RESUMO
Addition of 0.07 mM zinc ions to the culture medium induced death of cerebellar granule neurons. This was preceded by a decrease in intracellular pH by 0.86±0.12 and an increase in the level of intracellular zinc registered by increasing fluorescence of FluoZin3. However, intracellular acidosis caused by acidification of the culture medium to pH 6.0 was not toxic to neurons, and even significantly increased their survival under the action of zinc ions. In general, the overload of the neurons cytoplasm with zinc ions causes acidification of the cytoplasm, which is probably associated with the activation of Zn2+/H+ exchangers and is a protective mechanism for the neurocytotoxic effect of zinc ions.
Assuntos
Cerebelo , Zinco , Animais , Células Cultivadas , Grânulos Citoplasmáticos , Concentração de Íons de Hidrogênio , Íons , Neurônios , Ratos , Zinco/toxicidadeRESUMO
In primary dissociated hippocampal cell cultures from 18-day-old mouse embryos, streptozotocin in concentrations of 2-5 mM produced a dose-dependent cytotoxic effect on day 3 in vitro, whereas on day 11 of culturing, the neurons were resistant to streptozotocin. The neurons in the 3-day cultures were functionally immature, which was seen from their weak spontaneous bioelectric activity in the form of rare single action potentials; by day 11 of culturing, the neurons reached a high level of differentiation and their functional properties acquired a character of network burst activity. Thus, streptozotocin had the most pronounced cytotoxic effect on immature hippocampal neurons in vitro.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Neurônios/efeitos dos fármacos , Estreptozocina/toxicidade , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/citologia , Neurônios/fisiologia , Cultura Primária de Células , Fatores de TempoRESUMO
The protective effect of antioxidant SkQR1 was examined on the model of left-sided compression ischemia in rat sensorimotor cortex. The special tests aimed to determine the neurologic deficit in the limbs and assess performance of the forelimbs showed that a 2.5-min ischemia produced no disturbance in the limb functions on postsurgery days 1, 3, and 7. Elevation of compression time resulted in neurologic deficit in animals, and its severity depended on this time. A single intravenous injection of SkQR1 (250 nmol/kg body weight) performed 30 min after ischemia significantly reduced the degree of neurologic deficit. In vitro model of ischemia in surviving rat hippocampal slices showed that a 15-min-long ischemia significantly inhibited the population excitatory postsynaptic potentials, which did not restore during reperfusion. Preincubation of the slices with SkQR1 did not significantly affect recovery of these potentials.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Plastoquinona/análogos & derivados , Rodaminas/uso terapêutico , Animais , Antioxidantes/uso terapêutico , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Plastoquinona/uso terapêutico , RatosRESUMO
Thymoquinone (TQ) exhibits a wide spectrum of biological activities. Most studies on the neurotoxic action of TQ have been carried out in cancer cell lines. Here, we studied the toxic effect of TQ in primary neuronal cultures in vitro. Incubation with 0.04-0.05 mM TQ for 24 h induced the death of cultured cerebellar granule neurons (CGNs) in a dose-dependent manner. Neuronal death was preceded by an increase in the reactive oxygen species (ROS) generation, as demonstrated using CellROX Green and MitoSOX Red. Confocal and electron microscopy showed that incubation with 0.05 mM TQ for 5 h induced changes in the intracellular localization of mitochondria and mitochondria hypertrophy and cell swelling. The antioxidant N-acetyl-L-cysteine (2 mM) protected CGNs from the toxic action of TQ. Taken together, these facts suggest that TQ is toxic for normal neurons, while ROS-induced changes in the mitochondria can be one of the major causes of the TQ-induced neuronal damage and death.
Assuntos
Benzoquinonas/toxicidade , Grânulos Citoplasmáticos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Grânulos Citoplasmáticos/metabolismo , Relação Dose-Resposta a Droga , Mitocôndrias/metabolismo , Neurônios/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/análise , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Thymoquinone is one of the main active components of the essential oil from black cumin (Nigella sativa) seeds. Thymoquinone exhibits a wide range of pharmacological activities, including neuroprotective action demonstrated in the models of brain ischemia/reperfusion, Alzheimer's and Parkinson's diseases, and traumatic brain injury. The neuroprotective effect of thymoquinone is mediated via inhibition of lipid peroxidation, downregulation of proinflammatory cytokines, maintenance of mitochondrial membrane potential, and prevention of apoptosis through inhibition of caspases-3, -8, and -9. Thymoquinone-based mitochondria-targeted antioxidants are accumulated in the mitochondria and exhibit neuroprotective properties in nanomolar concentrations. Thymoquinone reduces the negative effects of acute and chronic forms of brain pathologies. The mechanisms of the pharmacological action of thymoquinone and its chemical derivatives require more comprehensive studying. In this paper, we formulated the prospects of application of thymoquinone and thymoquinone-based drugs in the therapy of neurodegenerative diseases.
