The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson's disease

J Exp Med. 2012 Apr 9;209(4):837-54. doi: 10.1084/jem.20112285. Epub 2012 Apr 2.

Abstract

Parkinson's disease (PD) is a progressive, chronic disease characterized by dyskinesia, rigidity, instability, and tremors. The disease is defined by the presence of Lewy bodies, which primarily consist of aggregated α-synuclein protein, and is accompanied by the loss of monoaminergic neurons. Current therapeutic strategies only give symptomatic relief of motor impairment and do not address the underlying neurodegeneration. Hence, we have identified Cu(II)(atsm) as a potential therapeutic for PD. Drug administration to four different animal models of PD resulted in improved motor and cognition function, rescued nigral cell loss, and improved dopamine metabolism. In vitro, this compound is able to inhibit the effects of peroxynitrite-driven toxicity, including the formation of nitrated α-synuclein oligomers. Our results show that Cu(II)(atsm) is effective in reversing parkinsonian defects in animal models and has the potential to be a successful treatment of PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cognition / drug effects*
  • Disease Models, Animal
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molsidomine / analogs & derivatives
  • Molsidomine / pharmacology
  • Motor Activity / drug effects*
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Organometallic Compounds / pharmacology
  • Organometallic Compounds / therapeutic use*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / psychology
  • Positron-Emission Tomography
  • Radiopharmaceuticals / pharmacology
  • Radiopharmaceuticals / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Thiosemicarbazones / pharmacology
  • Thiosemicarbazones / therapeutic use*
  • alpha-Synuclein / chemistry

Substances

  • Neuroprotective Agents
  • Organometallic Compounds
  • Radiopharmaceuticals
  • Thiosemicarbazones
  • alpha-Synuclein
  • copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
  • linsidomine
  • Molsidomine