Inhaling xenon ameliorates l-dopa-induced dyskinesia in experimental parkinsonism

Mov Disord. 2018 Oct;33(10):1632-1642. doi: 10.1002/mds.27404. Epub 2018 May 14.

Abstract

Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa-induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa-induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: NMDA; behavior; corticostriatal plasticity; primate; rodent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Animals
  • Antiparkinson Agents / adverse effects*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / etiology
  • Gait Disorders, Neurologic / drug therapy
  • Gait Disorders, Neurologic / etiology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Levodopa / adverse effects*
  • MPTP Poisoning / drug therapy
  • Mice
  • Mice, Transgenic
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / complications
  • Parkinsonian Disorders / drug therapy*
  • Rats
  • Sensation Disorders / drug therapy
  • Sensation Disorders / etiology
  • Sympatholytics / toxicity
  • Time Factors
  • Xenon / therapeutic use*

Substances

  • Antiparkinson Agents
  • Sympatholytics
  • Green Fluorescent Proteins
  • Xenon
  • Levodopa
  • Oxidopamine