Drosophila melanogaster

A new model to study cisplatin-induced neurotoxicity

Jewel L. Podratz, Nathan P Staff, Dara Froemel, Anna Wallner, Florian Wabnig, Allan J. Bieber, Amy Tang, Anthony John Windebank

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Platinum-based compounds are widely used and effective chemotherapeutic agents; however, sensory peripheral neuropathy is a dose-limiting and long term side effect for 20-30% of patients. A critical question is whether the mechanisms of cell death underlying clinical efficacy can be separated from the effects on neurons in order to develop strategies that prevent platinum-induced neuropathy. In rodent dorsal root ganglion neurons (DRG), cisplatin has been shown to bind and damage neuronal DNA, inducing apoptosis; however genetic manipulation in order to study mechanisms of this phenomenon in the rodent model system is costly and time-consuming. Drosophila melanogaster are commonly used to study neurological disorders, have DNA damage-apoptosis mechanisms homologous to mammalian systems, and have readily-available, inexpensive tools for rapid genetic manipulation. We therefore sought to develop adult Drosophila as a new model to study cisplatin-induced neurotoxicity. Adult Drosophila were exposed to 10, 25, 50, 100, 200 and 400μg/ml cisplatin for 3. days and observed for fly survival and geotactic climbing behavior, cisplatin-DNA binding and cellular apoptosis. On day 3, 50μg/ml cisplatin reduced the number of flies able to climb above 2. cm to 43% while fly survival was maintained at 92%. 100% lethality was observed at 400μg/ml cisplatin. Whole fly platinum-genomic DNA adducts were measured and found to be comparable to adduct levels previously measured in rat DRG neurons. Brain, ovaries, kidney and heart harvested from cisplatin treated flies were stained for active caspase 3. Apoptosis was found in ovaries and brain but not in heart and kidney. Brain apoptosis was confirmed by transmission electron microscopy. Expression of the anti-apoptotic baculoviral protein, p35, in neurons using the GAL4-UAS system prevented cisplatin-induced apoptosis in the brain and restored climbing behavior. In conclusion, cisplatin-induced behavioral and apoptotic changes in Drosophila resemble those seen in mammals. Furthermore, the use of lethality and climbing assays combined with powerful gene manipulation, make Drosophila a suitable model to study mechanisms of cisplatin neurotoxicity.

Original languageEnglish (US)
Pages (from-to)330-337
Number of pages8
JournalNeurobiology of Disease
Volume43
Issue number2
DOIs
StatePublished - Aug 2011

Fingerprint

Drosophila melanogaster
Cisplatin
Diptera
Apoptosis
Drosophila
Neurons
Brain
Spinal Ganglia
Platinum
DNA Damage
Ovary
Rodentia
Platinum Compounds
Kidney
Apoptosis Regulatory Proteins
DNA Adducts
Peripheral Nervous System Diseases
Nervous System Diseases
Transmission Electron Microscopy
Caspase 3

Keywords

  • Apoptosis
  • Behavior
  • Chemotherapy
  • Cisplatin
  • Drosophila
  • Genetics
  • Model
  • Neuropathy
  • Neuroprotection
  • Neurotoxicity

ASJC Scopus subject areas

  • Neurology

Cite this

Drosophila melanogaster : A new model to study cisplatin-induced neurotoxicity. / Podratz, Jewel L.; Staff, Nathan P; Froemel, Dara; Wallner, Anna; Wabnig, Florian; Bieber, Allan J.; Tang, Amy; Windebank, Anthony John.

In: Neurobiology of Disease, Vol. 43, No. 2, 08.2011, p. 330-337.

Research output: Contribution to journalArticle

Podratz, Jewel L. ; Staff, Nathan P ; Froemel, Dara ; Wallner, Anna ; Wabnig, Florian ; Bieber, Allan J. ; Tang, Amy ; Windebank, Anthony John. / Drosophila melanogaster : A new model to study cisplatin-induced neurotoxicity. In: Neurobiology of Disease. 2011 ; Vol. 43, No. 2. pp. 330-337.
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