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Effect of morphine preconditioning and mKATP channel activity on survival of differentiated SH-SY5Y cell line after oxidative stress
Paluba, Michal ; Hejnová, Lucie (advisor) ; Kolář, David (referee)
Morphine as one of the most effective analgesics has been used in medicine for more than a century. However, morphine is also known for its neuroprotective and cardioprotective effect in ischemic disorders, where it induces increased cellular resistance to oxidative stress. One of the aims of our study was to analyze the effect of chronic morphine treatment on the viability of differentiated cells of the neuroblastoma cell line SH-SY5Y after induction of oxidative stress by tert butyl hydroperoxide (tBHP). However, the detailed mechanism of the protective effect of morphine is still unknown. Current research on this topic, and in particular on morphine-induced preconditioning, has focused much attention on mitochondrial ATP- sensitive potassium channels (mKATPs). There is evidence that morphine, through activation of opioid receptors, mimics the protective effect of ischemic preconditioning precisely through activation of mKATP channels. Modulation of mKATP channel activity is thought to be responsible for the functional state of the mitochondria by altering mitochondrial membrane potential and regulating reactive oxygen species (ROS) production. Thus, the next aim of our work was to reveal the role of mKATP channels in morphine preconditioning and the effect of their activity on cell survival. The...
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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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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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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 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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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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Neuroprotective versus apoptotic effect of morphine
Paluba, Michal ; Hejnová, Lucie (advisor) ; Pačesová, Dominika (referee)
Morphine, which is primarily used in medicine as a strong analgesic, has been studied for a long amount of time for its protective effects on neural tissue. Morphine demonstrates its neuroprotective role in ischemic disorders because it induces a higher tolerance to glucose and oxygen deprivation among neurons. However, morphine has a protective influence not only on neurons, but also on neuroglia, especially on astrocytes. Pathological disorders can result in the over-release of neurotransmitters, which include glutamate, which is known for its excitotoxicity at excessive concentration. Morphine even in this case effectively blocks the effect of glutamate, thus preventing apoptosis of cells. However, there is also evidence of an apoptotic effect of morphine on cells, as in some cases it increases the synthesis and activity of proapoptotic factors. However, the apoptotic effect of morphine does not always affect the organism only negatively. There is also evidence of its effect on the regulation of the tumour development by using morphine-induced apoptosis.
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Neurological deficit after focal cerebral ischemia in rat - pharmacological intervention
Eliášová, Karolína ; Otáhal, Jakub (advisor) ; Svoboda, Jan (referee)
Title: Neurological deficit after focal cerebral ischemia in rats - pharmacological intervention Objectives: The goal of the thesis was to determine the effect of 7-nitroindazole, a selective inhibitor of neuronal nitric oxide synthase, after focal ischemic stroke in rats. Methods: Twenty adult male Wistar rats were used in this experiment. The rats were randomly divided into four groups: ischemic stroke was given to half of them, the rest were sham operated. 10 animals were given 7-nitroindazole (25mg/kg) to protect neuronal ischemic brain damage. After a few weeks the rats were tested with a set of behavioral tests: Ladder rung walking test, Bar holding test, Rotarod test and Open field test. To evaluate the volume of brain damage the stereotactic method was used. The brain sections were cut and compared with atlas. This study was supported by Institute of Physiology, Academy of Sciences ČR in Prague. Results: The present results show that the 7-nitroindazole has no side effects on healthy rats. The long-term effect on rats after ischemic stroke was not proved. There were a few positive trends observed such as an increase of locomotor speed, increased explorative behaviour and better coordination outcome on RotaRod. On the other hand the brain tissue damage was bigger and the time of hanging in...
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The role of cannabinoid signaling in neuroprotection
Mádrová, Eliška ; Novotný, Jiří (advisor) ; Červená, Kateřina (referee)
The name of the endocannabinoid system comes from Cannabis sativa which contains Δ9 -THC that causes psychotropic effects through cannabinoid receptors. It was discovered that Δ9 -THC is not the only ligand of the cannabinoid system but there also naturally exist endogenous cannabinoids in the human body. The main endogenous cannabinoids are anandamide and 2-arachidonoylglycerol which act on various receptors, primarily cannabinoid receptors CB1 and CB2 that fall into a group of G-protein coupled receptors, but they may also affect vanilloid receptor TRPV1 or nuclear peroxisome proliferator-activated receptor PPARγ. By studying the cannabinoid system, it was discovered that cannabinoids can modulate some of the cellular processes such as cell growth, proliferation and differentiation of cells, apoptosis and intracellular concentration of Ca2+ . Recently they have been primarily studied for their usefulness in the treatment of neurodegenerative diseases, for example, Alzheimer's disease, multiple sclerosis or epilepsy because it has been shown that they support the survival of neurons during excitotoxicity and they modulate the release of cytokines responsible for the regulation of the immune system and inflammatory response. Key words: cannabinoid receptors, G proteins, neuroprotection, Δ9 -THC,...
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Adenosine signaling: the role in neuroprotection and neurodegeneration
Hrušovská, Kateřina ; Novotný, Jiří (advisor) ; Kolář, David (referee)
The aim of this bachelor thesis is to describe basic and the most important mechanisms of adenosine signaling, especially in the central nervous system, where the purine nucleoside adenosine plays important role like significant neuromodulator. Strong release of adenosine to extracellular space may occur under some pathological conditions. Adenosine works throught his four receptors, which have very diverse functions. Some effects are neuroprotective - these are predominantly mediated throught the inhibitory A1 receptor, which can reduce neurotoxicity, others may also induce neurodegeneration, mainly due to increased activation of A2A receptors. This signaling system can be diversely modulated, for example by inhibition of enzymes, which can provide adenosine formation or degradation, blocking its transporters, by agonists or adenosine antagonists, or by inhibition of second messengers and various protein kinases by which adenosine affects cellular processes. Interactions of adenosine receptors with other types of receptors in the brain are also important. Adenosine and adenosine receptors can participate in neurodegenerative processes. A detailed understanding of the specific effects of adenosine can bring great progress in the treatment of neurodegenerative diseases. At present, intensive...
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