Brain Sciences

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30 pages, 5326 KiB

Open AccessFeature PaperArticle

Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis

by Fatima M. Shakova, Yuliya I. Kirova, Denis N. Silachev, Galina A. Romanova and Sergey G. Morozov

Brain Sci. 2021, 11(3), 325; https://doi.org/10.3390/brainsci11030325 - 4 Mar 2021

Cited by 4 | Viewed by 3872

Abstract

The pharmacological induction and activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a key regulator of ischemic brain tolerance, is a promising direction in neuroprotective therapy. Pharmacological agents with known abilities to modulate cerebral PGC-1α are scarce. This study focused on [...] Read more.

The pharmacological induction and activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a key regulator of ischemic brain tolerance, is a promising direction in neuroprotective therapy. Pharmacological agents with known abilities to modulate cerebral PGC-1α are scarce. This study focused on the potential PGC-1α-modulating activity of Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) and Semax (ACTH_(4–7) analog) in a rat model of photochemical-induced thrombosis (PT) in the prefrontal cortex. Mexidol (100 mg/kg) was administered intraperitoneally, and Semax (25 μg/kg) was administered intranasally, for 7 days each. The expression of PGC-1α and PGC-1α-dependent protein markers of mitochondriogenesis, angiogenesis, and synaptogenesis was measured in the penumbra via immunoblotting at Days 1, 3, 7, and 21 after PT. The nuclear content of PGC-1α was measured immunohistochemically. The suppression of PGC-1α expression was observed in the penumbra from 24 h to 21 days following PT and reflected decreases in both the number of neurons and PGC-1α expression in individual neurons. Administration of Mexidol or Semax was associated with preservation of the neuron number and neuronal expression of PGC-1α, stimulation of the nuclear translocation of PGC-1α, and increased contents of protein markers for PGC-1α activation. This study opens new prospects for the pharmacological modulation of PGC-1α in the ischemic brain. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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21 pages, 2714 KiB

Open AccessArticle

Potential Effects of Poloxamer 188 on Rat Isolated Brain Mitochondria after Oxidative Stress In Vivo and In Vitro

by Johannes A. Pille and Matthias L. Riess

Brain Sci. 2021, 11(1), 122; https://doi.org/10.3390/brainsci11010122 - 18 Jan 2021

Cited by 8 | Viewed by 2786

Abstract

Outcome after cerebral ischemia is often dismal. Reperfusion adds significantly to the ischemic injury itself. Therefore, new strategies targeting ischemia/reperfusion (I/R) injury are critically needed. Poloxamer (P)188, an amphiphilic triblock copolymer, is a highly promising pharmacological therapeutic as its capability to insert into [...] Read more.

Outcome after cerebral ischemia is often dismal. Reperfusion adds significantly to the ischemic injury itself. Therefore, new strategies targeting ischemia/reperfusion (I/R) injury are critically needed. Poloxamer (P)188, an amphiphilic triblock copolymer, is a highly promising pharmacological therapeutic as its capability to insert into injured cell membranes has been reported to protect against I/R injury in various models. Although mitochondrial function particularly profits from P188 treatment after I/R, it remains unclear if this beneficial effect occurs directly or indirectly. Here, rat isolated brain mitochondria underwent oxidative stress in vivo by asphyxial cardiac arrest or in vitro by the addition of hydrogen peroxide (H₂O₂) after isolation. Mitochondrial function was assessed by adenosine triphosphate synthesis, oxygen consumption, and calcium retention capacity. Both asphyxia and H₂O₂ exposure significantly impaired mitochondrial function. P188 did not preserve mitochondrial function after either injury mechanism. Further research is indicated. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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18 pages, 4085 KiB

Open AccessArticle

Loss of the Mitochondrial Fission GTPase Drp1 Contributes to Neurodegeneration in a Drosophila Model of Hereditary Spastic Paraplegia

by Philippa C. Fowler, Dwayne J. Byrne, Craig Blackstone and Niamh C. O'Sullivan

Brain Sci. 2020, 10(9), 646; https://doi.org/10.3390/brainsci10090646 - 17 Sep 2020

Cited by 11 | Viewed by 4642

Abstract

Mitochondrial morphology, distribution and function are maintained by the opposing forces of mitochondrial fission and fusion, the perturbation of which gives rise to several neurodegenerative disorders. The large guanosine triphosphate (GTP)ase dynamin-related protein 1 (Drp1) is a critical regulator of mitochondrial fission by [...] Read more.