Assuntos
Benzoquinonas/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença Aguda , Benzoquinonas/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Doença Crônica , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/químicaRESUMO
Peptide mimetic of nerve growth factor GK-2 in a dose of 1-2 mg/liter improves survival of cultured rat cerebellar granule neurons exposed to the cytotoxic effect of zinc ions, but has no protective effect against copper ion cytotoxicity. Experiments on cultured rat hippocampal slices demonstrated that GK-2 did not affect reactivity of pyramidal neurons and long-term potentiation in the hippocampal field CA1 and the probability of glutamate release from presynaptic terminals in the synapses of the CA3-CA1 fields. The results suggest that GK-2 does not affect the functional properties of synaptic transmission under normal conditions, but protects neurons from the toxic effects of zinc, which creates prerequisites for GK-12 use in the treatment of neurodegenerative diseases.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cloretos/antagonistas & inibidores , Dipeptídeos/farmacologia , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Compostos de Zinco/antagonistas & inibidores , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/fisiologia , Cerebelo/citologia , Cerebelo/fisiologia , Cloretos/toxicidade , Cobre/toxicidade , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Microtomia , Neurônios/citologia , Neurônios/fisiologia , Cultura Primária de Células , Ratos , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Compostos de Zinco/toxicidadeRESUMO
One of the most common models of sporadic form of Alzheimer's disease is injection of streptozotocin into the lateral ventricles of rat brain. In 3 months after this injection, an increase in the expression of astroglia in the corpus callosum and a decrease in the thickness of the corpus callosum and intensity of its staining with luxol fast blue were observed. This can reflect a decrease in the content of myelinated fibers. In layer V of the sensorimotor cortex, intensive degeneration of neurons was revealed. The lateral ventricles were significantly enlarged and the expression of PSA-NCAM protein, a marker of immature neurons, was reduced in subventricular zone, which can be associated with disturbed neurogenesi.
Assuntos
Doença de Alzheimer/patologia , Astrócitos/patologia , Corpo Caloso/patologia , Ventrículos Laterais/patologia , Fibras Nervosas Mielinizadas/patologia , Córtex Sensório-Motor/patologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Animais , Astrócitos/metabolismo , Biomarcadores/metabolismo , Corpo Caloso/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Indóis , Injeções Intraventriculares , Ventrículos Laterais/metabolismo , Masculino , Fibras Nervosas Mielinizadas/metabolismo , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Wistar , Córtex Sensório-Motor/metabolismo , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Técnicas Estereotáxicas , Estreptozocina/administração & dosagemRESUMO
Focal unilateral traumatic brain injury in the sensorimotor cortical region disturbed the functions of contralateral limbs controlled by the damaged hemisphere. A single intravenous injection of methylene blue (1 mg/kg) immediately before or 30 min after the injury significantly weakened functional disorders in the affected extremities. In vitro experiments showed that methylene blue effectively reduced death of cultured neurons provoked by paraquat or zinc ions producing the toxic effects on mitochondrias.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Azul de Metileno/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Células Cultivadas , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Paraquat/uso terapêutico , Ratos WistarRESUMO
Neuronal plastic rearrangements during the development and functioning of neurons are largely regulated by trophic factors, including nerve growth factor (NGF). NGF is also involved in the pathogenesis of Alzheimer's disease. In the brain, NGF is produced in structures innervated by basal forebrain cholinergic neurons and retrogradely transported along the axons to the bodies of cholinergic neurons. NGF is essential for normal development and functioning of the basal forebrain; it affects formation of the dendritic tree and modulates the activities of choline acetyltransferase and acetylcholinesterase in basal forebrain neurons. The trophic effect of NGF is mediated through its interactions with TrkA and p75 receptors. Experimental and clinical studies have shown that brain levels of NGF are altered in various pathologies. However, the therapeutic use of NGF is limited by its poor ability to penetrate the blood-brain barrier, adverse side effects that are due to the pleiotropic action of this factor, and the possibility of immune response to NGF. For this reason, the development of gene therapy methods for treating NGF deficit-associated pathologies is of particular interest. Another approach is creation of low molecular weight NGF mimetics that would interact with the corresponding receptors and display high biological activity but be free of the unfavorable effects of NGF.
