| dc.description.abstract | Major depressive disorder is a universal neuropsychiatric disorder affecting individuals on a global scale. It causes major disability independent of age, gender, ethnicity, sociological or economic status with an increasing prevalence and morbidity rate. The precise aetiological basis for this condition remains under investigation due to its complexity and several causalities thought to be related to its origin. Multiple hypotheses have been formulated in clarifying the existence of this disease which involves several systems, such as monoamines, glutamate regulation, neurotrophic factors, HPA-axis regulation, and several others. Not only are neurochemical imbalances associated with MDD; structural changes within the brain have also been documented. These changes have been investigated for involvement in depression-induced cognitive aberrations relating to memory and learning processes. The glutamatergic pathway is one of the systems suggested to be involved in the aforementioned deviations, linking a variety of other pathways, viz. the tryptophan metabolic pathway and N-methyl-D-aspartate (NMDA) receptor modulation. Currently, a vast array of treatment modalities are in place for treating MDD and treatment is more often focussed on the reversal of monoamine imbalances within the depressive brain. Though these compounds are effective in treating MDD, nearly 40% of patients never experience therapeutic effects and only 30 – 50% undergo successful remission. Consequently, the investigation into other biological targets and novel treatment options for MDD has been necessitated. Due to the structural brain alterations that co-present with MDD, several depression-induced cognitive abnormalities, viz. disrupted attention and concentration, declarative memory insufficiencies, disrupted thought processes and impaired neurogenesis have been unearthed and are now established as phenotypical of the condition. The aforementioned may stem from abnormal glutamate firing and NMDA receptor overexcitation in various brain regions for which supporting evidence does exist in both animal and human studies. However, no antidepressant compounds directly target the glutamatergic system and all of its involved components in order to reverse these irregularities. Therefore, it is essential to explore biological targets and new treatment options capable of exerting antidepressant-like and/or procognitive actions within the glutamatergic system.
Preclinical research has provided evidence in support of drug compounds exerting antidepressant-like effects via the glutamate pathway, either directly or indirectly, e.g. ketamine, memantine, allopurinol and sodium benzoate. However, evidence pertaining to the latter two compounds is in short supply. Therefore, the aim of this study was to investigate whether chronic treatment with allopurinol and sodium benzoate proved capable of reducing depressive-like behaviours and/or depression-induced cognitive impairments within the FSL model as well as their effects on monoaminergic - and BDNF concentrations in different brain areas linked to depression. Confirmation of the depression-like phenotype of the FSL rat model compared to its healthy cohort, the Flinders resistant line (FRL) rat, was accomplished using the FST. As a result,
the face validity of the model was reaffirmed allowing its application in investigating the
plausible antidepressant-like capabilities of allopurinol and sodium benzoate. However, the presence of depression-induced cognitive impairments could not distinctly be confirmed in this model using the MWM test even though a small difference was observed. The acute dose-ranging analysis with allopurinol and sodium benzoate proved effective in reducing depressive-like behaviours in the FSL rat in the FST. Consistent with earlier studies, administration of a chronic fixed dose protocol using allopurinol proved successful in significantly reducing depressive-like behaviours in the FSL rat using the FST. Similar outcomes were observed for sodium benzoate using the same protocol, although not to the same extent. Furthermore, the effects of fluoxetine drifted toward reduced immobility in the FST though no significant results were obtained. Ketamine and memantine similarly reduced immobile behaviour, although the latter not significantly so. Neither allopurinol nor sodium benzoate proved capable of significantly reducing depressioninduced
memory impairments (viz. memory retrieval) in the FSL rat during MWM testing. Yet, both compounds promoted memory consolidation over the 5 days of acquisition training. Interestingly, fluoxetine significantly impaired memory retrieval whereas ketamine visibly enhanced it. Memantine appeared to have had similar effects to that of fluoxetine. Only sodium benzoate proved capable of significantly enhancing striatal dopamine levels, though it may appear as if allopurinol had a positive effect in this regard. Predictably, fluoxetine enhanced prefrontocortical noradrenaline and serotonin levels. Data obtained for the rest of the compounds in the various brain regions proved inadequate and could not be used to corroborate the findings in the FST. With the exception of memantine, none of the other treatment options proved successful in enhancing brain BDNF concentrations. Though these results may appear inconclusive, current literature in association with the findings in this study support the antidepressant-like capabilities and potential procognitive effects of allopurinol and sodium benzoate and, therefore, the practical implications of the
results from this study should not be overlooked. However, further studies are necessary in order to clarify the investigated effects surrounding allopurinol and sodium benzoate in the treatment of depression and associated depression-induced cognitive impairments. | en_US |
