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Targeting soluble guanylyl cyclase in experimental Parkinsonism
Author(s) -
West Anthony R,
Park Diana J,
Sammut Stephen,
Sunu Elizabeth,
Park Michael J,
BlumeRice Shan,
Tseng Kuei Y
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb467
Subject(s) - striatum , soluble guanylyl cyclase , neuroscience , basal ganglia , subthalamic nucleus , parkinsonism , substantia nigra , excitatory postsynaptic potential , chemistry , medicine , dopamine , endocrinology , biology , parkinson's disease , central nervous system , inhibitory postsynaptic potential , dopaminergic , nitric oxide , deep brain stimulation , disease , guanylate cyclase
Alterations in striatal cyclic nucleotide homeostasis are apparent following loss of dopamine (DA) innervation and may contribute to pathophysiological changes observed in basal ganglia circuits in Parkinson's disease (PD). This study examined the utility of systemic administration of the soluble guanylyl cyclase (sGC) inhibitor [1H‐[1,2,4] oxadiazolo‐[4,3‐a]quinoxalin‐1‐one] (ODQ) for reversing electrophysiological, histochemical, and behavioral abnormalities observed in 6‐hydroxydopamine (6‐OHDA)‐lesioned rats. Striatal single‐units recorded in DA‐depleted rats exhibited robust spontaneous firing and burst activity which was temporally associated with the depolarizing phase of local field potentials recorded in the motor cortex. ODQ administration reversed the pathological elevations in striatal unit activity and cytochrome oxidase staining observed in the subthalamic nucleus (STN) of 6‐OHDA‐lesioned rats. Moreover, ODQ treatment transiently attenuated forelimb akinesia in 6‐OHDA‐lesioned rats exhibiting incomplete (<85%) DA cell loss. These observations suggest that cGMP signaling contributes in an important manner to the overactive excitatory transmission observed in striatopallidal neurons in the DA‐depleted striatum. Thus, sGC inhibition may represent an effective therapeutic strategy for restoring motor deficits observed in PD following incomplete DA cell loss.