Assuntos
Barreira Hematoencefálica/metabolismo , Neurônios Colinérgicos/metabolismo , Fator de Crescimento Neural/metabolismo , Plasticidade Neuronal/fisiologia , Prosencéfalo/metabolismo , Animais , HumanosRESUMO
Addition into the culture medium of the antioxidant N-acetylcysteine (NAC, 1 mM) in the presence of Cu2+ (0.0005-0.001 mM) induced intensive death of cultured rat cerebellar granule neurons, which was significantly decreased by the zinc ion chelator TPEN (N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine). However, the combined action of NAC and Zn2+ did not induce destruction of the neurons. Measurement of the relative intracellular concentration of Zn2+ with the fluorescent probe FluoZin-3 AM or of free radical production using a CellROX Green showed that incubation of the culture for 4 h with Cu2+ and NAC induced an intensive increase in the fluorescence of CellROX Green but not of FluoZin-3. Probably, the protective effect of TPEN in this case could be mediated by its ability to chelate Cu2+. Incubation of cultures in a balanced salt solution in the presence of 0.01 mM Cu2+ caused neuronal death already after 1 h if the NAC concentration in the solution was within 0.005-0.05 mM. NAC at higher concentrations (0.1-1 mM) together with 0.01 mM Cu2+ did not cause the death of neurons. These data imply that the antioxidant NAC can be potentially harmful to neurons even in the presence of nanomolar concentrations of variable valence metals.
Assuntos
Acetilcisteína/toxicidade , Apoptose/efeitos dos fármacos , Cobre/toxicidade , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Células Cultivadas , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Quelantes/farmacologia , Cobre/química , Etilenodiaminas/farmacologia , Microscopia de Fluorescência , Neurônios/citologia , Neurônios/metabolismo , Compostos Policíclicos/química , Ratos , Ratos Wistar , Zinco/farmacologiaRESUMO
A cascade of pathological changes in the intact hemisphere developed in rats 6 months after focal unilateral traumatic brain injury: neuronal degeneration, hyperexpression of α-synuclein, APP (ß-amyloid peptide precursor) protein, and glutamine synthetase in cells other than astrocytes. The development of these changes in the contralateral hemisphere indicated the emergence of extensive delayed neurodegenerative processes in the brain after traumatic brain injury, which were characteristic of diseases associated with pathological aging.
Assuntos
Lesões Encefálicas Traumáticas/patologia , Cérebro/patologia , Doenças Neurodegenerativas/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/fisiopatologia , Cérebro/metabolismo , Cérebro/fisiopatologia , Diagnóstico Tardio , Expressão Gênica , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Masculino , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Ratos , Ratos Wistar , Fatores de Tempo , Regulação para Cima , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
Rat cultured cerebellar granule neurons (CGNs) were not sensitive to CuCl2 (1-10 µM, 24 h), whereas paraquat (150 µM) decreased neuronal survival to 79 ± 3% of control level. Simultaneous treatment of CGNs with paraquat and CuCl2 (2, 5, or 10 µM Cu2+/paraquat) caused significant copper dose-dependent death, lowering their survival to 56 ± 4, 37 ± 3, or 16 ± 2%, respectively, and stimulating elevated production of free radicals in CGNs. Introduction of vitamin E, a non-competitive antagonist of NMDA subtype of glutamate receptors (MK-801), and also removal of glutamine from the incubation medium decreased toxicity of Cu2+/paraquat mixture. However, addition of Cu2+ into the incubation medium did not affect CGNs death caused by glutamate. These data emphasize that excessive copper in the brain may trigger oxidative stress, which in turn results in release of glutamate, overstimulation of glutamate receptors, and neuronal death.
