A Systematic Review of Neuroprotective Effects of Mangosteen and its Xanthones Against Oxidative Stress and Inflammation

Abstract

Mangosteen has garnered increasing attention for its medicinal properties against oxidative stress and inflammation–two major causative and progressive agents of neurodegenerative diseases. This systematic review explores the antioxidative and anti-inflammatory effects of mangosteen crude extracts and their purified bioactive compounds, highlighting their neuroprotective potential against neurodegenerative conditions.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) strategy was used to identify studies published in English up to July 2024 across five databases (Cochrane, PubMed, Scopus, Web of Science, and Google Scholar). The Population, Intervention, Comparison, and Outcome (PICO) framework guided the search strategy, and duplicate records were removed using Covidence software. Of the 149 studies screened, 40 met the predefined inclusion criteria and were included in the review. The quality of the included studies was assessed using criteria adapted from the Cochrane Handbook, focusing on risk of bias and methodological rigor.

Mangosteen extract and xanthones consistently reduced oxidative markers in various models. Anti-inflammatory effects were evident as mangosteen extract reduced pro-inflammatory cytokines and modulated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2) pathways in neuroinflammation models. Xanthones further suppressed inflammatory mediators and enhanced cellular resilience.

The in vitro and in vivo results suggested the neuroprotective capabilities of mangosteen extracts and its purified bioactives. Despite that, gaps remain in understanding the potential synergistic effects of these bioactives, their druggability properties, and clinical applicability. Further research, especially clinical trials, will be necessary to further impel mangosteen and its derivatives into therapeutic applications.

 

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Keywords

Garcinia mangostana - Clusiaceae - xanthone - oxidative stress - inflammation

Abbreviations

3-NP: 3-Nitropropionic acid

3-NT: 3-Nitrotyrosine

4-HNE: 4-Hydroxy-2-nonenal

6-OHDA: 6-Hydroxydopamine

AD: Alzheimerʼs disease

AMPK: AMP-activated protein kinase

Aβ : Amyloid beta

BW: Body weight

CAT: Catalase

COX-2: Cyclooxygenase-2

DPPH: 2,2-Diphenyl-1-picrylhydrazyl

ERK 1/2: Extracellular signal-regulated kinases 1 and 2

FOXO3a: Forkhead box O3a

GC: Garcinone C

GCLM: Glutamate-cysteine ligase modifier subunit

GD: Garcinone D

GPx: Glutathione peroxidase

GRe: Glutathione reductase

GSH: Glutathione

GST: Glutathione S-transferase

H₂O₂ : Hydrogen peroxide

HO-1: Heme oxygenase-1

IL: Interleukin

iNOS: Inducible nitric oxide synthase

JNK: c-Jun N-terminal kinase

LDH: Lactate dehydrogenase

LPS: Lipopolysaccharide

MAPK: Mitogen-activated protein kinase

MDA: Malondialdehyde

MMP-2: Matrix metallopeptidase 2

MPP+: 1-methyl-4-phenylpyridinium

MX-IC: Mangostanaxanthone IC

MyD88: Myeloid differentiation primary response 88

NADH: Reduced nicotinamide adenine dinucleotide

NADPH: Nicotinamide adenine dinucleotide phosphate

NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells

NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3

NMDA: N-methyl-D-aspartic acid

NO: Nitric oxide

Nrf2: Nuclear factor erythroid 2–related factor 2

PD: Parkinsonʼs disease

PGC-1α : Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

ROS: Reactive oxygen species

SIRT: Sirtuin

SOD: Superoxide dismutase

TAK1: Transforming growth factor-beta-activated kinase 1

TLR-4: Toll-like receptor 4

TNF-α : Tumour necrosis factor alpha

TSPO: Translocator protein

α-M: α-mangostin

γ-M: γ-mangostin
 

Introduction

Neuroprotection involves preserving neuronal structure and function to prevent or slow the progression of neuronal damage while facilitating recovery within the central nervous system [1]. It is crucial for both acute injuries, such as stroke or trauma, and chronic neurodegenerative diseases like Alzheimerʼs (AD) and Parkinsonʼs disease (PD). Given the growing prevalence of these conditions and the current focus on symptom management, the development of effective neuroprotective interventions has become an urgent matter. The absence of curative treatments underscores the necessity of halting or preventing neuronal deterioration, which invariably leads to severe cognitive and motor impairments [2].

