benzofurans and Cataract

Cataract is one of the most important causes of blindness worldwide, with age-related cataract being the most common one. Agents preventing cataract formation are urgently required. Substantial evidences point out aggravated oxidative stress as a vital factor for cataract formation. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like erythroid-cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) system is considered as one of the main cellular defense mechanisms against oxidative stresses. This review discusses the role of Nrf2 pathway in the prevention of cataracts and highlights that Nrf2 suppressors may augment oxidative stress of the lens, and Nrf2 inducers may decrease the oxidative stress and prevent the cataract formation. Thus, Nrf2 may serve as a promising therapeutic target for cataract treatment.

Topics: Aging; Antioxidants; Benzofurans; Blindness; Cataract; Flavonoids; Gene Expression Regulation, Developmental; Humans; Kelch-Like ECH-Associated Protein 1; Lens, Crystalline; NF-E2-Related Factor 2; Oxidative Stress; Quercetin; Signal Transduction; Transcription, Genetic

DL-3-n-butylphthalide (NBP) is a therapeutic drug used for ischemic stroke treatment. Here, we investigated the impact of NBP on the development of rat diabetic cataract induced by intraperitoneal injection of streptozotocin (STZ). NBP was then administrated by oral gavage for nine weeks. Cataract development was monitored through ophthalmoscope inspections. The levels of blood glucose and serum reactive oxygen species (ROS), malondialdehyde (MDA) and 8-Hydroxydeovexyguanosine (8-OHdG) were measured. Total and soluble protein and oxidative stress parameters, such as 2, 4- dinitrophenylhydrazone (DNP), 4-hydroxynonenal (4-HNE) and MDA in the lenses were determined by Western blot and thiobarbituric acid analyses. The expressions of NF-E2-related factor 2 (Nrf2) and its downstream antioxidant enzymes, thioredoxin (TRX), Catalase and nuclear accumulation of Nrf2 were determined by Western blot and immunohistochemistry analyses. We showed that NBP treatment significantly improved the cataract scores, the levels of DNP, 4-HNE, and MDA in the lens compared to the non-treated groups. NBP also enhanced the expressions of Nrf2, TRX and catalase in the lens of diabetic rats. In addition, NBP treatment also decreased levels of blood glucose, serum MDA and 8-OHdG. These results suggested that NBP treatment significantly delayed the onset and progression of diabetic cataract by inhibiting the oxidative stresses.

Topics: Animals; Benzofurans; Biomarkers; Blood Glucose; Body Weight; Catalase; Cataract; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Disease Progression; Immunohistochemistry; Lens, Crystalline; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Thioredoxins

High sugar levels found in diabetic cataract cause the opacification of lenses by osmotic changes induced via the aldose reductase (AR)-mediated polyol pathway. In this study, puerariafuran, a 2-arylbenzofuran from Pueraria lobata, investigated the inhibitory effects upon AR, antioxidant contents and enzyme activities in the lens. The effect of puerariafuran on xylose-induced lens opacity was also examined. Puerariafuran showed potential inhibitory activity with an IC50 value of 22.34 microM against rat lens AR. The xylose-induced opacity of lenses was significantly improved when treated with puerariafuran. Xylose exposure of rat lenses significantly decreased the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, superoxide dismutase (SOD), and catalase (CAT) activity and treatment with puerariafuran significantly increased these factors. These results suggest that puerariafuran may provide a potential therapeutic approach for prevention of diabetic complications, such as cataracts.

Topics: Aldehyde Reductase; Animals; Benzofurans; Cataract; Plant Extracts; Plant Roots; Pueraria; Rats; Rats, Sprague-Dawley; Xylose

OP-lysine, a glycation product of lysine residues of proteins, has been reported to be formed with glyceraldehyde and glycolaldehyde as precursors in the lens, and has been suggested to play a role in senile cataracts. However, there has been no reliable information regarding the content of glyceraldehyde in tissues. This study determined the glyceraldehyde levels in the lenses of normal and diabetic rats.. Glyceraldehyde was derivatized to a fluorescent compound, and the compound was then quantified by high-performance liquid chromatography.. The lens glyceraldehyde levels in normal and diabetic rats were 0.75 +/- 0.06 and 1.26 +/- 0.21 nmol/g wet weight (means +/- standard deviations of 6 animals, p < 0.01), respectively. Isolated rat lenses accumulated a higher level of glyceraldehyde when cultured for 6 days in 25.5 mM glucose than when cultured in 5.5 mM glucose.. Glyceraldehyde was found to be present in the lens and was increased in diabetes mellitus. OP-lysine is thus likely to be a potential risk factor for senile and diabetic cataracts.

