| Summary: | Hypericum perforatum is a herbal medicine that has been used for centuries for the treatment of depression. Many studies have been conducted in the Northern hemisphere on the efficacy of the HP extracts produced there. These studies include clinical trials and pharmacological investigations using a standardised HP extract or a fraction of the HP extract containing certain compounds, such as hypericin, pseudohypericin, hyperforin and several of the flavonoids thought to be responsible for the antidepressant activity. The mechanism of action of HP and its constituents is still not completely clear and it is speculated that the antidepressant activity is the result of several of the compounds acting synergistically. HP is indigenous to and also cultivated in the Western Cape of South Africa. Extracts from these plants are sold in the local health shops and there are no previous studies evaluating the efficacy of these products. The aim of this thesis is to investigate the antidepressant activity of one of these products and two of its constituents, quercetin and caffeic acid, to gain further insight into their mode of antidepressant action and to compare these results with similar studies which used a standardised extract produced in the northern hemisphere. The first study investigated the effect of HP, quercetin and caffeic acid on pineal metabolism. Changes in the synthesis of melatonin produced by the pineal gland have been implicated in depression. The results showed an increase in the level of melatonin produced in the animals treated with quercetin, which suggests that this compound may mediate antidepressant activity through such a mechanism. There are no previous reports on the in vivo effects of HP or any of its constituents on pineal metabolism. The second study investigated the effect of HP, quercetin and caffeic acid on the activity of the liver enzyme, tryptophan-2,3-dioxygenase (TDO). Inhibition of this enzyme has been shown to increase plasma levels of tryptophan, a precursor of serotonin and thereby result in increased serotonin levels in the brain. Low levels of serotonin in the brain have been implicated in depression. This study revealed significant inhibition of TDO by caffeic acid and this suggests that this constituent of HP could be contributing to its antidepressant activity through such a mechanism. There are no previous reports investigating the in vivo effect of HP or any of its constituents on TDO activity. Modulation of the levels of indoleamines, serotonin (5-HT) and dopamine (DA) as well as the metabolites, 3,4 dihydroxyphenyl acetic acid (DOPAC), 5-hydroxyindole acetic acid (5-HIAA) and homovallinic acid (HVA) in the brain have been implicated in the neuropharmacology of depression. Different studies using enzyme-linked immunosorbant assay (ELISA), high performance liquid chromatography with electrochemical detection (HPLC-ECD) and liquid chromatography-mass spectrometry (LC-MS) were used to determine changes in the levels of these indoleamines brought about after treatment with HP caffeic acid and quercetin. The results of the ELISA study showed significant increases in 5-HT levels in the brains of the animals treated with caffeic acid and quercetin. The results of the HPLC-ECD studies also revealed significant increases in 5-HT levels and a decrease in the turnover of 5-HT in the animals treated with quercetin. A significant increase in DA levels in the animals treated with quercetin was shown in both the HPLC-ECD and LC-MS studies. There was also an increase in DA turnover in the animals treated with HP shown in the HPLC-ECD and LC-MS studies. These results suggest that HP and its constituents, quercetin and caffeic acid mediate their antidepressant effects through serotonergic and dopaminergic neurotransmission. Adaptive changes in the density of b-adrenergic (b-AR), 5-HT2 and N-methyl-D-aspartate (NMDA) receptors have been implicated in depression. Several studies, investigating the effect of treatment with HP and quercetin on these different receptor densities, were undertaken using radioactive binding assays. Treatment with HP resulted in significant down regulation of b-AR and NMDA receptor densities and up-regulation of 5HT2 receptors. The effects on the b-AR and 5-HT2 receptors are similar to the results reported using HP in the Northern hemisphere, but the effect on the NMDA receptors is novel providing insight into the mode of action of HP. Apoptosis of neuronal cells has been implicated in neuro-degenerative and depressive disorders. Detection of apoptosis, using fluorescent microscopy observed through the labelling of DNA strand breaks, showed a decrease in the amount of apoptosis in the animals treated with HP and quercetin. This adds further support for the use of HP as an antidepressant and these results are similar to results reported from the Northern hemisphere. The results of all these studies suggest that the quality of the locally produced tincture is similar in efficacy to that of the standardised product of the Northern hemisphere.
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