title: Investigation of the therapeutic potential of N-acetyl cysteine and the tools used to define nigrostriatal degeneration in vivo.
abstract: The glutathione precursor N-acetyl-L-cysteine (NAC) is currently being tested on Parkinson's patients for its neuroprotective properties. Our studies have shown that NAC can elicit protection in glutathione-independent manners in vitro. Thus, the goal of the present study was to establish an animal model of NAC-mediated protection in which to dissect the underlying mechanism. Mice were infused intrastriatally with the oxidative neurotoxicant 6-hydroxydopamine (6-OHDA; 4 μg) and administered NAC intraperitoneally (100mg/kg). NAC-treated animals exhibited higher levels of the dopaminergic terminal marker tyrosine hydroxylase (TH) in the striatum 10d after 6-OHDA. As TH expression is subject to stress-induced modulation, we infused the tracer FluoroGold into the striatum to retrogradely label nigrostriatal projection neurons. As expected, nigral FluoroGold staining and cell counts of FluoroGold(+) profiles were both more sensitive measures of nigrostriatal degeneration than measurements relying on TH alone. However, NAC failed to protect dopaminergic neurons 3 weeks following 6-OHDA, an effect verified by four measures: striatal TH levels, nigral TH levels, nigral TH(+) cell counts, and nigral FluoroGold levels. Some degree of mild toxicity of FluoroGold and NAC was evident, suggesting that caution must be exercised when relying on FluoroGold as a neuron-counting tool and when designing experiments with long-term delivery of NAC--such as clinical trials on patients with chronic disorders. Finally, the strengths and limitations of the tools used to define nigrostriatal degeneration are discussed.
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United States.
authors.forename: Negin
authors.initials: N
authors.lastname: Nouraei
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Zarger
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United States.
authors.forename: Justin N
authors.initials: JN
authors.lastname: Weilnau
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United States.
authors.forename: Jimin
authors.initials: J
authors.lastname: Han
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United States.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Mason
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, United States. Electronic address: leakr@duq.edu.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*
chemical_list: D018696:Neuroprotective Agents; D016627:Oxidopamine; D000111:Acetylcysteine
keywords: Dopamine; FluoroGold; N-acetylcysteine; Neurodegeneration; Parkinson's disease; Retrograde; The reference trap