Effects of Piperazine Derivatives on Hippocampal and Dopaminergic Neurotransmission
Type of DegreePhD Dissertation
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Designer Drugs are a group of psychoactive substances synthesized from chemicals to emulate the pharmacodynamic and pharmacokinetic actions of widely used substances of abuse. A minor modification of the chemical structure can alter the pharmacodynamic and pharmacokinetic profile. These designer drugs affect the neurotransmitters, endocrine and/or exocrine systems. Most of the pathologies associated with the central (CNS) and peripheral nervous system (PNS) occur due to the alteration in the content of a single neurotransmitter in a specific or multiple region of the brain or spinal cord. Moreover, these pathologies can occur due to the imbalance in the content of two or more neurotransmitters in a specific or multiple region of the brain. The change in neurotransmitter content occurs due to interference by designer drugs in the basic process of neurotransmission, which in turn can affect the synthesis (precursor, cofactors synthesizing enzymes), storage (vesicular), release, pre- and/or post-synaptic receptor action(s), as well as metabolism (degrading enzymes) and reuptake of the neurotransmitters. The designer drugs exert their actions by affecting various sites through single or multiple pharmacodynamic effects, which can increase or decrease the neurotransmission. Alterations of the neurotransmission (augmented or diminished) by the designer drugs are mostly detrimental to humans; however, there are certain mechanisms that can reduce the symptoms and provide beneficial effects in numerous pathologies. Currently, there is a substantial increase in the manufacture and usage of piperazine designer drugs worldwide. In the current study, we illuminate the site(s) and mechanism(s) of action of the piperazine designer drugs affecting the cholinergic, and dopaminergic neurotransmission. There are very limited studies on the hippocampal and dopaminergic neurotoxicity of 1-(3-trifluoromethylphenyl) piperazine (3-TFMPP) and its derivatives (2-TFMPP, 4-TFMPP). N27 rat dopaminergic cells are valid in vitro model to investigate the dopaminergic neurotoxic effects and establish the neurotoxic mechanisms of various substances associated with movement disorders. Furthermore, HT-22 mouse hippocampal cells have been used to study the cholinergic / glutamatergic neurotransmission as well as the etiopathology of various types of dementia (Alzheimers disease). Furthermore, in this study, we assessed the possible pharmacodynamic and pharmacokinetic effects of (2, 3 and 4-TFMPP) derivatives using receptor binding assay and QikProp software. Additionally, we established the mechanisms of hippocampal and dopaminergic neurotoxicity of TFMPP derivatives. TFMPP derivatives caused dose-dependent and time-dependent neurotoxicity and produced hippocampal and dopaminergic neuronal death. Furthermore, TFMPP derivatives altered dopaminergic and cholinergic neurotransmission through decreasing the synthesis and increasing the breakdown of dopamine and acetylcholine. Moreover, TFMPP derivatives instigated oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. The usage and manufacture of designer drugs need to be strictly regulated in order to avoid numerous central and peripheral disorders leading to a liability to the current and future society.
- M.Majrashi Dissertation.pdf