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Opioids and neuroprotection: the role of glial cells
Honc, Ondřej ; Novotný, Jiří (advisor) ; Kováčová, Ľubica (referee)
High energy deamand and insulation via the blood-bain barrier are the main reasons for neuronal sensitivity to oxygen or energy deficiency. Even short or mild periods of hypoxia/ischemia (H/I) could fataly impact the CNS enviroment. The area on the edge of the tissue affected by H/I and adjacent unaffected tissue is called the penumbra. Here, we can observe additional H/I related processes - gliosis allied with sterile inflammation and censecutive apoptosis. Opioid receptors attenuate H/I impact on CNS in both acute and consecutive phases. In acute phases, opioid receptors regulate ion homeostasis and attenuate glutamate toxicity; in consecutive phases, lower gliosis manifestation. Both these actions have significant neuroprotective effects. Ability of opioid receptor to lower sterile inflammation in CNS could be used in a series of neurodegenerative diseases, eg. Alzheimer disease or amyotrophic lateral screlosis. Glial cells participate on ion homeostasis, glutamate uptake, and production of antiinflammatory substances; one can, therefore, assume that a significant part of neuroprotective effects of OR is related to glial cells. The opioid system and its signaling pathways has not been fully elucidated yet. I present global overview of this phenomenon and describe some recent findings regarding...
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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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The role of glia in neuroprotection
Fider, Jan ; Novotný, Jiří (advisor) ; Telenský, Petr (referee)
Verterbate brain is extremely demanding on energy and oxygen consumption. A few seconds of the oxygen deprivation can disrupt brain homeostasis and cause an ionic imbalance, resulting in neuronal death by apoptosis or necrosis. The mechanisms, that are responsible for protection of the CNS against the disruption of homeostasis are called neuroprotection. Neuroprotection in the brain is mostly provided by glial cells. There are several types of glia in the human brain, but not all of them are responsible for neuroprotection equally. However, in general we can say that all the glial cells are responsible for the maintainance of ionic balance, which play an important role in neuroprotection. Astroglia and mikroglia dominantly contribute to protectiion of the CNS. These cells can be activated by any disruption of the CNS and actively execute a number of neuroprotective actions. Activated astrocytes form astrogliosis, which covers and separates the affected area of the brain from healthy tissue, thereby preventing further spread of ischemic damage. Activated microglia can transform into phagocytes which clean the extracellular space from dead cells and their parts. Neuroprotection research is nowadays very popular. This is because of urgent need better understanding of the causes of neurodegenerative...
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The influence of the neuroactive steroids inhibiting NMDA receptors on behaviour
Chvojková, Markéta ; Valeš, Karel (advisor) ; Mareš, Pavel (referee)
The neuroactive steroid pregnanolone glutamate (Pg glu), a synthetic analogue of the naturally occurring pregnanolone sulfate (3alpha5betaS), has neuroprotective properties and a minimum of adverse effects. The subject of my thesis is the influence of selected structural modifications of the molecule Pg glu on biological effects. The first modification involves an increase of lipophilicity, the second involves the attachment of a positively charged group to C3. All these neuroactive steroids are use-dependent inhibitors of NMDA receptors. The first aim of this thesis was to determine the neuroprotective effectiveness of the neuroactive steroids chosen. The second aim was to explore the influence of selected neuroactive steroids on motor coordination, reflexes, anxiety and locomotor activity, as well as the effect of their high doses. The third aim was to create a battery of behavioural tests for screening the biological effects of analogues of Pg glu in laboratory rodents. The neuroprotective effects were evaluated in a model of excitotoxic damage of hippocampus in the rat on the basis of its behavioural consequences. The neuroprotective efficacy of androstane glutamate (And glu) and Pg glu was demonstrated. In the case of positively charged molecules, neuroprotective efficacy was not demonstrated....
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Ionotropic glutamate receptors and excitotoxicity
Skřenková, Kristýna ; Vyklický, Ladislav (advisor) ; Moravec, Jan (referee)
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and its excitatory role is mediated trough activation of glutamatergic ionotropic receptors which are responsible for synaptic transmission and play an important role in learning and memory formation. However, excessive exposure to glutamate can result in excitotoxicity which may lead to cell death. The following text is focused on one group of glutamate receptors - NMDA receptors. The study of the receptors is in the centre of current neurobiology research because there is a series of experimental and clinical evidences that they directly participate in the development of serious diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and may cause neuronal damage in trauma, hypoxia and embolia. The aim of this bachelor thesis is to give a brief overview of current knowledge about the structure and function of NMDA receptors and mechanisms of their activation which leads to excitotoxicity and related neuroprotection.
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Potential role of opioids in neuroprotection
Gebauer, Martin ; Novotný, Jiří (advisor) ; Rudajev, Vladimír (referee)
The opioids have been used by mankind for more than two millennia, but effect and mechanism of their action on the cells has been unveiling in the last few decades. The mechanism itself is often still unknown, but its effect is observed only. There are several groups of opioid receptors which are able to bind opioids. These groups are characterized by their differe nt affinity to opioids, in some cases by their different effects on cells and by their representation in the various areas in the CNS. Thus, the effects induces by these opioid are very different in many cases. This thesis summarizes the current knowledge about coronary heart disease and the potential of opioids for the prevention and their effect during ischemia, also summarizes the effects of morphine on the CNS. During ischemia δ-opioid receptors play a major role, because they inhibit or block the proapoptotic effects of ischemia on many levels. These receptors are also involved in inducing and maintaining the animal hibernation and protect animal's body against very harmful effects of hibernation, e.g lack of oxygen and nutrients. Morphine is opioid which has been used as anesthetic for longest time. It is well-known opioid and it has the most known derivates. This thesis also summarizes most significant effects of morphine on...
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The behavioral effects of NMDA receptor antagonists
Chvojková, Markéta ; Valeš, Karel (advisor) ; Horák, Martin (referee)
NMDA (N-methyl-D-aspartate) receptors are glutamate-gated ion channels, which are located in the central nervous system. They permit excitatory neurotransmission and are crucial for synaptic plasticity and other functions, but on the other hand for excitotoxicity. By the administration of NMDA receptor antagonists it would be possible to restrict the consequences of excessive glutamate exposure. However, the use of many of these drugs is made impossible by their serious behavioral side effects. NMDA receptor antagonists can influence cognitive and motor functions in laboratory animals and also in humans, and can cause temporary psychosis. These negative behavioral effects are most pronounced in the case of non-competitive antagonists. Conversely, the behavioral side effects of uncompetitive antagonists, antagonists selective for NMDA receptors containing a NR2B subunit or NMDA receptor glycine binding site antagonists are milder. From a clinical point of view, some other behavioral effects of NMDA receptor antagonists are beneficial. These effects include anxiolytic and antidepressant effects and also an alleviation of cognitive deficit and behavioral aberration in Alzheimer's disease through the administration of memantine. The aim of this thesis is to summarize the main behavioral effects known to us of...
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