Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis

Exp Neurol. 2015 May:267:115-22. doi: 10.1016/j.expneurol.2015.03.004. Epub 2015 Mar 13.

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease in which the majority of upper and lower motor neurons are degenerated. Despite intensive efforts to identify drug targets and develop neuroprotective strategies, effective therapeutics for ALS remains unavailable. The identification and characterization of novel targets and pathways remain crucial in the development of ALS therapeutics. Adenosine is a major neuromodulator that actively regulates synaptic transmission. Interestingly, adenosine levels are significantly elevated in the cerebrospinal fluid (CSF) of progressing human ALS patients. In the current study, we showed that adenosine 2a receptor (A2aR), but not adenosine 1 receptor (A1R), is highly enriched in spinal (motor) neurons. A2aR expression is also selectively increased at the symptomatic onset in the spinal cords of SOD1G93A mice and end-stage human ALS spinal cords. Interestingly, we found that direct adenosine treatment is sufficient to induce embryonic stem cell-derived motor neuron (ESMN) cell death in cultures. Subsequent pharmacological inhibition and partial genetic ablation of A2aR (A2aR(+/-)) significantly protect ESMN from SOD1G93A(+) astrocyte-induced cell death and delay disease progression of SOD1G93A mice. Taken together, our results provide compelling novel evidence that A2aR-mediated adenosine signaling contributes to the selective spinal motor neuron degeneration observed in the SOD1G93A mouse model of ALS.

Keywords: A(2a) receptor; Adenosine; Amyotrophic lateral sclerosis (ALS); Astrocyte; KW6002; Motor neuron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism*
  • Adenosine / therapeutic use
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Adenosine A2 Receptor Antagonists / therapeutic use
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Astrocytes / drug effects
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mediator Complex / genetics
  • Mediator Complex / metabolism
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Muscle Strength / drug effects
  • Muscle Strength / genetics
  • Purines / pharmacology
  • Purines / therapeutic use
  • Receptor, Adenosine A2A / deficiency*
  • Receptor, Adenosine A2A / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics

Substances

  • Adenosine A2 Receptor Antagonists
  • Mediator Complex
  • Purines
  • Receptor, Adenosine A2A
  • istradefylline
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Adenosine