Molecular Mechanisms of Neurotoxicity Induced by Polymyxins and Chemoprevention

Chongshan Dai, Xilong Xiao, Jichang Li, Giuseppe D. Ciccotosto, Roberto Cappai, Shusheng Tang, Elena K. Schneider-Futschik, Daniel Hoyer, Tony Velkov, Jianzhong Shen

Research output: Contribution to journalReview ArticleResearchpeer-review

43 Citations (Scopus)

Abstract

Neurotoxicity is one major unwanted side-effects associated with polymyxin (i.e., colistin and polymyxin B) therapy. Clinically, colistin neurotoxicity is characterized by neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, and facial and peripheral paresthesias. Pathologically, colistin-induced neurotoxicity is characterized by cell injury and death in neuronal cell. This Review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuroprotective agents to limit this neurotoxicity. In recent years, an increasing body of literature supports the notion that polymyxin-induced nerve damage is largely related to oxidative stress and mitochondrial dysfunction. P53, PI3K/Akt, and MAPK pathways are also involved in colistin-induced neuronal cell death. The activation of the redox homeostasis pathways such as Nrf2/HO-1 and autophagy have also been shown to play protective roles against polymyxin-induced neurotoxicity. These pathways have been demonstrated to be upregulated by neuroprotective agents including curcumin, rapamycin and minocycline. Further research is needed toward the development of novel polymyxin formulations in combination with neuroprotective agents to ameliorate this unwanted adverse effect during polymyxins therapy in patients.

Original languageEnglish
Pages (from-to)120-131
Number of pages12
JournalACS Chemical Neuroscience
Volume10
Issue number1
DOIs
Publication statusPublished - 16 Jan 2019
Externally publishedYes

Keywords

  • apoptosis
  • autophagy
  • chemoprevention
  • mitochondria dysfunction
  • neuroprotective agents
  • neurotoxicity
  • Polymyxins

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