pantetheine and Cataract

Topics: Animals; Antioxidants; Apolipoproteins B; Cataract; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Lipid Peroxides; Pantetheine

Pantethine, the stable disulfide form of pantetheine, is the major precursor of coenzyme A, which plays a central role in the metabolism of lipids and carbohydrates. Coenzyme A is a cofactor in over 70 enzymatic pathways, including fatty acid oxidation, carbohydrate metabolism, pyruvate degradation, amino acid catabolism, haem synthesis, acetylcholine synthesis, phase II detoxification, acetylation, etc. Pantethine has beneficial effects in vascular disease, it able to decrease the hyperlipidaemia, moderate the platelet function and prevent the lipid-peroxidation. Moreover its neuro-endocrinological regulating role, its good influence on cataract and cystinosis are also proved. This molecule is a well-tolerated therapeutic agent; the frequency of its side-effect is very low and mild. Based on these preclinical and clinical data, it could be recommended using this compound as adjuvant therapy.

Topics: Acetylcholine; Animals; Antioxidants; Atherosclerosis; Blood Platelets; Cataract; Central Nervous System; Coenzyme A; Cystine; Cystinosis; Dietary Carbohydrates; Fatty Acids; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipid Peroxidation; Oxidation-Reduction; Pantetheine; Pantothenic Acid; Pyruvates

Cataract is the major cause of blindness and of visual impairment worldwide, so its prevention is of the greatest importance. At present no drug therapy is licensed for use in the UK or the US, so the only treatment for cataract is by surgery, which is expensive and has adverse effects. This article reviews research on prevention of cataract by a variety of agents, including micronutrients as well as drugs. Benefits have been claimed for many compounds or mixtures and this review concentrates on those most extensively studied. Information on possible benefits of putative anticataract agents comes from a variety of approaches, from laboratory experiments, both in vitro and in vivo, to epidemiological studies in patients. Sorbitol-lowering drugs were the first to be examined systematically and progressed to clinical trials which were disappointing, and now the entire rationale for their use in prevention of cataract is questionable. Micronutrients showed little promise in animals but came to clinical trial in patients with cataract without the publication of any major benefit. Pantethine showed more promise in animal studies but the only clinical trial was abandoned early. A variety of laboratory and epidemiological evidence supports the benefits of aspirin-like drugs but there has been no trial specifically in patients with cataract. Add-on studies to trials of aspirin for other indications have not been encouraging. Research into other compounds is interesting but less advanced.

Topics: Aldehyde Reductase; Aspirin; Cataract; Clinical Trials as Topic; Drug Design; Estrogens; Glutathione; Humans; Pantetheine

The effect of a mixture of N-acetylcarnosine and D-pantethine (1 : 1, m/m) on UV-A induced cataract in rats was studied. It is shown that instillation of a 5% mixture into the eyes or intraperitoneal injections (25 or 150 mg/kg) inhibit the formation of cataracts, starting from 82nd day of the experiment (p < 0.03), after which the protective effect of the mixture significantly increases (p = 0.0003). UV-A irradiation significantly (p < 0.01) increased the content of water-insoluble proteins in the lens. The use of the mixture of N-Acetylcarnosine and D-pantethine prevented (p < 0.001) an increase in the content of water-insoluble proteins caused by UV-A irradiation. Gel permeation chromatography data showed that, in the control group, water insoluble proteins consist of 3 fractions (40 kDa, 100 - 200 kDa, and1000 kDa). UV-A irradiation reduced the amount of protein in fraction 1 and increases the amount of protein in the fractions 2 and 3. The use of the mixture of N-acetylcarnosine and D-pantethine reduced the effects of UV-A light. The authors attribute the effect of the N-acetylcarnosine and D-pantethine mixture to their chaperone-like properties.

