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The role of G protein-coupled receptor signaling systems in neuroprotection
Hofmannová, Adéla ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
Nervous tissue, especially the brain, is very sensitive to the lack of oxygen and nutrients. Without supply of these components, the tissue endures only a few minutes and then, after the depletion of all ATP, permanent damage or even cell death occurs in neurons and glial cells. During ischemia or hypoxia, an excessive amount of the excitant neurotransmitter glutamate is released, which is neurotoxic. It causes ion imbalance and also apoptotic signaling pathways may be triggered because of the high level of intracellular calcium. Signaling through G protein-coupled receptors (GPCRs) can be involved in the establishment of increased cell resilience to hypoxic injury. Stimulation of some GPCRs, e.g. adenosine, opioid, cannabinoid and melatonin receptors, can afford neuroprotection. Activation of their cognate G proteins may lead to blockade of ion channels or affect the effector proteins, thus helping the stabilization of ion homeostasis and the inhibition of glutamate release. Moreover, some of the receptor agonists have antioxidant character, whereby they prevent the harmful action of free radicals. Neuroprotective mechanisms promote neuronal survival during harmful conditions and are also able to slow down the processes responsible for the development of neurodegenerative diseases. Key words: G...
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Mitochondrial protein 17β-hydroxysteroid dehydrogenase type 10 in the brain of a genetic animal model of Alzheimer's disease (McGill-R-Thy1-APP rats)
Hofmannová, Adéla ; Krištofíková, Zdena (advisor) ; Benek, Ondřej (referee)
Transgenic McGill-R-Thy1-APP rats are one of the best animal genetic models of Alzheimer's disease (AD). Significant intracellular elevation of soluble amyloid β (Aβ) and cognitive deficits are observed already in 3-month-old rats, prior to extracellular plaque deposition. Mitochondrial bioenergetic capacity appears to be altered via defects in complex I enzymatic activity in the electron transport chain already in 6-month-old rats. Nucleus-encoded mitochondrial matrix protein 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) operates via multiple enzymatic and non-enzymatic functions and is known as a binding partner of intracellular Aβ. In patients with AD, 17βHSD10 overexpression has been reported in brain and increased levels in cerebrospinal fluid. Cytoplasmic 17βHSD10 is imported via the PINK1-Parkin-TOM/TIM pathway into mitochondrial matrix, where it binds e.g. cyclophilin D (CypD) and prevents its translocation to the inner mitochondrial membrane. By this mechanism, 17βHSD10 can regulate the opening of the mitochondrial permeability transition pore mediated by CypD. It seems that accumulated mitochondrial Aβ may influence this regulation. In this study, we measured 17βHSD10 levels in mitochondria isolated from the brain of 11-month-old homozygous McGill-R Thy1-APP rats and we evaluated...
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The role of G protein-coupled receptor signaling systems in neuroprotection
Hofmannová, Adéla ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
Nervous tissue, especially the brain, is very sensitive to the lack of oxygen and nutrients. Without supply of these components, the tissue endures only a few minutes and then, after the depletion of all ATP, permanent damage or even cell death occurs in neurons and glial cells. During ischemia or hypoxia, an excessive amount of the excitant neurotransmitter glutamate is released, which is neurotoxic. It causes ion imbalance and also apoptotic signaling pathways may be triggered because of the high level of intracellular calcium. Signaling through G protein-coupled receptors (GPCRs) can be involved in the establishment of increased cell resilience to hypoxic injury. Stimulation of some GPCRs, e.g. adenosine, opioid, cannabinoid and melatonin receptors, can afford neuroprotection. Activation of their cognate G proteins may lead to blockade of ion channels or affect the effector proteins, thus helping the stabilization of ion homeostasis and the inhibition of glutamate release. Moreover, some of the receptor agonists have antioxidant character, whereby they prevent the harmful action of free radicals. Neuroprotective mechanisms promote neuronal survival during harmful conditions and are also able to slow down the processes responsible for the development of neurodegenerative diseases. Key words: G...
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