Antidepressants are widely used in the treatment of depressive illnesses associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Neuroprotection in such disorders is of vital importance in order to delay the progression of the primary disorder. The pathology of neurodegeneration is not fully understood. It is however widely accepted that oxidative stress and excitotoxicity play a major role. Brain tissue is rich in phospholipids, which are especially prone to oxidation due to the high level of oxygen utilization in the brain. In addition, the brain lacks defence mechanisms to protect it against the wrath of free radicals. Presently, there is a wide variety of antidepressant drugs available. These range from the original tricyclic antidepressants to the newer selective serotonin reuptake inhibitors. It is not known whether antidepressant drugs, old or new, offer neuroprotection or how the existing state and/or the progression of neurodegeneration, is influenced by these agents. The present study was undertaken to determine how nortriptyline, trimipramine and fluoxetine affect neurodegeneration. Initial in vitro and in vivo studies show that all three of the antidepressants (0-1mM) studied provide neuroprotection from quinolinic acid induced lipid peroxidation. A histological investigation supported these findings by showing that a marginal degree of neuroprotection is apparent when treating animals with antidepressants (10mg/kg) before and following quinolinic acid intrastriatal injection. Further studies were undertaken in an attempt to determine the mode of neuroprotective action of the agents studied. An in vitro study of superoxide anion induced lipid peroxidation indicates that these agents do not act as antioxidants. The influence of the antidepressants on tryptophan 2,3-dioxygenase activity was assessed, based on the understanding that inhibition of this enzyme results in increased levels of the known antioxidant indoleamine, melatonin. Nortriptyline hydrochloride is seen to inhibit tryptophan 2,3-dioxygenase activity and as such it is possible that this antidepressant can indirectly provide neuroprotection by increasing available melatonin. Electrochemical and UV/visible studies show that trimipramine maleate interacts with free iron (II) and iron (III) ions. Free metal ions can catalyse the formation of damaging free radicals. Through interaction with trimipramine maleate, these ions will be unavailable to the system and thus cannot contribute to oxidative stress. The findings of this study indicate that antidepressants may be able to provide neuroprotection to neuronal cells. The mode of such neuroprotective actions need to be further examined so that patients suffering from depression coexisting with neurodegenerative diseases can be safely and effectively treated.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:rhodes/vital:3792 |
| Date | January 2002 |
| Creators | Steiner, Claire |
| Publisher | Rhodes University, Faculty of Pharmacy, Pharmacy |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis, Masters, MSc |
| Format | 162 p., pdf |
| Rights | Steiner, Claire |
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