Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis.

Abstract

Imidazoline compounds have been considered for the treatment of type 2 diabetes. We have now investigated the effects of imidazolines on interleukin (IL)-1beta-induced beta-cell apoptosis and the signal transduction pathways involved. Inhibition of Ca2+ influx into beta-cells by D-600, a blocker of voltage-gated L-type Ca2+ channels, suppressed IL-1beta-induced apoptosis. Our data show that calcineurin, Ca2+/calmodulin-dependent serine/threonine protein phosphatase 2B, is responsible for the effect of Ca2+ on beta-cell apoptosis. We also demonstrate that IL-1beta-mediated apoptosis correlates with expression of inducible nitric oxide synthase (iNOS) and the increase in intracellular production of nitric oxide. An inhibitor of cGMP-dependent protein kinase (PKG), KT5823, suppressed IL-1beta-induced apoptosis, suggesting the involvement of a PKG-dependent pathway in the apoptotic process. One of the major findings in this study is that imidazoline compounds RX871024 and efaroxan, suggested as prototypes of a new generation of drugs against type 2 diabetes, can protect against IL-1beta-induced apoptosis in pancreatic beta-cells, possibly by their inhibition of the expression of iNOS, a key element in the IL-1beta-induced apoptotic pathway in pancreatic beta-cells. These data suggest that imidazoline compounds should be explored as a potential therapeutic agent for the treatment of both type 1 and type 2 diabetes.

• Authors: S V Zaitsev, I B Appelskog, I L Kapelioukh, S N Yang, M Köhler, S Efendic, P O Berggren
• Journal: Diabetes (Diabetes) Vol. 50 Suppl 1 Pg. S70-6 (Feb 2001) ISSN: 0012-1797 [Print] United States
• PMID: 11272206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-imidazolin-2-yl)-1-phenyl-1H-indole
• Benzofurans
• Calcineurin Inhibitors
• Calcium Channel Blockers
• Calcium Channels
• Enzyme Inhibitors
• Imidazoles
• Indoles
• Interleukin-1
• Nitriles
• Pyrethrins
• decamethrin
• Gallopamil
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Calcineurin
• efaroxan
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Apoptosis (drug effects)
• Benzofurans (pharmacology)
• Calcineurin (metabolism)
• Calcineurin Inhibitors
• Calcium Channel Blockers (pharmacology)
• Calcium Channels (physiology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Gallopamil (pharmacology)
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Interleukin-1 (pharmacology)
• Islets of Langerhans (cytology, drug effects, physiology)
• Membrane Potentials (drug effects)
• Mice
• Mice, Obese
• Models, Biological
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Nitric Oxide Synthase Type II
• Nitriles
• Patch-Clamp Techniques
• Pyrethrins (pharmacology)