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Effects of Neurotransmission-Modulating Multipotent Compounds in Pharmacological Animal Models of Cognitive Deficit
Chvojková, Markéta ; Valeš, Karel (advisor) ; Kuchař, Martin (referee) ; Rudá, Jana (referee)
In preclinical research on Alzheimer's disease pharmacotherapy, attention is paid to multipotent compounds, enabling intensification of the effect by targeting multiple pathophysiological mechanisms. The aim of the thesis was to assess the effect of multipotent compounds and combination therapy in models of cognitive deficit in the rat. The mechanism of action of the tested compounds was modulation of neurotransmitter systems. The aim of the first part of the study was to compare the effect of experimental monotherapy and combination therapy with an N-methyl-D-aspartate (NMDA) receptor antagonist and a γ-aminobutyric acid type A (GABAA) receptor positive modulator in the trimethyltin-induced model. Superiority of the combination therapy was proven by histological analysis of hippocampal neurodegeneration; however, it did not reach statistical significance in the cognitive test. The other part of the thesis focused on multipotent tacrine derivatives. We demonstrated a positive effect of 6- chlorotacrine-6-nitrobenzothiazole hybrid, as well as 6-chlorotacrine-L-tryptophan hybrid, acting as acetylcholinesterase inhibitors, in the scopolamine-induced model of cognitive deficit. Besides, we demonstrated a low risk of serious side effects of other tacrine derivatives acting as NMDA receptor antagonists....
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The comparation of triggerlytic effect of combination therapy (ultrasound + TENS) and ultra electrostimulation
Klesnilová, Eliška ; Demeková, Júlia (advisor) ; Kavka, Tomáš (referee)
The thesis deals with the effect of two methods of physical therapy on myofascial trigger point, in particular combined therapy (US + TENS) and ultra- electrostimulation. Furthermore, there is investigated whether the release of MTrP is reflected in values of pressure pain threshold in chained muscles and there is discussed the use of combined therapy as an objectification tool. The theoretical part of the thesis deals with general and latest knowledge about myofascial trigger points. There are discussed some possibilities of the therapy with emphasis on physical therapy and transcutaneous electroneurostimulation, which form the basis for combined therapy (CT) and ultra-electrostimulation. The research part evaluates the effect of combined therapy and ultra-electrostimulation on a group of 12 probands randomly divided into two subgroups. Values of pressure pain threshold sensitivity, visual analogue pain scale (VAS) and the minimum intensity of electric current necessary to induce muscle contraction (measured by combined therapy) are used for objectification. Ultra-electrostimulation has proven to be a more effective method in VAS values, but in summary, the results cannot be considered statistically significant. The effect of MTrP release (of the trapezius muscle) on the chained muscles could not...
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Molecular mechanisms responsible for regulation of apoptosis in prostate cancer cells treated with TRAIL and chemotherapeutic drugs
Tománková, Silvie ; Hyršlová Vaculová, Alena (advisor) ; Špegárová, Jarmila (referee)
Prostate cancer is one of the most common cancer-related causes of death among men. Chemotherapy is mainly used for treatment of its later stages, accompanied by unpleasant side effects. So far, the treatment of advanced stages of prostate cancer has not been sufficient, and new more effective alternatives are needed. The application of the TRAIL cytokine, which induces apoptosis in tumor cell, but is not toxic to nonmalignant cells, seems to be a promissing approach. However, TRAIL-based therapy is often limited by the emerging cancer cell resistance. Overcoming the resistance can be achieved by combination therapy of TRAIL with effective sensitizers. Within this work, a combination of TRAIL with platinum-based chemotherapeutic drugs such as cisplatin or its novel derivative LA-12 was applied in order to facilitate the elimination of prostate cancer cells. In the experimental part of this work, using Western blot and flow cytometry analysis it was shown that TRAIL in combination with CDDP or LA-12 effectively enhanced apoptosis in three human prostate cancer cell lines. This effect was accompanied with increased activation/amount of several proapoptotic Bcl-2 family proteins, while no changes in the level of the receptors for TRAIL were observed. These results demonstrated that especially the combination...
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Molecular mechanisms of tumor pathogenesis of Hedgehog signaling pathway in selected tumor types
Kreisingerová, Kateřina ; Vachtenheim, Jiří (advisor) ; Macůrek, Libor (referee) ; Uldrijan, Stjepan (referee)
The presented doctoral thesis is focused on the role of the Hedgehog (HH) signaling pathway in cancer pathogenesis. HH signaling pathway is an evolutionarily conserved signaling pathway that plays an essential role in embryonic development. Its activity is strictly limited to stem and progenitor cells for example in brain, lung, skin or prostate. HH pathway also plays a key role in tissue homeostasis and regeneration. Aberrantly activated HH pathway is essential in cancer progression. The aim of the presented thesis was to elucidate new details about the HH signaling pathway. We identified a new target gene of the HH pathway - the anti-apoptotic protein survivin. Survivin is considered to be an important tumor marker associated with a poor prognosis of patients. We showed that the inhibitor of HH pathway effectors GLI1 and GLI2 GANT61 reduced the survivin level in cancer cells. Subsequently, we used GANT61 and the inhibitor of the anti-apoptotic BCL2 protein family obatoclax to inhibit melanoma cells growth. We showed that the combination of these inhibitors was very effective in the eradication of melanoma cells in vitro. We also proved that GANT61 triggers the process of apoptosis in melanoma cells. We found out that the HH signaling pathway is canonically activated in many cell lines of various...
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