title: Inhibition of striatal soluble guanylyl cyclase-cGMP signaling reverses basal ganglia dysfunction and akinesia in experimental parkinsonism.
abstract: OBJECTIVE
  There is clearly a necessity to identify novel non-dopaminergic mechanisms as new therapeutic targets for Parkinson's disease (PD). Among these, the soluble guanylyl cyclase (sGC)-cGMP signaling cascade is emerging as a promising candidate for second messenger-based therapies for the amelioration of PD symptoms. In the present study, we examined the utility of the selective sGC inhibitor 1H-[1], [2], [4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) for reversing basal ganglia dysfunction and akinesia in animal models of PD.
  
  
  METHODS
  The utility of the selective sGC inhibitor ODQ for reversing biochemical, electrophysiological, histochemical, and behavioral correlates of experimental PD was performed in 6-OHDA-lesioned rats and mice chronically treated with MPTP.
  
  
  RESULTS
  We found that one systemic administration of ODQ is sufficient to reverse the characteristic elevations in striatal cGMP levels, striatal output neuron activity, and metabolic activity in the subthalamic nucleus observed in 6-OHDA-lesioned rats. The latter outcome was reproduced after intrastriatal infusion of ODQ. Systemic administration of ODQ was also effective in improving deficits in forelimb akinesia induced by 6-OHDA and MPTP.
  
  
  CONCLUSIONS
  Pharmacological inhibition of the sGC-cGMP signaling pathway is a promising non-dopaminergic treatment strategy for restoring basal ganglia dysfunction and attenuating motor symptoms associated with PD.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Rosalind Franklin University/The Chicago Medical School, North Chicago, Illinois, United States of America.
authors.forename: Kuei Y
authors.initials: KY
authors.lastname: Tseng
authors.forename: Adriana
authors.initials: A
authors.lastname: Caballero
authors.forename: Alexander
authors.initials: A
authors.lastname: Dec
authors.forename: Daryn K
authors.initials: DK
authors.lastname: Cass
authors.forename: Natalie
authors.initials: N
authors.lastname: Simak
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sunu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Park
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Blume
authors.forename: Stephen
authors.initials: S
authors.lastname: Sammut
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Park
authors.forename: Anthony R
authors.initials: AR
authors.lastname: West
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000201:enzymology*; D006152:Cyclic GMP / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071756:Soluble Guanylyl Cyclase
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
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