Novel N-phenyl-substituted thiazolidinediones protect neural cells against glutamate- and tBid-induced toxicity.
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.
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Sina
S
Oppermann
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Florian C
FC
Schrader
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Katharina
K
Elsässer
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Amalia M
AM
Dolga
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Anna Lena
AL
Kraus
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Nunzianna
N
Doti
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Christof
C
Wegscheid-Gerlach
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.).
Martin
M
Schlitzer
Institute for Pharmacology and Clinical Pharmacy, Faculty of Pharmacy (S.O., K.E., A.M.D., C.C.) and Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Philipps University of Marburg, Marburg, Germany (F.C.S., A.L.K., C.W.-G., M.S.); and Institute of Biostructures and Bioimaging, Naples, Italy (N.D.) culmsee@staff.uni-marburg.de.
Carsten
C
Culmsee
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000633:toxicity*; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000494:pharmacology*
D051023:BH3 Interacting Domain Death Agonist Protein; D018696:Neuroprotective Agents; D045162:Thiazolidinediones; D018698:Glutamic Acid