioxidant molecule.

Topics: Antioxidants; Apoptosis; bcl-2-Associated X Protein; Catalase; Cell Survival; Cytoprotection; Fatty Acids; Free Radical Scavengers; Gene Expression Regulation; Glucokinase; Glucose Transporter Type 2; Glutathione Peroxidase; Humans; Insulin; Islets of Langerhans; Molecular Weight; Oxidative Stress; Peptides; Piperidines; RNA, Messenger; Superoxide Dismutase; Tyrosine

We examined a possible protective effect of the nonpeptidyl low molecular weight radical scavenger IAC [bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decanedioate di-hydrochloride] on isolated human islet cells against isolation and culture oxidative stress. Islets isolated from pancreases of nondiabetic multiorgan donors by collagenase digestion were purified by density gradient centrifugation. After the isolation, islets were either exposed or not exposed for 7 days to 10 micromol/L IAC. We found that IAC markedly reduced oxidative stress and ameliorated islets function. These results suggest that the use of IAC could be an interesting pharmacological approach for the treatment of the islets before transplantation.

Topics: Adult; Aged; Antioxidants; Catalase; Cell Culture Techniques; Cells, Cultured; Esters; Female; Free Radical Scavengers; Gene Expression Regulation, Enzymologic; Humans; Hypoglycemic Agents; Islets of Langerhans; Male; Middle Aged; Molecular Weight; Oxidative Stress; Piperidines; Superoxide Dismutase; Tyrosine

Experimental evidence suggests that reactive free radicals are generated during brain ischemia. We investigated the effect of a novel brain penetrant, low molecular weight, non-peptidyl carbon, oxygen- and nitrogen-centered radical scavenger, IAC, on infarct volume and sensory-motor performance in a rat transient middle cerebral artery occlusion model (tMCAO). Rats received 90 min tMCAO and treated with i.p. or i.v. injections of vehicle or IAC following tMCAO. Sensory-motor performance was evaluated by neuroscore tests (NS). Cerebral infarct volume was evaluated at 72 h after tMCAO. Rats treated with IAC i.p. (1 or 6 h after the onset of tMCAO) or i.v. (1 h after the onset of tMCAO) showed significant improvement in NS during the 3 or 21 day follow-up period when compared to vehicle treated rats. Cerebral infarct volumes were significantly decreased compared to vehicle in rats receiving IAC i.p. 1 h or 6 h after occlusion, approximately 30.5% decrease compared to vehicle, or i.v. 1 h after the onset of tMCAO, 48.6% decrease compared to vehicle. These results demonstrate that IAC has neuroprotective properties with a wide therapeutic window following tMCAO in rats. IAC could therefore be a candidate for the treatment of stroke.

Topics: Analysis of Variance; Animals; Behavior, Animal; Cerebral Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Esters; Ischemic Attack, Transient; Male; Neuroprotective Agents; Piperidines; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Time Factors

We have previously established a nonobese diabetes mouse model characterized by moderate hyperglycemic levels, like those usually occurring in human type 2 diabetes. As oxidative stress is considered a major mechanism of progressive beta-cell damage in diabetes, we tested in this model the protective effects of a new low-molecular-weight antioxidant, namely, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate dihydrochloride (IAC).. Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Two weeks later, STZ-NA mice were treated for 5 weeks with different doses of IAC (15 or 30 mg/kg per day intraperitoneally) and monitored for glycemia, insulinemia, glucose tolerance, and pancreatic insulin content.. Streptozotocin-NA mice showed moderate hyperglycemia, hypoinsulinemia, glucose intolerance, growth impairment, and markedly reduced pancreatic insulin content (22% of controls). IAC-treated STZ-NA mice showed clear-cut reduction of hyperglycemia and attenuation of glucose intolerance, associated to higher residual pancreatic insulin content with respect to untreated diabetic animals. Plasma nitrotyrosine levels (an index of oxidative stress), enhanced 3-fold in diabetic mice, were significantly reduced by IAC treatment. Significant correlations were found between plasma nitrotyrosine values and either blood glucose levels or pancreatic insulin content.. In the STZ-NA diabetic mouse model, the new antioxidant, IAC, improves diabetic metabolic alterations, likely by counteracting beta-cell dysfunction and loss associated with oxidative stress.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Esters; Fatty Acids, Nonesterified; Glucose Intolerance; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Molecular Weight; Niacinamide; Oxidative Stress; Pancreas; Piperidines; Streptozocin; Time Factors; Tyrosine