Evaluation of putative inhibitors of mitochondrial permeability transition for brain disorders--specificity vs. toxicity.
Inhibition of mitochondrial permeability transition (mPT) has emerged as a promising approach for neuroprotection and development of well-tolerated mPT inhibitors with favorable blood-brain barrier penetration is highly warranted. In a recent study, 28 clinically available drugs with a common heterocyclic structure were identified as mPT inhibitors e.g. trifluoperazine, promethazine and nortriptyline. In addition, neuroprotection by structurally unrelated drugs e.g. neurosteroids, 4-hydroxy-tamoxifen and trimetazidine has been attributed to direct inhibition of mPT. The regulation of mPT is complex and highly dependent on the prevailing experimental conditions. Several features of mPT, such as swelling, depolarization or NADH oxidation, can also occur independently of the mPT phenomenon. Here, in isolated rodent brain-derived and human liver mitochondria, we re-evaluate drugs promoted as potent mPT inhibitors. We address the definition of an mPT inhibitor and present strategies to reliably detect mPT inhibition in vitro. Surprisingly, none of the 12 compounds tested displayed convincing mPT inhibition or effects comparable to cyclophilin D inhibition by the non-immunosuppressive cyclophilin inhibitor D-MeAla(3)-EtVal(4)-Cyclosporin (Debio 025). Propofol and 2-aminoethoxydiphenyl borate (2-APB) inhibited swelling in de-energized mitochondria but did not increase calcium retention capacity (CRC). Progesterone, trifluoperazine, allopregnanolone and 4-hydroxy-tamoxifen dose-dependently reduced CRC and respiratory control and were thus toxic rather than beneficial to mitochondrial function. Interestingly, topiramate increased CRC at high concentrations likely by a mechanism separate from direct mPT inhibition. We conclude that a clinically relevant mPT inhibitor should have a mitochondrial target and increase mitochondrial calcium retention at concentrations which can be translated to human use.
Morota
Saori
S
Department of Clinical Sciences, Lund University, Sweden.
Månsson
Roland
R
Hansson
Magnus J
MJ
Kasuya
Kazuhiko
K
Shimazu
Motohide
M
Hasegawa
Erika
E
Yanagi
Shigeru
S
Omi
Akibumi
A
Uchino
Hiroyuki
H
Elmér
Eskil
E
D000591:Amino Acid Isomerases / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001896:Boron Compounds / Q000009:adverse effects / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001927:Brain Diseases / Q000188:drug therapy / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D011280:Pregnanolone / Q000009:adverse effects / Q000494:pharmacology; D011374:Progesterone / Q000009:adverse effects / Q000494:pharmacology; D015742:Propofol / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D014268:Trifluoperazine / Q000009:adverse effects / Q000494:pharmacology; D014292:Trimetazidine / Q000009:adverse effects / Q000494:pharmacology
D001896:Boron Compounds; D000081406:Peptidyl-Prolyl Isomerase F; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013629:Tamoxifen; C016601:afimoxifene; D014268:Trifluoperazine; D011374:Progesterone; D011280:Pregnanolone; C109986:2-aminoethoxydiphenyl borate; D000591:Amino Acid Isomerases; D021983:Cyclophilins; D014292:Trimetazidine; D002118:Calcium; D015742:Propofol