n-acetylcarnosine and Disease-Models--Animal

The lens epithelium is especially vulnerable to oxidative stress. The erosion and shortening of telomeres in human lens epithelial cells in the lack of telomerase activity has been recognized as a primary cause of premature lens senescence phenotype that trigger human cataractogenesis. Carnosine, released ophthalmically from N-acetylcarnosine prodrug lubricant eye drops , at physiological concentration might remarkably reduce the rate of telomere shortening in the lens cells subjected to oxidative stress in the lack of efficient antioxidant lens protection. The data of visual functions (visual acuity, glare sensitivity) in older adult subjects and older subjects with cataract treated with 1% N-acetylcarnosine lubricant eye drops showed significant improvement as compared, by contrast with the control group which showed generally no improvement in visual functions, with no difference from baseline in visual acuity and glare sensitivity readings. Prevention of cellular senescence with ophthalmic prodrug N-acetylcarnosine may be a novel therapeutic target in a management of cataract, basic preventive health care and in arresting of after-cataract following extracapsular cataract extraction.

Topics: Aged; Animals; Carnosine; Cataract; Disease Models, Animal; Humans; Lens, Crystalline; Telomere; Vision, Ocular; Visual Acuity

In human diabetes, the deleterious effects of chronic hyperglycemia are the result of excessive nonenzymatic modification of proteins and phospholipids by glucose and its by-products leading to the formation of irreversible oxidized, aromatic, and fluorescent ligands known as advanced glycation end products. This glycation process has been associated with deleterious health effects. The present invention provides the potent inhibitors of protein glycation and AGEs formation, which are particularly advantageous for eyedrop delivery in the prevention and treatment of diabetes- and age-related pathologies.. We proposed a deglycation system involving removal, by transglycation of sugar or aldehyde moieties from the Schiff bases by ophthalmic aldehyde scavenger L-carnosine derived from its ocular bioactivating sustained release prodrug 1% N-acetylcarnosine (NAC) lubricant eyedrops containing a mucoadhesive cellulose compound combined with corneal absorption promoters in drug delivery system. Carnosine analogs bearing the histidyl-hydrazide moiety were synthesized and patented in ophthalmic formulations with NAC bioactivating prodrug to moderate the enzymatic hydrolysis of a dipeptide by carnosinase (inhibited by a nonhydrolyzable substrate analog so that this keeps steadier levels of the drug active principle in the aqueous humor). Leucyl-histidylhydrazide peptidomimetic demonstrated the transglycation activity more pronounced than L-carnosine accounting for the ability of either molecule to reverse pre-existing, glycation-induced, cross-linking, and checking the nonenzymatic glycation cascade in the ophthalmic pathologies. The ophthalmic drug N-acetylcarnosine eye drop formulation with sustained time- release and increased absorption of L-carnosine in the aqueous humor (a prolonged effective dose) showed follow-up treatment efficacy for age-related cataracts for enrolled patients into the randomized double blind placebo controlled crossover clinical trial, and in over 50250 various cohort patients, was demonstrated to have an efficacy, safety and good tolerability for prevention and treatment of visual impairment in the older population data base.. The bioactivating antioxidant NAC and histidyl-hydrazide are potent agents with the pleiotropic effects for ophthalmic therapy of senile cataracts and diabetic ocular complications.

Topics: Aged; Aged, 80 and over; Aldehydes; Aminooxyacetic Acid; Animals; Biological Availability; Carnosine; Cataract; Cornea; Cross-Over Studies; Diabetes Complications; Disease Models, Animal; Drug Administration Schedule; Drug Delivery Systems; Drug Synergism; Female; Glycosylation; Histidine; Humans; Hydrazines; Lubricants; Male; Middle Aged; Ophthalmic Solutions; Ophthalmologic Surgical Procedures; Ophthalmoscopy; Rabbits

The neuroprotective effect of N-acetylcysteine (NAC), a sulfhydryl-containing antioxidant, on experimentally induced subarachnoid hemorrhage (SAH) in rats was assessed. NAC was administered to rats after the induction of SAH. Neurological deficits and brain edema were investigated. The activity of antioxidant defense enzymes, copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px), were measured in the brain cortex by spectrophotometer. The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. We found that NAC markedly reversed the SAH-induced neurological deficit and brain edema. We further investigated the mechanism involved in the neuroprotective effects of NAC on rat brain tissue and found that NAC significantly increased CuZn-SOD and GSH-Px activity and decreased MDA content in the SAH brain. NAC has the potential to be a novel therapeutic strategy for the treatment of SAH, and its neuroprotective effect may be partly mediated via enhancing the activity of endogenous antioxidant enzymes and inhibiting free radical generation.

Topics: Analysis of Variance; Animals; Brain Edema; Carnosine; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Glutathione Peroxidase; Lipid Peroxidation; Male; Malondialdehyde; Nervous System Diseases; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Superoxide Dismutase