In neurodegeneration, processes like the accumulation of toxic proteins, impaired cellular energy production, and oxidative stress gradually drive neuronal loss [3]. Acute nervous system injuries also trigger immediate damage, followed by secondary processes including oxidative stress and inflammation, which contribute to further neuronal decline [4]. The brainʼs high oxygen demand and limited antioxidant defences make it particularly susceptible to oxidative damage, while inflammation exacerbates injury [5]. Therefore, neuroprotective strategies that target these mechanisms are crucial in both chronic and acute conditions.

Given the central role of oxidative stress and inflammation in both chronic neurodegenerative diseases and acute neuronal injuries, therapeutic strategies that target these mechanisms have garnered significant attention [6]. While many traditional drugs have focused on specific pathological features with limited success [7], [8], natural products, such as those derived from medicinal plants, offer a promising alternative [9]. These compounds often possess antioxidant and anti-inflammatory properties, making them well-suited for addressing the multifactorial nature of neurological disorders. Targeting oxidative stress and inflammation through natural products could provide a broader, more effective approach to neuroprotection, offering the potential for both disease modification and symptom management.

With growing interest in natural products for neuroprotection, mangosteen (Garcinia mangostana L., Clusiaceae) and its bioactive compounds have attracted significant attention. Mangosteen extract, rich in xanthones, has demonstrated strong antioxidant [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46] and anti-inflammatory [10], [12], [13], [17], [21], [22], [23], [28], [30], [35], [38], [43], [44], [45], [47], [48], [49] properties. Among these, α-mangostin (α-M) and γ-mangostin (γ-M) are the most extensively studied. Both compounds modulate key molecular pathways involved with oxidative stress and inflammation, critical drivers of neuronal injury and neurodegeneration. Despite the growing interest in neuroprotective agents, there remains a gap in comprehensive evaluations of their efficacy across diverse experimental models. This systematic review aims to fill this void by critically assessing the neuroprotective effects of mangosteen extract and its xanthones. Specifically, it examines how these compounds mitigate oxidative stress and inflammatory responses induced by various insults, thereby elucidating their potential to preserve neuronal function and integrity. By addressing this gap, the review seeks to provide a comprehensive understanding of the antioxidant and anti-inflammatory effects of mangosteen and its xanthones in neuroprotection.

 

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Methods

Research question

The research question was formulated and organised using the Population, Intervention, Comparison, and Outcome (PICO) framework [50]. Key concepts and search terms were identified through this framework and used to search through five electronic databases: PubMed, Cochrane, Scopus, Web of Science, and Google Scholar. The structure of the research question was based on the four elements of the PICO tool, along with the inclusion and exclusion criteria (see Supplementary Information 1).

 

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Sources and search strategy

The study systematically reviewed the previous literature on mangosteen extract and its xanthonesʼ neuroprotective properties by conducting a comprehensive search across five electronic databases: PubMed, Cochrane, Scopus, Web of Science, and Google Scholar. All relevant articles published up to July 2024 were identified. The search terms included Medical Subject Headings (MeSH) terms and relevant text words to the research questions. The following keywords were used for retrieval purposes: Neuro* [MeSH Terms] AND (Antioxidant OR Oxidative* [MeSH Terms] OR oxidant OR ROS OR reactive oxygen species OR inflammation OR Anti-inflamma* [MeSH Terms] OR Neuroinflamma* [MeSH Terms]) AND (xanthone* [MeSH Terms] OR mangostin* [MeSH Terms] OR garcinone* [MeSH Terms] OR pericarp OR extract) AND (mangosteen OR Garcinia mangostana).

