Systemic administration of N-acetylcysteine protects dopaminergic neurons against 6-hydroxydopamine-induced degeneration.
The results of several in vitro studies have shown that cysteine prodrugs, particularly N-acetylcysteine, are effective antioxidants that increase the survival of dopaminergic neurons. N-acetylcysteine can be systemically administered to deliver cysteine to the brain and is of potential use for providing neuroprotection in the treatment of Parkinson's disease. However, it has also been reported that an excess of cysteine may induce neurotoxicity. In the present study, we injected adult rats intrastriatally with 2.5 microl of 6-hydroxydopamine (7.5 microg) and N-acetylcysteine (240 mM) or cysteine (240 mM) or intraventricularly with 6-hydroxydopamine (200 microg) and subcutaneously with N-acetylcysteine (10 and 100 mg/kg). We studied the effects of these compounds on both the nigrostriatal dopaminergic terminals and the surrounding striatal tissue. The tissue was stained with fluoro-jade (a marker of neuronal degeneration) and processed by immunohistochemistry to detect tyrosine hydroxylase, neuronal and glial markers, and the stress protein heme-oxygenase-1. After intrastriatal injection, both cysteine and N-acetylcysteine had clear neuroprotective effects on the striatal dopaminergic terminals, but also led to neuronal degeneration (as revealed by fluoro-jade staining) and astroglial and microglial activation, as well as intense induction of heme-oxygenase-1 in astrocytes and microglial cells. Subcutaneous administration of N-acetylcysteine also induced significant reduction of the dopaminergic lesion (about 30% reduction). However, we did not observe appreciable N-acetylcysteine-induced fluoro-jade labeling in striatal neurons or any of the above-mentioned changes in striatal glial cells. The results suggest that low doses of cysteine prodrugs may be useful neuroprotectors in the treatment of Parkinson's disease.
Muñoz
Ana M
AM
Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.
Rey
Pablo
P
Soto-Otero
Ramon
R
Guerra
Maria J
MJ
Labandeira-Garcia
Jose L
JL
D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D001205:Ascorbic Acid; D030161:Avian Proteins; D051926:Basigin; D001798:Blood Proteins; D002452:Cell Count; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D003545:Cysteine / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism*; D004333:Drug Administration Routes; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes / Q000378:metabolism; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006892:Hydroxydopamines; D007150:Immunohistochemistry / Q000379:methods; D008562:Membrane Glycoproteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009930:Organic Chemicals; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D005452:Fluoresceins; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D005904:Glial Fibrillary Acidic Protein; D006892:Hydroxydopamines; D008562:Membrane Glycoproteins; D009930:Organic Chemicals; C435731:fluoro jade; D051926:Basigin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; D003545:Cysteine; D001205:Ascorbic Acid; D004298:Dopamine; D000111:Acetylcysteine