Neuroprotective Effects of Mitochondria-Targeted Plastoquinone and Thymoquinone in a Rat Model of Brain Ischemia/Reperfusion Injury.
We explored the neuroprotective properties of natural plant-derived antioxidants plastoquinone and thymoquinone (2-demethylplastoquinone derivative) modified to be specifically accumulated in mitochondria. The modification was performed through chemical conjugation of the quinones with penetrating cations: Rhodamine 19 or tetraphenylphosphonium. Neuroprotective properties were evaluated in a model of middle cerebral artery occlusion. We demonstrate that the mitochondria-targeted compounds, introduced immediately after reperfusion, possess various neuroprotective potencies as judged by the lower brain damage and higher neurological status. Plastoquinone derivatives conjugated with rhodamine were the most efficient, and the least efficiency was shown by antioxidants conjugated with tetraphenylphosphonium. Antioxidants were administered intraperitoneally or intranasally with the latter demonstrating a high level of penetration into the brain tissue. The therapeutic effects of both ways of administration were similar. Long-term administration of antioxidants in low doses reduced the neurological deficit, but had no effect on the volume of brain damage. At present, cationic decylrhodamine derivatives of plastoquinone appear to be the most promising anti-ischemic mitochondria-targeted drugs of the quinone family. We suggest these antioxidants could be potentially used for a stroke treatment.
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia. silachevdn@genebee.msu.ru.|Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. silachevdn@genebee.msu.ru.
Denis N
DN
Silachev
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia. plotnikov@genebee.msu.ru.|Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. plotnikov@genebee.msu.ru.
Egor Y
EY
Plotnikov
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. lju_2003@list.ru.|International Laser Center, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 62, 119992 Moscow, Russia. lju_2003@list.ru.
Ljubava D
LD
Zorova
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia. irinapevzner@mail.ru.|Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. irinapevzner@mail.ru.
Irina B
IB
Pevzner
Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. sumbatyan@belozersky.msu.ru.|Faculty of Chemistry, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 3, 119992 Moscow, Russia. sumbatyan@belozersky.msu.ru.
Natalia V
NV
Sumbatyan
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia. korsh@belozersky.msu.ru.|Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. korsh@belozersky.msu.ru.
Galina A
GA
Korshunova
Faculty of Fundamental Medicine, Lomonosov Moscow State University, Lomonosovsky Prospekt, House 31-5, 117192 Moscow, Russia. mihon-epsilon@yandex.ru.
Mikhail V
MV
Gulyaev
Faculty of Physics, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 2, 119992 Moscow, Russia. yupi937@gmail.com.
Yury A
YA
Pirogov
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia. skulach@belozersky.msu.ru.|Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. skulach@belozersky.msu.ru.
Vladimir P
VP
Skulachev
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 40, 119992 Moscow, Russia. zorov@genebee.msu.ru.|Institute of Mitoengineering, Lomonosov Moscow State University, Leninskye Gory, House 1, Building 73A, 119992 Moscow, Russia. zorov@genebee.msu.ru.
Dmitry B
DB
Zorov
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010971:Plastoquinone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy
D000975:Antioxidants; D016227:Benzoquinones; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C003466:thymoquinone; D010971:Plastoquinone
brain ischemia; mitochondria; mitochondria-targeted antioxidants; plastoquinone, thymoquinone