Assuntos
Cerebelo/metabolismo , Cobre/toxicidade , Glutamina/metabolismo , Neurônios/metabolismo , Paraquat/toxicidade , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/patologia , Maleato de Dizocilpina/farmacologia , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Alzheimer's disease is characterized by progressive memory loss and cognitive decline accompanied by degeneration of neuronal synapses, massive loss of neurons in the brain, eventually resulting in complete degradation of personality and death. Currently, the cause of the disease is not fully understood, but it is believed that the person's age is the major risk factor for development of Alzheimer's disease. People who have survived after cerebral stroke or traumatic brain injury have substantially increased risk of developing Alzheimer's disease. Social exclusion, low social activity, physical inactivity, poor mental performance, and low level of education are among risk factors for development of this neurodegenerative disease, which is consistent with the concept of phenoptosis (Skulachev, V. P., et al. (1999) Biochemistry (Moscow), 64, 1418-1426; Skulachev, M. V., and Skulachev, V. P. (2014) Biochemistry (Moscow), 79, 977-993) stating that rate of aging is related to psychological and social aspects in human behavior. Here we assumed that Alzheimer's disease might be considered as an exacerbation of senile phenoptosis. If so, then development of this disease could be slowed using mitochondria-targeted antioxidants due to the accumulated data demonstrating a link between mitochondrial dysfunction and oxidative stress both with normal aging and Alzheimer's disease.
Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/psicologia , Fatores Etários , Doença de Alzheimer/patologia , Feminino , Humanos , Masculino , Estresse Oxidativo/fisiologiaRESUMO
Cultured cerebellar granule neurons (CGNs) are resistant to the toxic effect of ZnCl2 (0.005 mM, 3 h) and slightly sensitive to the effect of kainate (0.1 mM, 3 h). Simultaneous treatment of CGNs with kainate and ZnCl2 caused intensive neuronal death, which was attenuated by external acidosis (pH 6.5) or 5-(N-ethyl-N-isopropyl)amiloride (EIPA, Na+/H+ exchange blocker, 0.03 mM). Intracellular zinc and calcium ion concentrations ([Zn2+]i and [Ca2+]i) were increased under the toxic action of kainate + ZnCl2, this effect being significantly decreased on external acidosis and increased in case of EIPA addition. Neuronal Zn2+ imaging demonstrated that EIPA increases the cytosolic concentration of free Zn2+ on incubation in Zn2+-containing solution. These data imply that acidosis reduces ZnCl2/kainate toxic effects by decreasing Zn2+ entry into neurons, and EIPA prevents zinc stores from being overloaded with zinc.
Assuntos
Acidose/metabolismo , Amilorida/análogos & derivados , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Amilorida/farmacologia , Animais , Cálcio/farmacologia , Cátions Bivalentes , Morte Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Grânulos Citoplasmáticos/patologia , Interações Medicamentosas , Ácido Caínico/metabolismo , Ácido Caínico/toxicidade , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Receptores de Ácido Caínico/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Zinco/metabolismo , Zinco/toxicidadeRESUMO
A single intraperitoneal injection to rats of the mitochondria-targeted plastoquinone antioxidant SkQR1 at dose 1 µmol/kg significantly improved reproduction by the rats of the passive avoidance conditional reflex. In vitro experiments on hippocampal slices showed that a single intraperitoneal injection of SkQR1 24 h before the preparation of the slice significantly increases the synaptic transmission efficiency of the pyramidal neurons of the CA1 field. The findings indicate that SkQR1 has a positive effect on memory processes.
Assuntos
Memória/efeitos dos fármacos , Mitocôndrias/metabolismo , Plastoquinona/análogos & derivados , Células Piramidais/metabolismo , Rodaminas/farmacologia , Animais , Masculino , Plastoquinona/farmacologia , Células Piramidais/patologia , Ratos , Ratos WistarRESUMO
Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), ß-amyloid (Abeta), tau-protein, metallothioneins, and GSK3ß are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+.
