title: Pharmacological evaluation of novel alagebrium analogs as methylglyoxal scavengers in vitro in cardiac myocytes and in vivo in SD rats.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Arti
authors: A
authors: Dhar
authors: Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India.
authors: Mary Priyanka
authors: MP
authors: Udumula
authors: Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India.
authors: Brahmam
authors: B
authors: Medapi
authors: Center for Molecular Biology, Central University of Jammu, India.
authors: Audesh
authors: A
authors: Bhat
authors: Department of Clinical Science, University of Bergen, Norway.
authors: Indu
authors: I
authors: Dhar
authors: Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India.
authors: Prasanthi
authors: P
authors: Malapati
authors: Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India.
authors: Mangali Suresh
authors: MS
authors: Babu
authors: Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India.
authors: Jaspreet
authors: J
authors: Kalra
authors: Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad, Andhra Pradesh 500078, India.
authors: Dharamrajan
authors: D
authors: Sriram
authors: Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
authors: Kaushik M
authors: KM
authors: Desai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017127:Glycation End Products, Advanced / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D017127:Glycation End Products, Advanced; D013844:Thiazoles; D011765:Pyruvaldehyde; C406794:alagebrium
keywords: Alagebrium; Apoptosis; Cardiomyocytes; Compound 13; Methylglyoxal; Oxidative stress