Topics: Animals; Carnosine; Cataract; Chromatography, Gel; Drug Combinations; Eye Proteins; Injections, Intraperitoneal; Lens, Crystalline; Male; Ophthalmic Solutions; Pantetheine; Protective Agents; Protein Aggregates; Radiation Injuries, Experimental; Rats; Rats, Wistar; Solubility; Ultraviolet Rays

Cataract, neurodegenerative disease, macular degeneration and pathologies of ageing are often characterized by the slow progressive destabilization of proteins and their self-assembly to amyloid-like fibrils and aggregates. During normal cell differentiation, protein self-assembly is well established as a dynamic mechanism for cytoskeletal organization. With the increased emphasis on ageing disorders, there is renewed interest in small-molecule regulators of protein self-assembly. Synthetic peptides, mini-chaperones, aptamers, ATP and pantethine reportedly regulate self-assembly mechanisms involving small stress proteins, represented by human αB-crystallin, and their targets. Small molecules are being considered for direct application as molecular therapeutics to protect against amyloid and protein aggregation disorders in ageing cells and tissues in vivo. The identification of specific interactive peptide sites for effective regulation of protein self-assembly is underway using conventional and innovative technologies. The quantification of the functional interactions between small stress proteins and their targets in vivo remains a top research priority. The quantitative parameters controlling protein-protein interactions in vivo need characterization to understand the fundamental biology of self-assembling systems in normal cells and disorders of ageing.

Topics: Aging; alpha-Crystallin B Chain; Animals; Cataract; Lens, Crystalline; Models, Biological; Molecular Chaperones; Pantetheine; Protein Conformation; Protein Unfolding

Few studies have examined the impact of long-term treatments or exposures on the development of cataract in maturity-onset animal models. We studied the effect of treatment with D-pantethine and exposure to ultraviolet-B (UVB) radiation on the development of lenticular opacity in the Emory mouse.. A total of 164 Emory mice were randomized by litter at weaning to exposure to UVB light at 12 mJ/cm(2) for 6 hr/day (UV) or usual room light (A), and within litter, were further randomized to bi-weekly intra-peritoneal injections of 0.8 g/kg pantethine (T) or no treatment (C). Retro illumination lens photos were taken at 2, 4, 6, 8, and 10 months after weaning, and graded in masked fashion. The animals were sacrificed at 10 months and the lenses analyzed for total pantethine and total cysteamine.. Lens pantethine and cysteamine levels were significantly (P < 0.001) higher for the T as compared to C litters. Mean cataract grade increased monotonically over time for all four groups. Unadjusted mean grade for the AT group at 8 (1.32) and 10 (1.86) months appeared lower than for the other groups (AC: 2.17, 2.39; UVC: 1.77, 2.40; UVT: 1.88, 2.37). However, the mean grade for the pantethine-treated litters did not differ significantly from the untreated litters except at 2 months (when untreated litters had significantly lower grades), when adjusting for UV treatment, gender and litter effect. No significant difference in cataract score existed between UV-exposed and ambient litters. Mortality was higher among pantethine-treated (hazard ratio = 1.8, p = 0.05) and UV-exposed animals (hazard ratio = 1.8, p = 0. 03) than among the untreated and unexposed litters.. Significantly increased lens levels of pantethine are achieved with long-term intra-peritoneal dosing. The impact of pantethine on the progression of lenticular opacity in the Emory mouse is less than has been reported in other models. This level of chronic UVB exposure appeared to have no effect on the development of cataract in this model.

Topics: Animals; Cataract; Cysteamine; Disease Models, Animal; Disease Progression; Female; Lens, Crystalline; Male; Mice; Mice, Inbred Strains; Pantetheine; Ultraviolet Rays

This study of lens protein composition found that some cytoskeletal proteins were degraded during the earliest stages of cataract formation. Cataract was induced in 13-14 day old rats by a single subcutaneous injection of sodium selenite (19 mumol kg-1). By 24 hr after the injection of selenite, the ratio of insoluble to soluble protein increased as lens opacification began. The increase in insoluble protein aggregates was correlated with an accelerated loss of proteins having molecular weights of 42, 55/57 and 235 kDa which reacted with antibodies to the cytoskeletal proteins actin, tubulin/vimentin and spectrin, respectively. We observed the loss of 49, 60 and 90 kDa proteins which were not identified. In the lenses of animals protected from protein aggregation and opacification by administration of 1.5 mmol kg-1 pantethine, the pattern of proteins in SDS-PAGE gels resembled the pattern for proteins from transparent lenses of normal untreated animals and loss of cytoskeletal proteins was prevented.