Assuntos
Doença de Alzheimer/metabolismo , Cobre/metabolismo , Doença de Parkinson/metabolismo , Zinco/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Metalotioneína/metabolismo , Estresse Oxidativo , Doença de Parkinson/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas tau/metabolismoRESUMO
Bivalent metal cations are key components in the reaction of DNA synthesis. They are necessary for all DNA polymerases, being involved as cofactors in catalytic mechanisms of nucleotide polymerization. It is also known that in the presence of Mn2+ the accuracy of DNA synthesis is considerably decreased. The findings of this work show that Cd2+ and Zn2+ selectively inhibit the Mn2+-induced error-prone DNA polymerase activity in extracts of cells from human and mouse tissues. Moreover, these cations in low concentrations also can efficiently inhibit the activity of homogeneous preparations of DNA polymerase iota (Pol ι), which is mainly responsible for the Mn2+-induced error-prone DNA polymerase activity in cell extracts. Using a primary culture of granular cells from postnatal rat cerebellum, we show that low concentrations of Cd2+ significantly increase cell survival in the presence of toxic Mn2+ doses. Thus, we have shown that in some cases low concentrations of Cd2+ can display a positive influence on cells, whereas it is widely acknowledged that this metal is not a necessary microelement and is toxic for organisms.
Assuntos
Cádmio/farmacologia , Replicação do DNA/efeitos dos fármacos , DNA Polimerase Dirigida por DNA/metabolismo , DNA/biossíntese , Manganês/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Zinco/farmacologia , Animais , Biocatálise/efeitos dos fármacos , Encéfalo/enzimologia , Cádmio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Fígado/enzimologia , Manganês/metabolismo , Melanoma/enzimologia , Camundongos , Inibidores da Síntese de Ácido Nucleico/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Neoplasias Uveais/enzimologia , Zinco/metabolismo , DNA Polimerase iotaRESUMO
Normal brain aging leads to decrease in cognitive functions, shrink in brain volume, loss of nerve fibers and degenerating myelin, reduction in length and branching of dendrites, partial loss of synapses, and reduction in expression of genes that play central roles in synaptic plasticity, vesicular transport, and mitochondrial functioning. Impaired mitochondrial functions and mitochondrial reactive oxygen species can contribute to the damage of these genes in aging cerebral cortex. This review discusses the possibility of using mitochondria-targeted antioxidants to slow the processes of brain aging.
Assuntos
Envelhecimento/metabolismo , Antioxidantes/metabolismo , Encéfalo/crescimento & desenvolvimento , Mitocôndrias/metabolismo , Plastoquinona/metabolismo , Envelhecimento/genética , Animais , Encéfalo/metabolismo , Humanos , Plastoquinona/análogos & derivados , Espécies Reativas de Oxigênio/metabolismoRESUMO
Mitochondrial medicine was established more than 50 years ago after discovery of the very first pathology caused by impaired mitochondria. Since then, more than 100 mitochondrial pathologies have been discovered. However, the number may be significantly higher if we interpret the term "mitochondrial medicine" more widely and include in these pathologies not only those determined by the genetic apparatus of the nucleus and mitochondria, but also acquired mitochondrial defects of non-genetic nature. Now the main problems of mitochondriology arise from methodology, this being due to studies of mitochondrial activities under different models and conditions that are far from the functioning of mitochondria in a cell, organ, or organism. Controversial behavior of mitochondria ("friends and foes") to some extent might be explained by their bacterial origin with possible preservation of "egoistic" features peculiar to bacteria. Apparently, for normal mitochondrial functioning it is essential to maintain homeostasis of a number of mitochondrial elements such as mitochondrial DNA structure, membrane potential, and the system of mitochondrial quality control. Abrogation of these elements can cause a number of pathologies that have become subjects of mitochondrial medicine. Some approaches to therapy of mitochondrial pathologies are discussed.
Assuntos
Mitocôndrias/genética , Antioxidantes/uso terapêutico , Bactérias/genética , Bactérias/metabolismo , DNA Mitocondrial/genética , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genéticaRESUMO
A protective effect of a mitochondria-targeted antioxidant, a cationic rhodamine derivative linked to a plastoquinone molecule (10-(6'-plastoquinonyl)decylrhodamine-19, SkQR1) was studied in the model of open focal trauma of rat brain sensorimotor cortex. It was found that daily intraperitoneal injections of SkQR1 (100 nmol/kg) for 4 days after the trauma improved performance in a test characterizing neurological deficit and decreased the volume of the damaged cortical area. Our results suggest that SkQR1 exhibits profound neuroprotective effect, which may be explained by its antioxidative activity.