 

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Study selection

A total of 4 papers were sourced from Cochrane, 17 from Scopus, 61 from PubMed, 74 from Web of Science, and 100 from Google Scholar. Typically, the first 100 references from Google Scholar, ordered by relevance, were utilised. Due to the lower number of references from other databases, the overall number of potentially relevant studies was also expected to be lower, which led to a limit of 100 hits from Google Scholar. Duplicate records were identified and removed using Covidence systematic review software [51]. After eliminating duplicates, 149 titles were selected for title and abstract screening. Two reviewers (THY: Thew Hin Yee and TYC: Tan Yong Chiang) independently assessed these titles and abstracts. Full-text articles were then evaluated based on the predefined inclusion and exclusion criteria (see Supplementary Information 1). Articles marked as ʼmaybeʼ during initial screening were retrieved in full text for further review, with both reviewers reaching a consensus on their inclusion. Out of 55 articles reviewed in full text, 40 were included in the data extraction process. The final selection of articles adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow method ([Fig. 1]) [52].

Fig. 1 PRISMA flowchart detailing the selection process and search strategy for the systematic review.

 

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Data extraction

A standardised data extraction tool was developed, and data from the selected articles were extracted according to the PICO framework. Any discrepancies in the extracted data were discussed among the reviewers until consensus was reached. Data from all included studies were then presented in a summary table, highlighting key points of each study. These key points included the intervention, study design, subject-disease model, dosage, frequency and duration, markers for oxidative stress and inflammation, and outcome.

 

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Quality assessment

Selected articles were subjected to quality assessment using criteria adapted from the Cochrane Handbook for Systematic Reviews of Interventions [53]. For in vitro and in vivo studies, the Cochrane Handbook was modified to focus on key aspects such as study design, methodology, and outcome measures. Clinical trials involving human participants adhered strictly to the original Cochrane Handbook guidelines. To assess the quality and risk of bias, we used a series of specific risk-of-bias questions. Each study was evaluated based on several criteria, including study design and methodology, selection and handling of models, intervention and comparators, outcome measures, bias control, data analysis, and reporting and transparency. Each of these criteria was assessed and categorised as either ʼhigh risk of biasʼ or ʼlow risk of biasʼ based on predefined risk of bias questions. All articles were independently reviewed and assessed by two reviewers (i.e., THY and TYC). Any disagreements that arise between the reviewers at each stage of the selection process will be resolved through discussion with an independent reviewer, Khaw Kooi Yeong (KKY). A summary of the quality assessment was presented in Supplementary Information 2.

 

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Results

The review included a total of 40 studies that met the inclusion criteria, of which 19 were in vitro studies, 18 were in vivo studies, 1 was a clinical trial, and 2 studied both in vitro and in vivo. [Table 1] summarises the included papers reporting on respective intervention, study design, subject-disease model, dosage, frequency and duration, markers for oxidative stress and inflammation, and outcome. [Fig. 2] illustrates the antioxidative and anti-inflammatory mechanisms of mangosteen extract and its xanthones, highlighting their modulation of the nuclear factor erythroid 2–related factor 2 (Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, regulation of reactive oxygen species (ROS) and inflammatory mediators, and impact on oxidative stress markers.

Table 1 Study characteristics.

