Role of A3 adenosine receptor in diabetic neuropathy

J Neurosci Res. 2016 Oct;94(10):936-46. doi: 10.1002/jnr.23774. Epub 2016 Jun 19.

Abstract

Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc.

Keywords: A3; adenosine; diabetic neuropathy; neuropathic pain; spinal cord; streptozocin.

MeSH terms

  • Action Potentials / drug effects
  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Animals
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Diabetic Neuropathies / chemically induced
  • Diabetic Neuropathies / metabolism*
  • Diabetic Neuropathies / pathology
  • Diabetic Neuropathies / physiopathology
  • Disease Models, Animal
  • Eating / drug effects
  • Hyperalgesia / drug therapy
  • Hyperalgesia / etiology
  • Male
  • Mice
  • Muscle, Skeletal / drug effects
  • NF-kappa B / metabolism
  • Neural Conduction / drug effects
  • Pain Threshold / drug effects
  • Receptor, Adenosine A3 / metabolism*
  • Sciatic Nerve / drug effects
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Streptozocin / toxicity

Substances

  • Blood Glucose
  • NF-kappa B
  • Receptor, Adenosine A3
  • N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine
  • Streptozocin
  • Adenosine