Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats

Respir Physiol Neurobiol. 2014 Jun 15;197:19-28. doi: 10.1016/j.resp.2014.03.005. Epub 2014 Mar 28.

Abstract

In rats over-expressing SOD1G93A, ventilation is preserved despite significant loss of respiratory motor neurons. Thus, unknown forms of compensatory respiratory plasticity may offset respiratory motor neuron cell death. Although mechanisms of such compensation are unknown, other models of respiratory motor plasticity may provide a conceptual guide. Multiple cellular mechanisms give rise to phrenic motor facilitation; one mechanism requires spinal serotonin receptor and NADPH oxidase activity whereas another requires spinal adenosine receptor activation. Here, we studied whether these mechanisms contribute to compensatory respiratory plasticity in SOD1G93A rats. Using plethysmography, we assessed ventilation in end-stage SOD1G93A rats after: (1) serotonin depletion with parachlorophenylalanine (PCPA), (2) serotonin (methysergide) and A2A (MSX-3) receptor inhibition, (3) NADPH oxidase inhibition (apocynin), and (4) combined treatments. The ability to increase ventilation was not decreased by individual or combined treatments; thus, these mechanisms do not maintain breathing capacity at end-stage motor neuron disease. Possible mechanisms giving rise to enhanced breathing capacity with combined treatment in end-stage SOD1G93A rats are discussed.

Keywords: Compensatory plasticity; Facilitation; Plethysmography; Respiration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetophenones / pharmacology
  • Adenosine / physiology*
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Male
  • Methysergide / pharmacology
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Motor Neurons / physiology
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / metabolism
  • Phrenic Nerve / drug effects
  • Phrenic Nerve / pathology
  • Phrenic Nerve / physiopathology
  • Plethysmography
  • Pulmonary Ventilation / drug effects*
  • Pulmonary Ventilation / physiology*
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Respiration* / drug effects
  • Serotonin / physiology*
  • Serotonin Antagonists / pharmacology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Tidal Volume / drug effects
  • Tidal Volume / physiology
  • Xanthines / pharmacology

Substances

  • Acetophenones
  • Adenosine A2 Receptor Antagonists
  • Enzyme Inhibitors
  • MSX 3 compound
  • SOD1 protein, human
  • Serotonin Antagonists
  • Xanthines
  • Serotonin
  • acetovanillone
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • NADPH Oxidases
  • Adenosine
  • Methysergide