Arti Dhar1, Mary Priyanka Udumula2, Brahmam Medapi2, Audesh Bhat3, Indu Dhar4, Prasanthi Malapati2, Mangali Suresh Babu2, Jaspreet Kalra2, Dharamrajan Sriram2, Kaushik M Desai5. 1. Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India. Electronic address: artidhar@hyderabad.bits-pilani.ac.in. 2. Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India. 3. Center for Molecular Biology, Central University of Jammu, India. 4. Department of Clinical Science, University of Bergen, Norway. 5. Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Abstract
BACKGROUND: Methylglyoxal (MG) is a byproduct of glucose metabolism and an inducer of advanced glycation end products (AGEs). AGEs are implicated in the pathogenesis of diabetes as well as hypertension. Most of the currently available MG scavengers are non-specific and have other effects as well. Alagebrium (ALA), developed by Alteon Corporation is a MG scavenger. Thus the aim of the present study was to investigate the potential of novel ALA analogs as possible MG scavengers and whether they could prevent any deleterious effects of MG. METHODS AND RESULTS: MG levels were measured by HPLC. The different biochemical and molecular parameters were measured by assay kits, RT-PCR and immunocytochemistry. Out of the 15 ALA analogs tested in vitro, compound no. 13 was found to be an effective inhibitor of MG in a concentration and time dependent manner. Compound no. 13 significantly attenuated the MG levels in vitro in MG treated cultured H9C2 cardiomyocytes as well as in vivo in MG treated SD rats. MG induced oxidative stress and apoptosis were attenuated by pretreatment of H9C2 cardiac myocytes with compound no. 13. MG induced cardiac hypertrophy and apoptosis were also attenuated by treating MG treated SD rats with compound no. 13. CONCLUSION: Our results indicate compound 13 as an effective inhibitor of MG in vitro in cultured cardiomyocytes and in vivo in SD rats and thus it may prove very useful in blocking the multiple deleterious effects of MG, including AGEs and vascular complications of diabetes.
BACKGROUND:Methylglyoxal (MG) is a byproduct of glucose metabolism and an inducer of advanced glycation end products (AGEs). AGEs are implicated in the pathogenesis of diabetes as well as hypertension. Most of the currently available MG scavengers are non-specific and have other effects as well. Alagebrium (ALA), developed by Alteon Corporation is a MG scavenger. Thus the aim of the present study was to investigate the potential of novel ALA analogs as possible MG scavengers and whether they could prevent any deleterious effects of MG. METHODS AND RESULTS:MG levels were measured by HPLC. The different biochemical and molecular parameters were measured by assay kits, RT-PCR and immunocytochemistry. Out of the 15 ALA analogs tested in vitro, compound no. 13 was found to be an effective inhibitor of MG in a concentration and time dependent manner. Compound no. 13 significantly attenuated the MG levels in vitro in MG treated cultured H9C2 cardiomyocytes as well as in vivo in MG treated SD rats. MG induced oxidative stress and apoptosis were attenuated by pretreatment of H9C2 cardiac myocytes with compound no. 13. MG induced cardiac hypertrophy and apoptosis were also attenuated by treating MG treated SD rats with compound no. 13. CONCLUSION: Our results indicate compound 13 as an effective inhibitor of MG in vitro in cultured cardiomyocytes and in vivo in SD rats and thus it may prove very useful in blocking the multiple deleterious effects of MG, including AGEs and vascular complications of diabetes.