Topics: Actins; Animals; Blotting, Western; Cataract; Crystallins; Cytoskeletal Proteins; Disease Progression; Lens Cortex, Crystalline; Lens Nucleus, Crystalline; Pantetheine; Rats; Rats, Sprague-Dawley; Sodium Selenite; Spectrin; Tubulin; Vimentin

A systematic study of the anti-cataract activity of 14 reagents was conducted using the selenite model. The reagents or their derivatives were identified from literature reports of their potential effectiveness against cataract formation. The effects of each reagent were measured on the phase separation temperature, Tc, of lens homogenate in vitro. Tc is a direct measure of molecular interactions leading to protein aggregation. The protective effect of a single subcutaneous injection of each reagent [at a dose of 1.5 mmol (kg body weight)-1] on lens opacification was evaluated in vivo using rats administered selenite [at a dose of 19 mumol (kg body weight)-1] to initiate cataract formation. The strongest effects on lens opacification in vivo were observed with reagents having the strongest effect on Tc, in vitro. The weakest effects in vivo were observed with the reagents having the weakest effect on Tc, in vitro. The results were suggestive of a relationship between the effect of a reagent on Tc and protection against cataract formation in vivo.

Topics: Animals; Antioxidants; Cataract; Chelating Agents; Disulfides; Pantetheine; Phosphates; Rats; Rats, Sprague-Dawley; Sodium Selenite; Temperature; Tissue Extracts

Pantethine and the amino phosphorothioate, WR-77913, protected lenses against increased light scattering and opacification during cataract formation in five animal models: (1) radiation, (2) selenite, (3) galactose, (4) streptozotocin and (5) Royal College of Surgeons. In the radiation or selenite models, each test reagent was administered 15 to 30 min prior to initiation of cataract by a single injection of Na2SeO3 or a single exposure to 15 Gy (gray) gamma radiation. In the galactose, streptozotocin and Royal College of Surgeons models where the cataractogenic insult was continuous, repeated administrations of pantethine and WR-77913 were necessary. The results suggested that protein aggregation and lens opacification associated with a variety of physiological and biochemical mechanisms can be delayed or inhibited using a systemic administration of pantethine or WR-77913.

Topics: Amifostine; Animals; Cataract; Female; Galactose; Lens, Crystalline; Male; Pantetheine; Protein Denaturation; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Sodium Selenite; Streptozocin

To characterize the time period during cataract formation in which administration of pantethine inhibits lens cell opacification in the selenite model for cataract.. Pantethine was administered to neonatal rat pups at selected time points from -0.5 to 17 hours with respect to injection of selenite at time = 0. The injection dose of pantethine was 820 mg/kg (1.5 mmol/kg) diluted in water at 410 mg/ml concentration. The injection dose of selenite was 3.28 mg/kg (19 mumol/kg) diluted in saline at 1.8 mg/ml concentration. Opacification was observed using a slit lamp microscope at selected time points over a 14-day period. Cataracts were staged using a classification of opacity from 0 (normal) to 6 (mature).. The effect of pantethine was characterized by three different time periods: administration -0.5 to 6 hours with respect to selenite injection provided highly significant protection, P < 0.001; administration 8 hours after selenite provided significant protection, P < 0.005; administration 10 to 17 hours after selenite was not protective.. The metabolite pantethine inhibited lens opacification during cataract formation in the selenite model. Even when pantethine was injected several hours after the administration of selenite, opacification was inhibited. Advanced stages of opacification were unresponsive to the administration of pantethine. The inhibitory effect of pantethine was statistically significant when administered during the earliest stage of opacification in the selenite model for cataract.

Topics: Animals; Animals, Newborn; Cataract; Disease Models, Animal; Female; Injections, Subcutaneous; Lens, Crystalline; Male; Pantetheine; Rats; Rats, Sprague-Dawley; Sodium Selenite; Time Factors