Intervention	Study design	Subject-disease model	Dosage	Frequency/Duration	Markers for oxidative stress and inflammation	Outcome
3-NP: 3-Nitropropionic acid, 3-NT: 3-Nitrotyrosine, 4-HNE: 4-Hydroxy-2-nonenal, 6-OHDA: 6-Hydroxydopamine, Aβ: Amyloid beta, AD: Alzheimerʼs disease, AMPK: AMP-activated protein kinase, BW: Body weight, CAT: Catalase, CDK5: Cyclin-dependent kinase 5, COX-2: Cyclooxygenase-2, DPPH: 2,2-Diphenyl-1-picrylhydrazyl, ERK: 1/2 Extracellular signal-regulated kinases 1 and 2, FOXO3a: Forkhead box O3a, GC: Garcinone C, GCLM: Glutamate-cysteine ligase modifier subunit, GD: Garcinone D, GPx: Glutathione peroxidase, GRe: Glutathione reductase, GSH: Glutathione, GSK3β: Glycogen synthase kinase 3 beta, GST: Glutathione S-transferase, GST-4: Glutathione S-transferase 4, H2O2: Hydrogen peroxide, HO: Heme oxygenase, HO-1: Heme oxygenase-1, Iba-1: Ionised calcium-binding adapter molecule 1, ICR: Institute of Cancer Research, IL: Interleukin, iNOS: Inducible nitric oxide synthase, JNK: c-Jun N-terminal kinase, LDH: Lactate dehydrogenase, LPS: Lipopolysaccharide, MAPK: Mitogen-activated protein kinase, MDA: Malondialdehyde, MMP-2: Matrix metallopeptidase 2, MPP: 1-methyl-4-phenylpyridinium, MX-IC: Mangostanaxanthone IC, MyD88: Myeloid differentiation primary response 88, NADPH: Nicotinamide adenine dinucleotide phosphate, NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells, NMDA: N-methyl-D-aspartic acid, NO: Nitric oxide, NQO-1/NAD(P)H: quinone dehydrogenase 1, Nrf2: Nuclear factor erythroid 2–related factor 2, PD: Parkinsonʼs disease, PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, ROS: Reactive oxygen species, SIRT: Sirtuin, SOD: Superoxide dismutase, SOD1: Superoxide dismutase 1, SOD2: Superoxide dismutase 2, TLR-4: Toll-like receptor 4, TMSE: Thai Mental State Examination, TNF-α: Tumour necrosis factor alpha, TSPO: Translocator protein, α-M: α-mangostin, γ-M: γ-mangostin
Mangosteen Extract	In vivo [48]	Wistar rats with obesity induced by high-fat diet	400 mg/kg	Daily for 6 weeks	IL-6 and IL-12	Significantly reduced IL-6 and IL-12.
	In vivo [35]	Sprague–Dawley rat with Parkinsonʼs disease induced by 6-OHDA	30 and 60 mg/kg	Daily for 8 weeks	ROS, SOD1, SOD2, CAT, GPx, Nrf2, TNF-α, IL-1β, and IL-6	Both concentrations decreased levels of ROS, TNF-α, IL-1β, and IL-6; reduced expression of SOD1, SOD2, CAT, and GPx; and increased Nrf2 expression.
	In vitro [37]	Primary cultured rat cortical cells induced by various insults (100 µM glutamate, 300 µM NMDA, or 40 µM Aβ25 – 35)	1, 3, 10, 30, and 100 µg/mL	In vitro: Single treatment for 2 hours In vivo: daily for 4 days	ROS, lipid peroxidation, and DPPH radicals	Inhibited ROS production at all concentrations for NMDA and glutamate, and at 10 and 30 µg/mL for Aβ25 – 30. Mangosteen extract also inhibited lipid peroxidation and scavenged DPPH radicals at 3, 10, 30, and 100 µg/mL in rat brain homogenates.
	In vivo [30]	Pregnant female Sprague-Dawley rats and their male pups were exposed to LPS (100 µg/kg) as part of a maternal immune activation model, resulting in immune-activation-induced deficits	50 mg/kg	Daily for 16 days from post-natal day 51 – 66	TNF-α, IL-6, and lipid peroxidation	Reduced IL-6 and TNF-α levels.
	In vivo [40]	ICR mice treated with 1% lead acetate	100 and 200 mg/kgBW	Daily for 38 days	MDA	Reduced MDA levels.
