| dc.description.abstract | The focus of determining the underlying pathophysiological pathways of major depressive
disorder (MDD) has shifted from identifying one single hypothesis to the incorporation of
various aspects of the disease. Increasing evidence implicates increased pro- vs. antiinflammatory
activity and oxidative stress as key pathophysiological factors in MDD
especially considering its relevance to psychological stress and monoamine mediators. With
the realization of the contribution of oxidative stress and inflammation to MDD, treatment
with antioxidant and anti-inflammatory compounds has attracted a great deal of attention.
One such group of compounds are the xanthones. Of relevance for this particular study, the
pericarp of Garcinia mangostana Linn. (GM) is an evergreen fruit tree originating from
Indonesia that produces approximately 50 bioactive xanthones. Xanthone compounds are
known for their antioxidant and anti-inflammatory potential. To establish the antidepressantlike
properties of the raw powdered pericarp from this fruit, GM will be compared to N-acetyl
cysteine (NAC), a glutathione precursor, antioxidant, and glutamate modulator as well as to
imipramine (IMI), a well-known tricyclic antidepressant. This study has set about to address
this research question by way of a genetic rodent model of MDD, the Flinders Sensitive Line
(FSL) rat. The FSL rat model is a validated genetic animal model of MDD that presents with
good face, construct and predictive validity. The aim of this study is therefore to establish an effective dosage for GM for application in a
chronic treatment study with respect to antidepressant effects in the acute forced swim test
(FST) in FSL rats. We will also aim to establish whether IMI, NAC and GM have broad
psychotropic actions in FSL and Flinders resistant line (FRL) animals using a number of
behavioral screening tests of relevance to MDD, and whether a therapeutic distinction with
regard to efficacy can be made between these three compounds. Lastly we will establish
whether IMI, NAC and GM can reverse redox, immune-inflammatory and monoamine
changes related to MDD in FSL and FRL rats, and whether a distinction can be made with
respect to the three compounds in this regard.
GM displayed dose-dependent antidepressant-like effects after acute treatment.
Translational relevance was established by a similar response after chronic treatment,
although a dose of 50 mg/kg may need further characterization for chronic treatment.
Behavioral and regional brain monoamine analysis supported early-onset noradrenergic
activity following acute administration of GM, as well as a late emerging bolstering of
serotonin with long-term administration. GM also displayed antioxidant and anti-inflammatory properties by reducing lipid peroxidation in brain tissue and increasing plasma IL-10 activity,
actions that may underlie the aforementioned behavioral and neurochemical changes.
Considering that the data were generated in a genetic animal model of MDD, the antioxidant
and anti-inflammatory potential of GM suggest it may be a valuable adjunctive treatment with
conventional antidepressants, and warrants further study. These results can be beneficial in
the development of a new approach to the treatment of MD.
Die fokus om ‘n onderliggende patofisiologiese weg te vind vir major depressie (MD) het
onlangs verskuif vanaf ‘n enkele hipotese na die inkorperasie van verskeie relevante
aspekte. Inflammatoriese sitokiene en oksidatiewe stres is ook geidentifiseer as
sleutelfaktore wat bydra tot die patofisiologie van hierdie toestand; veral as verwys word na
hul verwantskap met psigologiese stres en monoamien merkers. Navorsing ten opsigte van
antioksidante en anti-inflammatoriese middels neem ook toe as gevolg van die beduidende
rol wat oksidatiewe stres en inflammasie in MD speel.
Die bogenoemde het aanleiding gegee tot die bestudering van xantone en spesifiek tot
hierdie studie die perikarp van Garcinia mangostana Linn. (GM), ‘n immergroen vrugteboom
vanuit Indonesië wat omtrent 50 bioaktiewe xantone bevat. Xantoon samestellings is bekend
daarvoor dat hul as antioksidante en anti-inflammatoriese middels optree. Om die
effektiwiteit van die rou gepoeierde perikarp met betrekking tot sy antidepressiewe
eienskappe te bepaal, sal dit met N-asetielsisteïen (NAC), ‘n glutatioon voorloper,
antioksidant en glutamaat moduleerder, asook met imipramine (IMI), ‘n bekende trisikliese
antidepressant, vergelyk word. Hierdie navorsing het begin deur die navorsingsvraag te
beantwoord met behulp van ‘n geneties depressiewe dieremodel genaamd die Flinders
sensitiewe lyn (FSL) rot. Die FSL model is ‘n gevalideerde genetiese dieremodel van MD
met goeie gesig-, konstruktiewe- en voorspelbaarheidsgeldigheid. Die doel van hierdie studie is dus om ‘n geskikte chroniese dosis te bepaal waarby GM as ‘n
effektiewe antidepressant optree in FSL rotte deur van die akute geforseerde swem toets
(FST) gebruik te maak. Die breër psigotropese effekte van IMI NAC en XC sal met behulp
van verskeie gedragstoetse relevant tot MD bepaal word in FSL asook Flinders
weerstandbiedende lyn (FRL) rotte en ons sal poog om vas te stel of daar terapeutiese
verskille tussen die verskillende middels is. Laastens sal ons, ook met behulp van FSL en
FRL rotte, probeer vasstel of IMI, NAC of GM redoks, immuun-inflammatoriese en
monoamienergiese veranderinge teweeg bring wat verband hou met MD en of daar
onderskei kan word tussen die effektiwiteit van die drie behandelingsgroepe.
Akute behandeling met GM het ‘n dosis-verwante antidepressiewe effek getoon. ‘n
Soortgelyke effek is waargeneem na kroniese toediening, alhoewel die 50 mg/kg dosis nog
verder ondersoek moet word vir effektiewe kroniese behandeling. Gedrag en neurochemiese
analises van monoamiene ondersteun die aanvanklike noradrenergiese aktiwiteit na akute toediening asook die latere toename in serotonien na kroniese toediening van GM. GM toon
antioksidatiewe sowel as anti-inflammatoriese eienskappe deur die verhoogde
lipiedperoksidase in breinweefsel te verminder en IL-10 aktiwiteit in die plasma te verhoog
wat die grondslag kan wees vir die bogenoemde gedrags - en neurochemiese veranderinge.
Indien dit in ag geneem word dat die data verkry is met behulp van ‘n genetiese dieremodel
van MD, kan die antioksidant en anti-inflammatoriese potensiaal van GM waardevol wees
as bykomende terapie saam met konvensionele antidepressante en verdien dit verdere
bestudeering. Hierdie resultate kan van nut wees om ‘n nuwe benadering tot die
behandeling van MD te ontwikkel. | en_US |