Topics: Aldehyde Reductase; Animals; Benzofurans; Blood Glucose; Cataract; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Disease Models, Animal; Glyceraldehyde; Hydantoins; Lens, Crystalline; Lysine; Male; Pyridinium Compounds; Rats; Rats, Wistar

The present study was undertaken to assess whether A-3922, a dihydrobenzofuran derivative that possesses antioxidative effects, had any preventive effect on the onset and/or progression of diabetic cataract. Male Wistar rats were received a bolus intravenous injection of streptozotocin (65 mg/kg) and were given 5% glucose in drinking water for 10 weeks. The diabetic rats were divided into two groups and treated with 30 mg/kg/d A-3922 or vehicle during the experimental period. The opacities of eye lenses were observed by using both our original device and a slit lamp microscope. The lens opacities were initially detected as early as the 2nd week and the cataracts were developed in similar fashion in both A-3922-treated and untreated diabetic rats until 7th week, suggesting that A-3922 did not show any appreciable effect on the onset of diabetic cataract. In the later period (8th week or later), however, progression of cataract was retarded and significant reductions in both the total cataract score and the degree of opacity were apparently observed on 10th week of A-3922-treated diabetic rats. These results suggest that A-3922 can delay the progression but not the onset of diabetic cataract, and it has a possibility to be a candidate for drugs of cataract associated with diabetes.

Topics: Animals; Benzofurans; Blood Glucose; Body Weight; Cataract; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Progression; Lens, Crystalline; Male; Rats; Rats, Wistar

RG 12915, a selective 5-HT3 antagonist developed for the treatment of emesis and nausea associated with cancer chemotherapy, was administered by gavage to four groups of pregnant rats from Gestation Day 6 to 17 at doses of 0, 1, 10, and 100 mg/kg/day, as part of a Segment II (developmental toxicity) study. The 100 mg/kg/day dose was maternally toxic as indicated by decreased body weight gain and food consumption during the treatment period. A portion of the rats were allowed to deliver and rear their litters and three pups from two litters in the 100 mg/kg/day group were observed to have lens opacities (visible to the naked eye) at weaning. At a later examination, when the offspring were approximately 4 months old, four additional animals from the same two litters had cataracts. A slight growth retardation was also observed postweaning in the offspring of the 100 mg/kg/day group. To confirm the lens findings and more precisely define the no-effect dose, another study was conducted in which pregnant rats were administered daily RG 12915 doses of 0, 10, 30, 60, or 100 mg/kg/day from Gestation Day 6 to 17. There was a dose-related decrement in maternal body weight gain during the treatment period in the 30, 60, and 100 mg/kg/day groups (12, 28, and 47%, respectively) compared to the control group. A treatment-related incidence of nuclear cataract was observed in the offspring of the 60 and 100 mg/kg/day groups (litter incidence 6 and 45%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Body Weight; Bridged Bicyclo Compounds, Heterocyclic; Cataract; Female; Lens, Crystalline; Male; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Serotonin Antagonists

