piperidines and Cataract

The etiopathogenesis of steroid-induced cataracts is unknown. One hypothesis is that the higher reactive oxygen species (ROS) levels play an important role in the pathogenesis of several disorders, including the evolution of cataracts. This study investigated the antioxidant effects of piperine in our steroid-induced chick embryo lens model.. The study included 36 specific pathogen-free (SPF) fertilized eggs divided into six groups: phosphate buffer saline (PBS, pH 7.4 Saline Solution (0.9%) isotonic) group (G1), hydrocortisone succinate sodium (HC)-treated group (G2), 100 mg/kg piperine and HC treated group (G3), 50 mg/kg piperine and HC treated group (G4), 25 mg/kg piperine and HC treated group (G5), and 10 mg/kg piperine and HC treated group (G6). On the 15th day of incubation, the SPF eggs in the six groups were removed from the incubator; all were injected using insulin injectors into the chorioallantoic membrane. On day 17, all of the chick embryos were removed from the eggs and all lenses were dissected from the embryos. Cataract formation was evaluated in all lenses, and total antioxidant status (TAS), total oxidant status (TOS), reduced glutathione (GSH), and lipid peroxidation (MDA, malondialdehyde) levels were measured in all lens.. The lenses in the G1 group had higher levels of GSH and TAS (p < 0.01), and lower levels of MDA and TOS than the G2 group (p < 0.05 and p < 0.01, respectively). Group 3 had higher levels of GSH and TAS (p < 0.001 and p < 0.001 respectively), and lower levels of MDA and TOS than the G2 group (p < 0.01 and p < 0.001, respectively).. Steroid therapy causes a decrease in GSH and TAS levels and an increase in TOS and MDA levels in lens tissues, indicating increased oxidative stress. Piperine exerts its effects as an antioxidant substance, in increasing doses.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Cataract; Chick Embryo; Glutathione; Hydrocortisone; Lens, Crystalline; Malondialdehyde; Piperidines; Polyunsaturated Alkamides

Topics: Anesthesia, Intravenous; Cataract; Child; Craniofacial Abnormalities; Humans; Male; Nervous System Diseases; Piperidines; Propofol; Rare Diseases; Remifentanil

E2012, a gamma secretase modulator without affecting Notch processing, aimed at Alzheimer's disease by reduction of amyloid β-42, induced cataract following repeated doses in the rat. Cataract appeared first at week 10-11 of treatment as a posterior subcapsular area with granular/punctate opaque or shiny dots along the suture line, characterized histologically as lenticular fiber degeneration, which eventually coalesced to form a triangular or circular opacity. It was associated with prolonged and sustained elevation of lenticular desmosterol (24-dehydrocholesterol), the final precursor of cholesterol, and decrease in lenticular cholesterol. In vitro studies to investigate the effect of E2012 on cholesterol metabolism demonstrated that E2012 inhibits 3β-hydroxysterol Δ24-reductase (DHCR24) at the final step in the cholesterol biosynthesis. In vivo lenticular concentration of E2012 after 13-week repeated dose with cataract was well above those where inhibition was observed in vitro. There was no cataract formation at doses where desmosterol did not accumulate in the lens. The elevation of desmosterol and decreased cholesterol levels were also seen in the liver and plasma and preceded those in the lens. These results demonstrate that E2012 induces cataract in the rat by inhibiting DHCR24 at the final step of cholesterol synthesis with associated elevation in desmosterol within the lens, preceded by desmosterol changes that would serve as a predictive safety biomarker for lenticular opacity.

Topics: Amyloid Precursor Protein Secretases; Animals; Biomarkers; Cataract; Cholesterol; Desmosterol; Dose-Response Relationship, Drug; Female; Hep G2 Cells; Hepatocytes; Humans; Imidazoles; Lens, Crystalline; Male; Nerve Tissue Proteins; Oxidoreductases Acting on CH-CH Group Donors; Piperidines; Protease Inhibitors; Rats; Rats, Sprague-Dawley; Time Factors

We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.

Topics: Animals; Anticholesteremic Agents; Cataract; Cell Line, Tumor; Dyslipidemias; Enzyme Inhibitors; Eye; Female; Humans; Intramolecular Transferases; Liver; Male; Oxazoles; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley

Topics: Anesthetics, Combined; Anesthetics, Intravenous; Cataract; Cataract Extraction; Chondrodysplasia Punctata; Humans; Infant; Intubation, Intratracheal; Male; Monitoring, Intraoperative; Neuromuscular Nondepolarizing Agents; Piperidines; Propofol; Remifentanil; Vecuronium Bromide

Investigations on compound A, an M2-sparing M3 muscarinic receptor antagonist, showed that focal polar anterior subcapsular lenticular opacities, characterized by focal epithelial proliferation, developed in Sprague-Dawley rats. The incidence and bilateral localization of this change increased generally with dose and time, though plateauing after 8 months of treatment; however the severity progressed very slightly. Over a 1-year period, no anterior cortical lens fiber changes or other histological ocular changes developed. A decreased severity of the change and apoptosis suggested some regression after a 26-week recovery period. Two nonselective muscarinic receptor antagonists, atropine and tolterodine, induced similar lenticular changes in rats. A hypothesis in relation to an indirect effect of the drug, such as increased illumination of the lens due to mydriasis observed with all these compounds, was investigated and disproven. Because these opacities are induced by structurally unrelated muscarinic receptor antagonists (atropine and tolterodine), it is likely that these lenticular changes are the result of muscarinic receptor inhibition. However, hypotheses regarding a direct effect of the drug on muscarinic receptors in the lens epithelium, possibly mediated by drug and/or metabolite(s) in the aqueous humor and/or lens epithelium, remain to be investigated. This lenticular opacity is similar to that observed spontaneously in Sprague-Dawley rats, although the latter occur at a lower incidence. No such lenticular opacities have been reported in other animal species, including man, after treatment with muscarinic receptor antagonists.

Topics: Animals; Atropine; Benzeneacetamides; Benzhydryl Compounds; Cataract; Cresols; Dose-Response Relationship, Drug; Epithelium; Female; Lens, Crystalline; Male; Muscarinic Antagonists; Phenylpropanolamine; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Tolterodine Tartrate

Topics: Amphetamine; Appetite Depressants; Cataract; Ephedrine; Eye Diseases; Humans; Morpholines; Piperidines; Pupil; Retinal Hemorrhage; Retinal Vessels; Thrombosis; Vision Disorders