	Clinical Trial [34]	Participants over 50 years old with a TMSE score of 12 to 25, diagnosed with AD, and having a primary caregiver	Individuals ≤ 55 kg received 220 mg capsules; those > 55 kg received 280 mg capsules.	Daily for 24 weeks (4 mg/kg) or 12 weeks (8 mg/kg)	4-HNE	Decreased 4-HNE levels.
	In vivo [36]	Flinders Resistant Line rats	50, 150, and 200 mg/kg	Acute study: Single dose Chronic study: daily for 14 days	MDA	Reduced MDA levels.
	In vivo [24]	Sprague–Dawley rats with closed head injury induced by unilateral focal brain injury	100 mg/kg	Daily for 7 days	MDA and SOD	Significantly reduced MDA levels and increased SOD expression
	In vitro [26]	H2O2-induced (30 µM) oxidative stress in SK-N-SH	50, 100, 200, and 400 µg/mL	Single pretreatment for 24 hours	ROS, CAT, Mn-SOD, GRe, HO-1, DPPH, and lipid peroxidation	Mangosteen extract inhibited H2O2-induced ROS production, increased CAT activity, and elevated mRNA levels of CAT and HO-1. It also scavenged DPPH radicals and inhibited lipid peroxidation.
	In vivo [22]	3×Tg-AD mice with cognitive impairment	5000 ppm	Daily for 8 months	IL-6, phospho- p38 MAPK, p38 MAPK, COX-2, CDK5, GSK3β, JNK, ERK, and GSH	Significantly reduced IL-6 levels, increased serum GSH levels, and decreased phosphorylated p38 MAPK and COX-2 expression.
	In vitro [19]	3-NP-induced neurotoxicity and ROS production in primary cultures of cerebellar granule neurons	0.1, 1, and 10 µg/mL	Single pretreatment for 15 hours	ROS and DPPH	Decreased 3-NP induced ROS production and scavenged DPPH radicals.
	In vitro [33]	Aβ42-induced cytotoxicity in SK-N-SH cells	400 µg/mL	Single pretreatment for 30 minutes before exposure to Aβ42 (5, 10, 20 µM) for 24 hours	ROS	Reduced ROS levels.
Xanthone	In vivo [44]	Male B6C3 mice induced by Doxorubicin-Adriamycin (20 mg/kg)	200 mg/kgBW	Single dose	TNF-α, iNOS, NO, protein carbonyls, 3-NT, and 4-HNE	Xanthone reduced Doxorubicin-induced increases in TNF-α, iNOS, NO production, protein carbonyls, 3-NT, 4-HNE.
MX-IC	In vivo [10]	Swiss albino mice with sporadic AD	30 mg/kg	Daily for 3 weeks	TNF-α, IL-6, MDA, H2O2, GSH, and NADPH	Reduced MDA and H2O2 levels, increased GSH levels, reduced NADPH oxidase activity, reduced TNF-α and IL-6 levels.
α-M	In vitro [11]	Cadmium (45 µM) and arsenic (10.3 µM) cytotoxicity in PC12 cells	1.25, 2.5, and 5 µM	Single pretreatment for 2 hours	ROS	Reduced ROS production.
	In vivo [30]	Pregnant female Sprague–Dawley rats and their male pups were exposed to LPS (100 µg/kg) as part of a maternal immune activation model, resulting in immune-activation-induced deficits	20 mg/kg	Daily for 16 days from post-natal day 51 – 66	TNF-α, IL-6, and lipid peroxidation	Reduced IL-6 levels and lipid peroxidation.
	In vivo [15]	Rat cortical slices and C. elegans CL2166 strain induced with PD by 6-OHDA	25 and 50 µM for rat cortical slices, and 5, 25, and 50 µM for C. elegans.	Single pretreatment for 30 minutes for rat cortical slices. 48-hour treatment with α-M and 6-OHDA for C. elegans.	Lipid peroxidation and Gst-4	Decreased lipid peroxidation in rat cortical slices and preserved GST-4 expression in C. elegans
	In vivo [13]	Cuprizone-induced (0.4%) demyelination in the corpus callosum of female C57BL/6 mice	20, 40, and 80 mg/kg	Daily for 5 weeks	MDA and TNF-α	Decreased MDA content at all tested concentrations; however, α-M at 80 mg/kg only decreased TNF-α levels.