Mitochondrial morphology, distribution and function are maintained by the opposing forces of mitochondrial fission and fusion, the perturbation of which gives rise to several neurodegenerative disorders. The large guanosine triphosphate (GTP)ase dynamin-related protein 1 (Drp1) is a critical regulator of mitochondrial fission by mediating membrane scission, often at points of mitochondrial constriction at endoplasmic reticulum (ER)-mitochondrial contacts. Hereditary spastic paraplegia (HSP) subtype SPG61 is a rare neurodegenerative disorder caused by mutations in the ER-shaping protein Arl6IP1. We have previously reported defects in both the ER and mitochondrial networks in a Drosophila model of SPG61. In this study, we report that knockdown of Arl6IP1 lowers Drp1 protein levels, resulting in reduced ER–mitochondrial contacts and impaired mitochondrial load at the distal ends of long motor neurons. Increasing mitochondrial fission, by overexpression of wild-type Drp1 but not a dominant negative Drp1, increases ER–mitochondrial contacts, restores mitochondrial load within axons and partially rescues locomotor deficits. Arl6IP1 knockdown Drosophila also demonstrate impaired autophagic flux and an accumulation of ubiquitinated proteins, which occur independent of Drp1-mediated mitochondrial fission defects. Together, these findings provide evidence that impaired mitochondrial fission contributes to neurodegeneration in this in vivo model of HSP. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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12 pages, 2736 KiB

Open AccessArticle

Neuroanatomical Changes in Leber’s Hereditary Optic Neuropathy: Clinical Application of 7T MRI Submillimeter Morphometry

by Kamil Jonak, Paweł Krukow, Mark Symms, Ryszard Maciejewski and Cezary Grochowski

Brain Sci. 2020, 10(6), 359; https://doi.org/10.3390/brainsci10060359 - 9 Jun 2020

Cited by 10 | Viewed by 3820

Abstract

Leber’s hereditary optic neuropathy (LHON) is one of the mitochondrial diseases that causes loss of central vision, progressive impairment and subsequent degeneration of retinal ganglion cells (RGCs). In recent years, diffusion tensor imaging (DTI) studies have revealed structural abnormalities in visual white matter [...] Read more.

Leber’s hereditary optic neuropathy (LHON) is one of the mitochondrial diseases that causes loss of central vision, progressive impairment and subsequent degeneration of retinal ganglion cells (RGCs). In recent years, diffusion tensor imaging (DTI) studies have revealed structural abnormalities in visual white matter tracts, such as the optic tract, and optic radiation. However, it is still unclear if the disease alters only some parts of the white matter architecture or whether the changes also affect other subcortical areas of the brain. This study aimed to improve our understanding of morphometric changes in subcortical brain areas and their associations with the clinical picture in LHON by the application of a submillimeter surface-based analysis approach to the ultra-high-field 7T magnetic resonance imaging data. To meet these goals, fifteen LHON patients and fifteen age-matched healthy subjects were examined. For all individuals, quantitative analysis of the morphometric results was performed. Furthermore, morphometric characteristics which differentiated the groups were correlated with variables covering selected aspects of the LHON clinical picture. Compared to healthy controls (HC), LHON carriers showed significantly lower volume of both palladiums (left p = 0.023; right p = 0.018), the right accumbens area (p = 0.007) and the optic chiasm (p = 0.014). Additionally, LHON patients have significantly higher volume of both lateral ventricles (left p = 0.034; right p = 0.02), both temporal horns of the lateral ventricles (left p = 0.016; right p = 0.034), 3rd ventricle (p = 0.012) and 4th ventricle (p = 0.002). Correlation between volumetric results and clinical data showed that volume of both right and left lateral ventricles significantly and positively correlated with the duration of the illness (left R = 0.841, p = 0.002; right R = 0.755, p = 0.001) and the age of the LHON participants (left R = 0.656, p = 0.007; right R = 0.691, p = 0.004). The abnormalities in volume of the LHON patients’ subcortical structures indicate that the disease can cause changes not only in the white matter areas constituting visual tracts, but also in the other subcortical brain structures. Furthermore, the correlation between those results and the illness duration suggests that the disease might have a neurodegenerative nature; however, to fully confirm this observation, longitudinal studies should be conducted. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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Review

