Nucleic acid binding agents exert local toxic effects on neurites via a non-nuclear mechanism

Sokhon Pin, Huiling Chen, Pamela J Lein, Michael M. Wang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The mechanism by which drugs that target nucleic acids cause neurotoxicity is not well described. We characterized the neurotoxicity of Hoechst 33342 (bis-benzimide), a common cell permeable nuclear dye, in primary neuronal cultures. The mechanism of cell death was not apoptotic, as death is rapid, not accompanied by typical nuclear morphological changes, and is insensitive to inhibitors of transcription, translation and caspase activity. In addition, free-radical scavenging agents failed to attenuate cell death, and damage was not accompanied by mitochondrial dysfunction. Neuronal processes of cells exposed to Hoechst 33342 display dramatic fragmentation prior to cell death. When this compound was applied selectively to the distal axons of sympathetic neurons grown in compartmented cultures, the distal axons were destroyed. However, the proximal processes present in the cell body compartment were spared, demonstrating direct axonal toxicity rather than a remote effect of nuclear dysfunction. Other cell-permeable nucleic acid binding dyes similarly caused rapid dendritic and axonal toxicity. The hypothesis that these nucleic acid binding dyes target RNA localized to dendrites and axons is supported by observations that RNaseq2V1 induced similar, rapid neurite fragmentation. We conclude that the neurotoxic effects of nucleic acid binding compounds are mediated, at least in part, by direct neurite injury, which does not require involvement of the cell body and nucleus.

Original languageEnglish (US)
Pages (from-to)1253-1266
Number of pages14
JournalJournal of Neurochemistry
Volume96
Issue number5
DOIs
StatePublished - Mar 2006
Externally publishedYes

Fingerprint

Poisons
Neurites
Nucleic Acids
Cell death
Axons
Cell Death
Coloring Agents
Toxicity
Cells
Scavenging
Transcription
Caspases
Dendrites
Cell Nucleus
Cell culture
Neurons
Free Radicals
RNA
Wounds and Injuries
Pharmaceutical Preparations

Keywords

  • Cortical neurons
  • Hoechst
  • Neurite
  • Neurotoxicity
  • Nucleic acid dyes
  • RNase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Nucleic acid binding agents exert local toxic effects on neurites via a non-nuclear mechanism. / Pin, Sokhon; Chen, Huiling; Lein, Pamela J; Wang, Michael M.

In: Journal of Neurochemistry, Vol. 96, No. 5, 03.2006, p. 1253-1266.

Research output: Contribution to journalArticle

Pin, Sokhon ; Chen, Huiling ; Lein, Pamela J ; Wang, Michael M. / Nucleic acid binding agents exert local toxic effects on neurites via a non-nuclear mechanism. In: Journal of Neurochemistry. 2006 ; Vol. 96, No. 5. pp. 1253-1266.
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