	In vivo [49]	LPS (2 mg/kg)-induced inflammation in female C57BL/6 J mice	40 mg/kg	Daily for 2 weeks	TNF-α, IL-1β, IL-6, COX-2, TSPO, and Iba-1	Reduced IL-6, COX-2, and TSPO levels
	In vivo [14]	Scopolamine (2 mg/kg)-induced amnesic Wistar rats	50 and 100 mg/kg	Daily for 7 days	MDA	Reduced MDA levels at 50 mg/kg
	In vivo [23]	Abamectin-intoxicated pregnant rats and their male pups	20 mg/kgBW	Daily from gestation days 6 to 19	MDA, NO, GSH, GST, CAT, and SOD	α-M alone does not show significant effects compared to the control. However, co-treatment with abamectin reduces NO and MDA levels while increasing GSH, GST, CAT, and SOD levels.
	In vitro [32]	Rat brain synaptosomes P2 fractions	10, 25, and 50 µM	Single 1 hour incubation	GSH, GST, and GPx	Decreased levels of GSH and increased GPx activity.
	In vivo [43]	Wistar rats with ALS induced by methylmercury	100 and 200 mg/kg	Daily for 3 weeks	TNF-α, IL-1β, MDA, LDH, GSH, SOD, nitrite, GST, and ERK 1/2	Decreased levels of ERK 1/2, TNF-α, IL-1β, MDA, LDH, and nitrite, with increased levels of GSH and SOD.
	In vitro and in vivo [18]	PC12 cells and Wistar rats induced with acrylamide (50 mg/kg)	In vitro: 1.25, 2.5, and 5 µM In vivo: 20, 40, and 60 mg/kg	In vitro: Single pretreatment for 24 hours In vivo: daily for 11 days	MDA, GSH, and ROS	MDA levels decreased and GSH levels increased at doses of 40 and 60 mg/kg in vivo, while ROS levels decreased at a concentration of 1.25 µM in vitro.
	In vivo [17]	Male Wistar rat with chronic constriction injury induced with painful peripheral neuropathy	10, 50, and 100 mg/kg	Daily for 2 weeks	MDA, GSH, NO, iNOS, IL-1β, MMP-2, COX-2, TNF-α, and TLR-4	α-M (50 mg/kg) reduced levels of MDA, NO, iNOS, IL-1β, MMP-2, COX-2, TNF-α, TLR-4, increased levels of GSH.
	In vitro [29]	Primary culture of rat cortical cells induced with oxidative stress by H2O2	0.3 to 30 µM	Single co-treatment for 2 hours with H2O2 (100 µM)	ROS, DPPH radicals, and lipid peroxidation	There was no reduction in ROS production, no scavenging of DPPH radicals, and no inhibition of lipid peroxidation.
	In vitro [42]	H2O2-induced oxidative stress in SH-SY5Y cells	1, 5, 10, and 20 µM	Single pretreatment for 3 hours followed with H2O2 (400 µM) for 24 hours	ROS, SIRT1, SIRT3, FOXO3a, CAT, and SOD2	Reduced ROS production, increased protein expression of CAT and SOD2, and promoted expression of SIRT1, SIRT3, and FOXO3a.
	In vitro and in vivo [47]	LPS-induced inflammation in male C57BL/6 mice, BV2 microglial cells, and primary hippocampal neuron culture	In vitro: 100, 200, and 500 nM In vivo: 50 mg/kg	In vitro: Single pretreatment for 1 hour before LPS stimulation for 24 hours In vivo: Daily for 2 weeks	TNF-α, IL-6, NO, iNOS, TLR-4, MyD88, and phospho-TAK1, TAK1, phospho-p65, and p65	Suppressed LPS-induced TNF-α, IL-6, nitric oxide production, and iNOS expression; inhibited TLR-4, MyD88, TAK1, and NF-κB p65.
	In vitro [46]	Glutamate-induced oxidative stress in HT22 cells	10 µM	Single pretreatment for 30 minutes before glutamate stimulation for 12 hours	ROS, DPPH radical scavenging, GCLM, NQO-1, Nrf2, and HO-1	Increased HO-1 expression and decreased ROS production.