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15 pages, 860 KiB

Open AccessFeature PaperReview

Neuroprotective Potential of Mild Uncoupling in Mitochondria. Pros and Cons

by Dmitry B. Zorov, Nadezda V. Andrianova, Valentina A. Babenko, Irina B. Pevzner, Vasily A. Popkov, Savva D. Zorov, Ljubava D. Zorova, Egor Yu. Plotnikov, Gennady T. Sukhikh and Denis N. Silachev

Brain Sci. 2021, 11(8), 1050; https://doi.org/10.3390/brainsci11081050 - 8 Aug 2021

Cited by 17 | Viewed by 3764

Abstract

There has been an explosion of interest in the use of uncouplers of oxidative phosphorylation in mitochondria in the treatment of several pathologies, including neurological ones. In this review, we analyzed all the mechanisms associated with mitochondrial uncoupling and the metabolic and signaling [...] Read more.

There has been an explosion of interest in the use of uncouplers of oxidative phosphorylation in mitochondria in the treatment of several pathologies, including neurological ones. In this review, we analyzed all the mechanisms associated with mitochondrial uncoupling and the metabolic and signaling cascades triggered by uncouplers. We provide a full set of positive and negative effects that should be taken into account when using uncouplers in experiments and clinical practice. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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14 pages, 798 KiB

Open AccessReview

p62-Nrf2-p62 Mitophagy Regulatory Loop as a Target for Preventive Therapy of Neurodegenerative Diseases

by Artem P. Gureev, Irina S. Sadovnikova, Natalia N. Starkov, Anatoly A. Starkov and Vasily N. Popov

Brain Sci. 2020, 10(11), 847; https://doi.org/10.3390/brainsci10110847 - 12 Nov 2020

Cited by 39 | Viewed by 4125

Abstract

Turnover of the mitochondrial pool due to coordinated processes of mitochondrial biogenesis and mitophagy is an important process in maintaining mitochondrial stability. An important role in this process is played by the Nrf2/ARE signaling pathway, which is involved in the regulation of the [...] Read more.

Turnover of the mitochondrial pool due to coordinated processes of mitochondrial biogenesis and mitophagy is an important process in maintaining mitochondrial stability. An important role in this process is played by the Nrf2/ARE signaling pathway, which is involved in the regulation of the expression of genes responsible for oxidative stress protection, regulation of mitochondrial biogenesis, and mitophagy. The p62 protein is a multifunctional cytoplasmic protein that functions as a selective mitophagy receptor for the degradation of ubiquitinated substrates. There is evidence that p62 can positively regulate Nrf2 by binding to its negative regulator, Keap1. However, there is also strong evidence that Nrf2 up-regulates p62 expression. Thereby, a regulatory loop is formed between two important signaling pathways, which may be an important target for drugs aimed at treating neurodegeneration. Constitutive activation of p62 in parallel with Nrf2 would most likely result in the activation of mTORC1-mediated signaling pathways that are associated with the development of malignant neoplasms. The purpose of this review is to describe the p62-Nrf2-p62 regulatory loop and to evaluate its role in the regulation of mitophagy under various physiological conditions. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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13 pages, 710 KiB

Open AccessReview

Role of NAD⁺—Modulated Mitochondrial Free Radical Generation in Mechanisms of Acute Brain Injury

by Nina Klimova, Adam Fearnow and Tibor Kristian

Brain Sci. 2020, 10(7), 449; https://doi.org/10.3390/brainsci10070449 - 14 Jul 2020

Cited by 11 | Viewed by 4052

Abstract

It is commonly accepted that mitochondria represent a major source of free radicals following acute brain injury or during the progression of neurodegenerative diseases. The levels of reactive oxygen species (ROS) in cells are determined by two opposing mechanisms—the one that produces free [...] Read more.

