This Is AuburnElectronic Theses and Dissertations

Investigate the Effects of Designer Drugs on Amyloid Beta




Harshan, Aishah

Type of Degree

Master's Thesis




Designer drugs are structurally novel compounds that can exhibit several pharmacodynamic effects. The diverse pharmacodynamic effects of designer drugs are due to their significant interaction with the major drug targets in the body. The designer drugs can interact with several receptors, enzymes, and reuptake pumps which can lead to pharmacological or toxicological effects. Currently, there is a great prophylactic and therapeutic need to decrease the risk of neurodegeneration. Alzheimer’s disease is a neurodegenerative disorder that induces irreversible cognitive impairment. Based on the current therapeutic demand to decrease the risk associated with Alzheimer’s disease, there is an immediate need to develop new drugs with neuroprotective effects. Amyloid-beta (Aβ) and tau pathologies are mainly attributed to the neurodegeneration in Alzheimer’s disease. Therefore, in this study, we elucidated the effect of piperazine designer drugs on amyloid-beta (Aβ) metabolism. We used PS70 cells to evaluate the neuroprotective effects of piperazine designer drugs against Aβ neurotoxicity. Initially, we evaluated the effects of piperazine designer drugs (3-TFMPP-parent compound and 3-TFBzPP-derivative) on PS70 cell viability. Regarding the mechanism of cytotoxicity, we assessed the effects of piperazine designer drugs (3-TFMPP and 3-TFBzPP) on the markers of oxidative stress, mitochondrial function, apoptosis, and inflammation. The parent compound, 3-TFMPP, exhibited higher toxic effects due to the increased generation of pro-oxidants & decreased antioxidants, enhanced apoptosis and inflammatory markers as compared to the piperazine derivative, 3-TFMBZPP. We used non-toxic doses of 3-TFMP and 3-TFBzPP to study the effect on Aβ metabolism. 3-TFMBzPP exhibited significant neuroprotective effect as compared to 3-TFMPP. The neuroprotective effects of 3-TFMBzPP is attributed to their effect on amyloid precursor protein, and gamma (γ)-secretase which resulted in decreased Aβ-42 formation. Furthermore, we also validated our findings using molecular modelling. Thus, 3-TFMBzPP may be a potent molecule that can be used to reduce Aβ-induced neurodegeneration. Our further studies will use valid animal model to validate the in vivo neuroprotective effects against Aβ and tau pathologies