Properties and efficacies of novel aldose reductase (AR) inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), were examined in vitro and in vivo, compared with known AR inhibitors, ONO-2235 and sorbinil. These four compounds inhibited partially purified aldose reductases from various origins, and the potencies of M16209 and M16287 were on the whole similar to ONO-2235, and were greater than that of sorbinil. The IC50 values of the four AR inhibitors did not substantially depend on the substrate used. Kinetic studies of inhibition of partially purified bovine lens (BLAR) revealed that M16209, M16287 and sorbinil were uncompetitive with glyceraldehyde and noncompetitive with nicotineamide adenine dinucleotide phosphate (NADPH), whereas ONO-2235 was noncompetitive with both glyceraldehyde and NADPH. Aldose reductase became less sensitive to the four inhibitors as enzyme purification progressed, although the susceptibility to inhibition was partially reversed by incubation with dithiothreitol. In addition, the four compounds slightly affected those enzymes of carbohydrate and glutathione metabolism which were tested. M16209 and M16287 prevented sorbitol accumulation in isolated rat tissues as potently as ONO-2235 and sorbinil. M16209 and M16287 were effective in the prevention of galactosemic cataracts and amelioration of diabetic neuropathy with almost the same potency, while ONO-2235 was effective only in neuropathy, and sorbinil was effective in galactosemic cataracts and diabetic neuropathy with a different potency. These results indicate that M16209 and M16287 are potent aldose reductase inhibitors, which could be applicable to treatment for diabetic complications.

Topics: Aldehyde Reductase; Animals; Benzofurans; Cataract; Cattle; Diabetic Neuropathies; Hydantoins; Imidazoles; Imidazolidines; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Rhodanine; Sorbitol; Thiazolidines

Effects of novel aldose reductase inhibitors, M16209 (1-(3-bromobenzo[b]furan-2-ylsulfonyl)hydantoin) and M16287 (1-(3-chlorobenzo[b]furan-2-ylsulfonyl)hydantoin), on galactose-induced cataract formation in rats were investigated. Rats fed a 30% galactose diet developed lenticular opacity in the peripheral region by the 6th day of galactose feeding and showed gradual progression of opacity from the equator to the center of lenses. Histological study on the 15th day showed apparent lens fiber swelling and vacuolation predominantly in the equatorial and anterior cortical regions. Biochemical changes such as accumulation of galactitol, depletion of myo-inositol and decrease in glutathione (GSH) content in lenses preceded the appearance of opacity. Remarkable increase in NADPH content and decrease in NADP+ content, in addition to elevation of the ratio of Na+/K+, in lenses were also observed on the 15th day. Both M16209 and M16287 (10, 30 and 100 mg/kg/day, p.o.) dose-dependently ameliorated these morphological and biochemical changes except that restoration of myo-inositol content was incomplete. These results indicate that M16209 and M16287 can prevent galactose-induced cataract formation through amelioration of metabolic disorders and thus have high potential for clinical use in the treatment of some diabetic complications.

Topics: Aldehyde Reductase; Animals; Benzofurans; Cataract; Cattle; Enzyme Inhibitors; Galactose; Hydantoins; Lens, Crystalline; Male; Rats; Rats, Inbred Strains

Amiodarone hydrochloride is an antiarrhythmic drug which produces a keratopathy and anterior subcapsular lens opacities that are usually asymptomatic. Serial observations for eye findings were made in 21 patients on a daily dosage of 200-600 mg for periods ranging from six months to three years. Corneal deposits developed in all 21 patients and anterior lens opacities developed in 12 of 20 phakic patients. Resolving keratopathy was present in three patients for periods of at least seven to 20 months after amiodarone was discontinued.

Topics: Adult; Aged; Amiodarone; Benzofurans; Cataract; Corneal Opacity; Follow-Up Studies; Humans; Middle Aged; Risk; Tachycardia

Topics: Adolescent; Adult; Amiodarone; Benzofurans; Cataract; Child; Humans

Amiodarone hydrochloride is a benzofurane derivative used for cardiac abnormalities. Its use is commonly associated with an asymptomatic keratopathy. Although lipid deposits have been observed with the electron microscope in the lens epithelium of one patient with a history of amiodarone therapy, lens opacities have not been reported in patients using this drug. Visually inconsequential, anterior subcapsular lens opacities in seven of 14 patients using moderate to high doses of amiodarone who were examined at the Veterans Administration Hospital in San Francisco are reviewed.

Topics: Adult; Aged; Amiodarone; Benzofurans; Cataract; Humans; Male; Middle Aged

Topics: Adolescent; Adult; Aged; Amiodarone; Benzofurans; Cataract; Color Vision Defects; Corneal Diseases; Eye Diseases; Female; Humans; Lipidoses; Male; Middle Aged; Retinal Diseases