Skin beautification with oral non-hydrolized versions of carnosine and carcinine: Effective therapeutic management and cosmetic skincare solutions against oxidative glycation and free-radical production as a causal mechanism of diabetic complications and skin aging

Abstract

Advanced glycation Maillard reaction end products (AGEs) are causing the complications of diabetes and skin aging, primarily via adventitious and cross-linking of proteins. Long-lived proteins such as structural collagen are particularly implicated as pathogenic targets of AGE processes. The formation of α-dicarbonyl compounds represents an important step for cross-linking proteins in the glycation or Maillard reaction. The purpose of this study was to investigate the contribution of glycation coupled to the glycation free-radical oxidation reactions as markers of protein damage in the aging of skin tissue proteins and diabetes. To elucidate the mechanism for the cross-linking reaction, we studied the reaction between a three-carbon α-dicarbonyl compound, methylglyoxal, and amino acids using EPR spectroscopy, a spectrophotometric kinetic assay of superoxide anion production at the site of glycation and a chemiluminescence technique. The transglycating activity, inhibition of transition metal ions peroxidative catalysts, resistance to hydrolysis of carnosine mimetic peptide-based compounds with carnosinase and the protective effects of carnosine, carcinine and related compounds against the oxidative damage of proteins and lipid membranes were assessed in a number of biochemical and model systems. A 4-month randomized, double-blind, controlled study was undertaken including 42 subjects where the oral supplement of non-hydrolized carnosine (Can-C Plus® formulation) was tested against placebo for 3 months followed by a 1-month supplement-free period for both groups to assess lasting effects. Assessment of the age-related skin parameters and oral treatment efficacy measurements included objective skin surface evaluation with Visioscan® VC 98 and visual assessment of skin appearance parameters. The results together confirm that a direct one-electron transfer between a Schiff base methylglyoxal dialkylimine (or its protonated form) and methylglyoxal is responsible for the generation of the cross-linked radical cation and the radical counteranion of methylglyoxal. Under aerobic conditions, molecular oxygen can then accept an electron from the methylglyoxal anion to generate the superoxide radical anion causing the propagation of oxidative stress chain reactions in the presence of transition metal ions. Carnosine stabilized from enzymatic hydrolysis, carcinine and leucyl-histidylhydrazide in patented formulations thereof, demonstrate the Schiff bases' transglycating activities concomitant with glycation site specific antioxidant activities and protection of proprietary antioxidant enzymes in the skin during aging and with diabetes lesions. During oral supplementation with stabilized from enzymatic hydrolysis carnosine (Can-C Plus® formulation), the skin parameters investigated showed a continuous and significant improvement in the active group during the 3 months of supplementation as compared to placebo. Visual investigation showed improvement of the overall skin appearance and a reduction of fine lines. No treatment-related side effects were reported. The finding that already-formed AGE cross-links can be pharmacologically severed and attendant pathology thereby reversed by non-hydrolized carnosine or carcinine in patented oral formulations thereof has broad implications for the skin beautification and therapeutics of the complications of diabetes and skin diseases associated with aging.

Key words::

• advanced glycation Maillard reaction and lipoxidation end products
• complications of diabetes and skin aging
• α-dicarbonyl compounds
• imidazole-containing dipeptides
• Schiff bases' transglycating activities
• skin care
• superoxide anion radical production

Acknowledgements

This work was planned, organized, and supported by Innovative Vision Products, Inc. (New Castle, DE, USA).

Innovative Vision Products Inc. (IVP) is a Pharmaceutical and Nanotechnology Development Company with a focus on innovative chemical entities, drug delivery systems, and unique medical devices to target specific biomedical applications. Over the last decade IVP has developed a track record in developing these technologies to effectively address the unmet needs of specific diseased populations. The biologically significant applications of carnosine mimetics, including those in cosmetics and dermatology, were patented by Dr M. A. Babizhayev and the alliance groups (WO 2004/028536 A1; WO 94/19325; WO 95/12581; WO 2004/064866 A1).

Professor Y. E. Yegorov was supported by the Russian Foundation for Basic Research (grant 09-04-01071a) and the Federal Agency for Education (State contract P1293).

Declaration of interest: The author (Dr. Mark A. Babizhayev) reports his interest in the intellectual property and marketing of the described modalities protected with the patents. The authors bear primary responsibility for the accuracy of made statements and for the content and writing of the paper.