Comparative study of N-acetyl cysteine and an experimental xanthone compound on behavioral, immune-inflammatory and redox biomarkers of depression in the Flinders sensitive line rat

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.