Novel N-phenyl-substituted thiazolidinediones protect neural cells against glutamate- and tBid-induced toxicity

Sina Oppermann, Florian C Schrader, Katharina Elsässer, Amalia M Dolga, Anna Lena Kraus, Nunzianna Doti, Christof Wegscheid-Gerlach, Martin Schlitzer, Carsten Culmsee

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)

Abstract

Mitochondrial demise is a key feature of progressive neuronal death contributing to acute and chronic neurological disorders. Recent studies identified a pivotal role for the BH3-only protein B-cell lymphoma-2 interacting domain death antagonist (Bid) for such mitochondrial damage and delayed neuronal death after oxygen-glucose deprivation, glutamate-induced excitotoxicity, or oxidative stress in vitro and after cerebral ischemia in vivo. Therefore, we developed new N-phenyl-substituted thiazolidine-2,4-dione derivatives as potent inhibitors of Bid-dependent neurotoxicity. The new compounds 6, 7, and 16 were identified as highly protective by extensive screening in a model of glutamate toxicity in immortalized mouse hippocampal neurons (HT-22 cells). These compounds significantly prevent truncated Bid-induced toxicity in the neuronal cell line, providing strong evidence that inhibition of Bid was the underlying mechanism of the observed protective effects. Furthermore, Bid-dependent hallmarks of mitochondrial dysfunction, such as loss of mitochondrial membrane potential, ATP depletion, as well as impairments in mitochondrial respiration, are significantly prevented by compounds 6, 7, and 16. Therefore, the present study identifies a class of N-phenyl thiazolidinediones as novel Bid-inhibiting neuroprotective agents that provide promising therapeutic perspectives for neurodegenerative diseases, in which Bid-mediated mitochondrial damage and associated intrinsic death pathways contribute to the underlying progressive loss of neurons.

Original languageEnglish
Pages (from-to)273-289
Number of pages17
JournalJournal of Pharmacology and Experimental Therapeutics
Volume350
Issue number2
DOIs
Publication statusPublished - Aug-2014
Externally publishedYes

Keywords

  • Animals
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein
  • Cells, Cultured
  • Glutamic Acid
  • Humans
  • Membrane Potential, Mitochondrial
  • Neurons
  • Neuroprotective Agents
  • Rats
  • Structure-Activity Relationship
  • Thiazolidinediones

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