Studies on Haloperidol and Adjunctive α-Mangostin or Raw Garcinia mangostana Linn Pericarp on Bio-Behavioral Markers in an Immune-Inflammatory Model of Schizophrenia in Male Rats

Jana Lotter; Marisa Möller; Olivia Dean; Michael Berk; Brian H Harvey

doi:10.3389/fpsyt.2020.00121

Studies on Haloperidol and Adjunctive α-Mangostin or Raw Garcinia mangostana Linn Pericarp on Bio-Behavioral Markers in an Immune-Inflammatory Model of Schizophrenia in Male Rats

Front Psychiatry. 2020 Mar 31:11:121. doi: 10.3389/fpsyt.2020.00121. eCollection 2020.

Authors

Jana Lotter¹, Marisa Möller¹, Olivia Dean^{2

3}, Michael Berk^{2

3

4}, Brian H Harvey¹

Affiliations

¹ Division of Pharmacology, Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North West University, Potchefstroom, South Africa.
² Deakin University, IMPACT - The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.
³ Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁴ Orygen, Department of Psychiatry, The Centre of Excellence in Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.

Abstract

Schizophrenia is a severe brain disorder that is associated with neurodevelopmental insults, such as prenatal inflammation, that introduce redox-immune-inflammatory alterations and risk for psychotic symptoms later in life. Nutraceuticals may offer useful adjunctive benefits. The aim of this study was to examine the therapeutic effects of Garcinia mangostana Linn (GML) and one of its active constituents, α-mangostin (AM), alone and as adjunctive treatment with haloperidol (HAL) on schizophrenia related bio-behavioral alterations in a maternal immune-activation (MIA) model. Sprague-Dawley dams were exposed to lipopolysaccharide (LPS) (n = 18) or vehicle (n = 3) on gestational days 15 and 16. Male offspring (n = 72) were treated from PND 52-66 with either vehicle, HAL (2 mg/kg), GML (50 mg/kg), HAL + GML, AM (20 mg/kg), or HAL + AM. Control dams and control offspring were treated with vehicle. In order to cover the mood-psychosis continuum, prepulse inhibition (PPI) of startle, open field test (locomotor activity), and the forced swim test (depressive-like behavior) were assessed on PND's 64-65, followed by assay of frontal-cortical lipid peroxidation and plasma pro-inflammatory cytokines, viz. interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). MIA-induced deficits in sensorimotor gating were reversed by HAL and HAL + GML, but not GML and AM alone. MIA-induced depressive-like behavior was reversed by AM and GML alone and both in combination with HAL, with the combinations more effective than HAL. MIA-induced cortical lipid peroxidation was reversed by HAL and AM, with elevated IL-6 levels restored by GML, AM, HAL, and HAL + GML. Elevated TNF-α was only reversed by GML and HAL + GML. Concluding, prenatal LPS-induced psychotic- and depressive-like bio-behavioral alterations in offspring are variably responsive to HAL, GML, and AM, with depressive (but not psychosis-like) manifestations responding to GML, AM, and combinations with HAL. AM may be a more effective antioxidant than GML in vivo, although this does not imply an improved therapeutic response, for which trials are required.

Keywords: adjunctive treatment; antidepressant; antipsychotic; complimentary medicine; immunity; mangosteen; maternal inflammation; oxidative stress.