Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease.
BACKGROUND
Parkinson's disease (PD) is the most common movement disorder. Extrapyramidal motor symptoms stem from the degeneration of the dopaminergic pathways in patient brain. Current treatments for PD are symptomatic, alleviating disease symptoms without reversing or retarding disease progression. Although the cause of PD remains unknown, several pathogenic factors have been identified, which cause dopaminergic neuron (DN) death in the substantia nigra (SN). These include oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity. Manipulation of these factors may allow the development of disease-modifying treatment strategies to slow neuronal death. Inhibition of DJ-1A, the Drosophila homologue of the familial PD gene DJ-1, leads to oxidative stress, mitochondrial dysfunction, and DN loss, making fly DJ-1A model an excellent in vivo system to test for compounds with therapeutic potential.


RESULTS
In the present study, a Drosophila DJ-1A model of PD was used to test potential neuroprotective drugs. The drugs applied are the Chinese herb celastrol, the antibiotic minocycline, the bioenergetic amine coenzyme Q10 (coQ10), and the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo[f]-quinoxaline (NBQX). All of these drugs target pathogenic processes implicated in PD, thus constitute mechanism-based treatment strategies. We show that celastrol and minocycline, both having antioxidant and anti-inflammatory properties, confer potent dopaminergic neuroprotection in Drosophila DJ-1A model, while coQ10 shows no protective effect. NBQX exerts differential effects on cell survival and brain dopamine content: it protects against DN loss but fails to restore brain dopamine level.


CONCLUSIONS
The present study further validates Drosophila as a valuable model for preclinical testing of drugs with therapeutic potential for neurodegenerative diseases. The lower cost and amenability to high throughput testing make Drosophila PD models effective in vivo tools for screening novel therapeutic compounds. If our findings can be further validated in mammalian PD models, they would implicate drugs combining antioxidant and anti-inflammatory properties as strong therapeutic candidates for mechanism-based PD treatment.
Faust
Katharina
K
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. katharina.faust@charite.de
Gehrke
Stephan
S
Yang
Yufeng
Y
Yang
Lichuan
L
Beal
M Flint
MF
Lu
Bingwei
B
D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism*; D004330:Drosophila; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D011810:Quinoxalines / Q000627:therapeutic use; D014315:Triterpenes / Q000627:therapeutic use; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D053978:Pentacyclic Triterpenes; D011810:Quinoxalines; D014315:Triterpenes; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D014451:Ubiquinone; C024989:coenzyme Q10; C050414:celastrol; D004298:Dopamine