Theses - Graduate Program in Neuroscience
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Browsing Theses - Graduate Program in Neuroscience by Subject "Acetylcholinesterase"
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Item Open Access Age and gender alter synaptic proteins in zebrafish (Danio Rerio) models of normal and delayed aging(Bilkent University, 2017-07) Karoğlu, Elif TuğçeCognitive decline occurs during normal aging in some specific domains of cognitive abilities including but not limited to episodic memory, divided attention and executive functions, however, it is not a unitary decline since some cognitive domains, including vocabulary and implicit memory tend to be preserved and even improved at older ages. Normal aging is not associated with global and significant neuronal and synapse loss, yet subtle molecular alterations occurring in gene expression patterns, protein homeostasis, mitochondrial dynamics and hypofunction in the cholinergic system may account for the age related decline in some cognitive abilities. Additionally, males and females showed differential vulnerabilities against age-related alterations in the cognitive abilities, physiological integrity and subtle molecular dynamics. More direct relationships can be established between the age-related cognitive decline and subtle molecular changes by analyzing the elements of synaptic integrity, which could alter synaptic plasticity and result in the changes in learning and memory abilities. Post-synaptic 95 (PSD-95), gephyrin (GEP) and synaptophysin (SYP) are integral synaptic proteins and they could be attributed as indicators of excitatory post-synaptic, inhibitory post-synaptic and pre-synaptic integrities, respectively. The first aim of this study was to show effects of age and gender on the expression levels of PSD-95, GEP and SYP in young, middle-aged and old, female and male zebrafish cohorts. Significant age by gender interactions were revealed in the levels of PSD-95 and SYP. It was shown that PSD-95 and SYP levels tend to be preserved and increased in the female groups throughout the aging process, whereas, in male groups, expression levels of these proteins tend to be reduced at older ages. The second aim was to investigate whether ameliorating the cholinergic hypofunction might have beneficial effects on the aging-related protein expression alterations and check for sexually dimorphic patterns. For this aim old male and female zebrafish from a mutant line (ache), which has decreased levels of acetylcholinesterase and increased levels of acetylcholine, were compared with old male and female wildtype animals. In the ache old groups, significant increases in the expression levels of SYP and GEP were revealed compared to the wildtype, and also in the old ache females SYP expression was higher than the other groups. These studies emphasized the importance of gender and sexually dimorphic patterns in the context of aging andcholinergic manipulations could be a promising target of intervention to attenuate the effects of age-related synaptic alterations, which could have possible contributions to age-related cognitive decline. .Item Open Access Identification of preclinical implications for novel indole-benzimidazoles and phenothiazines using in vitro cancer cell line and in vivo zebrafish models(Bilkent University, 2020-09) Yaman, MuratBreast cancer (BC) and hepatocellular carcinoma (HCC) are two major health problems with significant mortality rates. Although drug therapies are available, therapeutic success remains limited. Because of low bioavailability, high toxicity and recurring drug resistance, novel therapeutic options are essential. In the present thesis, a multitude of in vitro, in silico and in vivo approaches were executed to test anti-cancer effects and preclinical potentials of novel indole-benzimidazoles and phenothiazines in BC and HCC, respectively. In the first component of the thesis, I evaluated BC cell line toxicity and estrogen receptor (ER) relationship of novel indole-benzimidazole derivatives using in vitro cancer lines, in vivo zebrafish embryos/larvae, and in silico comparative transcriptomics analyses. In the second part, antipsychotic compounds phenothiazines (PTZ) were repurposed for HCC therapy. Therefore, generic PTZ derivatives alone or in combination with sorafenib (SFB) were tested using in vitro cancer lines followed by zebrafish developmental assays and embryonic stage xenografts. In addition, RNAseq analyses were performed on trifluoperazine (TFP), SFB, and TFP+SFB combination treated Hep3B cells to understand synergistic/antagonistic effects of the drugs at gene expression level. Lastly, anti-HCC potential of novel PTZ derivatives were explored by in vitro and in vivo screenings. Moreover, effects of the novel and generic derivatives on neural pathways were evaluated by cholinesterase assays and motor response measurements. The findings of the dissertation present potential leads for conducting further preclinical studies tailored towards novel BC and HCC therapies.