Denis N Silachev1, Ljudmila S Khailova1, Valentina A Babenko1, Mikhail V Gulyaev2, Sergey I Kovalchuk3, Ljubava D Zorova4, Egor Y Plotnikov1, Yuri N Antonenko5, Dmitry B Zorov6. 1. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia. 2. Lomonosov Moscow State University, Faculty of Fundamental Medicine, Moscow 117192, Russia. 3. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia. 4. International Laser Center, Lomonosov Moscow State University, Moscow 119992, Russia. 5. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia. Electronic address: antonen@genebee.msu.ru. 6. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russia. Electronic address: zorov@genebee.msu.su.
Abstract
BACKGROUND: Reactive oxygen species are grossly produced in the brain after cerebral ischemia and reperfusion causing neuronal cell death. Mitochondrial production of reactive oxygen species is nonlinearly related to the value of the mitochondrial membrane potential with significant increment at values exceeding 150mV. Therefore, limited uncoupling of oxidative phosphorylation could be beneficial for cells exposed to deleterious oxidative stress-associated conditions by preventing excessive generation of reactive oxygen species. METHODS: Protonophoric and uncoupling activities of different peptides were measured using pyranine-loaded liposomes and isolated mitochondria. To evaluate the effect of glutamate-substituted analog of gramicidin A ([Glu1]gA) administration on the brain ischemic damage, we employed the in vitro model of neuronal hypoxia using primary neuronal cell cultures and the in vivo model of cerebral ischemia induced in rats by the middle cerebral artery occlusion. RESULTS: [Glu1]gA was the most effective in proton-transferring activity among several N-terminally substituted analogs of gramicidin A tested in liposomes and rat brain and liver mitochondria. The peptides were found to be protective against ischemia-induced neuronal cell death and they lowered mitochondrial membrane potential in cultured neurons and diminished reactive oxygen species production in isolated brain mitochondria. The intranasal administration of [Glu1]gA remarkably diminished the infarct size indicated in MR-images of a brain at day 1 after the middle cerebral artery occlusion. In [Glu1]gA-treated rats, the ischemia-induced brain swelling and behavioral dysfunction were significantly suppressed. CONCLUSIONS: The glutamate-substituted analogs of gramicidin A displaying protonophoric and uncoupling activities protect neural cells and the brain from the injury caused by ischemia/reperfusion. GENERAL SIGNIFICANCE: [Glu1]gA may be potentially used as a therapeutic agent to prevent neuron damage after stroke.
BACKGROUND:Reactive oxygen species are grossly produced in the brain after cerebral ischemia and reperfusion causing neuronal cell death. Mitochondrial production of reactive oxygen species is nonlinearly related to the value of the mitochondrial membrane potential with significant increment at values exceeding 150mV. Therefore, limited uncoupling of oxidative phosphorylation could be beneficial for cells exposed to deleterious oxidative stress-associated conditions by preventing excessive generation of reactive oxygen species. METHODS: Protonophoric and uncoupling activities of different peptides were measured using pyranine-loaded liposomes and isolated mitochondria. To evaluate the effect of glutamate-substituted analog of gramicidin A ([Glu1]gA) administration on the brain ischemic damage, we employed the in vitro model of neuronal hypoxia using primary neuronal cell cultures and the in vivo model of cerebral ischemia induced in rats by the middle cerebral artery occlusion. RESULTS: [Glu1]gA was the most effective in proton-transferring activity among several N-terminally substituted analogs of gramicidin A tested in liposomes and rat brain and liver mitochondria. The peptides were found to be protective against ischemia-induced neuronal cell death and they lowered mitochondrial membrane potential in cultured neurons and diminished reactive oxygen species production in isolated brain mitochondria. The intranasal administration of [Glu1]gA remarkably diminished the infarct size indicated in MR-images of a brain at day 1 after the middle cerebral artery occlusion. In [Glu1]gA-treated rats, the ischemia-induced brain swelling and behavioral dysfunction were significantly suppressed. CONCLUSIONS: The glutamate-substituted analogs of gramicidin A displaying protonophoric and uncoupling activities protect neural cells and the brain from the injury caused by ischemia/reperfusion. GENERAL SIGNIFICANCE: [Glu1]gA may be potentially used as a therapeutic agent to prevent neuron damage after stroke.
Authors: M M Moisenovich; E Y Plotnikov; A M Moysenovich; D N Silachev; T I Danilina; E S Savchenko; M M Bobrova; L A Safonova; V V Tatarskiy; M S Kotliarova; I I Agapov; D B Zorov Journal: Neurochem Res Date: 2018-12-05 Impact factor: 3.996
Authors: Ljubava D Zorova; Vasily A Popkov; Egor Y Plotnikov; Denis N Silachev; Irina B Pevzner; Stanislovas S Jankauskas; Valentina A Babenko; Savva D Zorov; Anastasia V Balakireva; Magdalena Juhaszova; Steven J Sollott; Dmitry B Zorov Journal: Anal Biochem Date: 2017-07-12 Impact factor: 3.365
Authors: Oleg V Kondrashov; Tatyana I Rokitskaya; Oleg V Batishchev; Elena A Kotova; Yuri N Antonenko; Sergey A Akimov Journal: Biophys J Date: 2021-10-27 Impact factor: 4.033
Authors: Valentina A Babenko; Denis N Silachev; Vasily A Popkov; Ljubava D Zorova; Irina B Pevzner; Egor Y Plotnikov; Gennady T Sukhikh; Dmitry B Zorov Journal: Molecules Date: 2018-03-19 Impact factor: 4.411