It is commonly accepted that mitochondria represent a major source of free radicals following acute brain injury or during the progression of neurodegenerative diseases. The levels of reactive oxygen species (ROS) in cells are determined by two opposing mechanisms—the one that produces free radicals and the cellular antioxidant system that eliminates ROS. Thus, the balance between the rate of ROS production and the efficiency of the cellular detoxification process determines the levels of harmful reactive oxygen species. Consequently, increase in free radical levels can be a result of higher rates of ROS production or due to the inhibition of the enzymes that participate in the antioxidant mechanisms. The enzymes’ activity can be modulated by post-translational modifications that are commonly altered under pathologic conditions. In this review we will discuss the mechanisms of mitochondrial free radical production following ischemic insult, mechanisms that protect mitochondria against free radical damage, and the impact of post-ischemic nicotinamide adenine mononucleotide (NAD⁺) catabolism on mitochondrial protein acetylation that affects ROS generation and mitochondrial dynamics. We propose a mechanism of mitochondrial free radical generation due to a compromised mitochondrial antioxidant system caused by intra-mitochondrial NAD⁺ depletion. Finally, the interplay between different mechanisms of mitochondrial ROS generation and potential therapeutic approaches are reviewed. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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Other

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9 pages, 2021 KiB

Open AccessBrief Report

Effect of Xenon Treatment on Gene Expression in Brain Tissue after Traumatic Brain Injury in Rats

by Anton D. Filev, Denis N. Silachev, Ivan A. Ryzhkov, Konstantin N. Lapin, Anastasiya S. Babkina, Oleg A. Grebenchikov and Vladimir M. Pisarev

Brain Sci. 2021, 11(7), 889; https://doi.org/10.3390/brainsci11070889 - 3 Jul 2021

Cited by 11 | Viewed by 2941

Abstract

The overactivation of inflammatory pathways and/or a deficiency of neuroplasticity may result in the delayed recovery of neural function in traumatic brain injury (TBI). A promising approach to protecting the brain tissue in TBI is xenon (Xe) treatment. However, xenon’s mechanisms of action [...] Read more.

The overactivation of inflammatory pathways and/or a deficiency of neuroplasticity may result in the delayed recovery of neural function in traumatic brain injury (TBI). A promising approach to protecting the brain tissue in TBI is xenon (Xe) treatment. However, xenon’s mechanisms of action remain poorly clarified. In this study, the early-onset expression of 91 target genes was investigated in the damaged and in the contralateral brain areas (sensorimotor cortex region) 6 and 24 h after injury in a TBI rat model. The expression of genes involved in inflammation, oxidation, antioxidation, neurogenesis and neuroplasticity, apoptosis, DNA repair, autophagy, and mitophagy was assessed. The animals inhaled a gas mixture containing xenon and oxygen (ϕXe = 70%; ϕO₂ 25–30% 60 min) 15–30 min after TBI. The data showed that, in the contralateral area, xenon treatment induced the expression of stress genes (Irf1, Hmox1, S100A8, and S100A9). In the damaged area, a trend towards lower expression of the inflammatory gene Irf1 was observed. Thus, our results suggest that xenon exerts a mild stressor effect in healthy brain tissue and has a tendency to decrease the inflammation following damage, which might contribute to reducing the damage and activating the early compensatory processes in the brain post-TBI. Full article

(This article belongs to the Special Issue Mitochondria as Therapeutic Target for Acute Brain Pathologies)

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