	In vitro [41]	Iodoacetate-induced (18 µM) ROS in primary cultures of cerebellar granule neurons	8, 12, and 14 µM	Single pretreatment for 16 hours	ROS, HO-1, and HO	α-M reduced ROS production, increased HO-1 protein levels and HO activity.
	In vivo [45]	Wistar rats with autism induced with propionic acid	100 and 200 mg/kg	Daily for 44 days	TNF-α, IL-1β, MDA, NO, SOD, and GSH	Reduced TNF-α, IL-1β, MDA, and NO levels; Increased of SOD, and GSH levels.
	In vitro [20]	Rotenone-induced (10 µM) model of PD in differentiated SH-SY5Y cells	0.03, 0.1, and 0.3 µM	Single pretreatment for 24 hours	ROS	Reduced ROS production.
	In vitro [27]	MPP+-induced (1000 µM) apoptosis in SH-SY5Y cells	10 µM	Single co-treatment with MPP+ for 38 hours	ROS	Reduced ROS levels.
	In vivo [38]	Sprague–Dawley rats with PD induced with rotenone (2 mg/kg/day)	10 mg/kg	Daily treatment for 3 weeks	NO, MDA, and GSH	Reduced NO and MDA levels, and restored GSH levels.
	In vitro [39]	3-NP-induced ROS in primary cultures of cerebellar granule neurons	6 and 12 µM	Single pretreatment for 24.5 hours	ROS	Reduced ROS levels.
	In vitro [31]	Rat brain homogenates and synaptosomal P2 fractions exposed to ferrous sulphate, quinolinate, and 3-NP	10, 25, 50, 100, and 500 µM	Single pretreatment for 1 hour	Lipid peroxidation	Reduced lipid peroxidation in all three toxic insults.
	In vitro [21]	Primary microglia cultures exposed to α-Synuclein (200 nM)	1, 10, and 100 nM	Single pretreatment for 24 hours	IL-1β, IL-6, TNF-α, NO, iNOS, NF-κB, H2O2, and superoxide	Inhibited IL-1β, IL-6, TNF-α, NO production, iNOS expression, NF-κB activation, and H2O2 production.
γ-M	In vitro [28]	Aβ42 oligomers (5 µM) cytotoxicity in BV2 microglia cells	1 and 5 µM	Single pretreatment for 2 hours followed with Aβ42 oligomers (5 µM) for 24 hours	ROS, NO, iNOS, IL-6, IL-1β, TNF-α, COX-2, phospho-JNK, JNK, phospho-p38 MAPK, p38 MAPK, phospho-ERK 1/2, and ERK 1/2	Decreased IL-6, IL-1β, and TNF-α mRNA and protein levels, reduced ROS and NO production, downregulated iNOS and COX-2 mRNA levels, reduced phosphorylation of p38 MAPK and JNK.
	In vitro [12]	Glutamate-induced (5 µM) cytotoxicity in HT22 hippocampal neuronal cells	2.5, 5, and 10 µM	Treatment of γ-M and glutamate 6 or 8 hours, depending on the assay	ROS, HO-1, phospho-JNK, JNK, phospho-p38 MAPK, and p38 MAPK	Significantly reduced ROS levels stimulate the expression of HO-1 and inhibit glutamate-induced MAPK phosphorylation.
	In vitro [29]	Primary culture of rat cortical cells induced with H2O2	0.3 to 30 µM	Single co-treatment for 2 hours with H2O2 (100 µM)	ROS, DPPH radicals and lipid peroxidation	Significantly reduced ROS production, scavenged DPPH radicals, and inhibited lipid peroxidation.
	In vitro [46]	Glutamate-induced oxidative stress in HT22 cells	10 µM	Single pretreatment for 30 minutes before glutamate stimulation for 12 hours	ROS, DPPH radical scavenging, GCLM, NQO-1, Nrf2, and HO-1	Scavenged DPPH radicals, decreased HO-1 expression and ROS production.
	In vitro [25]	6-OHDA-induced toxicity in SH-SY5Y cells	0.5, 1, and 2.5 µM	Single pretreatment for 1 hour before exposure to 6-OHDA (50 µM) for 24 hours	ROS	Reduced ROS production.
Gartanin	In vitro [16]	Glutamate-induced (2 mM) cytotoxicity in HT22 hippocampal neuronal cells	1, 3, and 10 µM	Single pretreatment for 30 minutes followed with/without 2 mM glutamate for 24 hours	ROS, HO-1, Nrf2, phospho-AMPK, AMPK, SIRT1, and PGC-1α,	Gartanin reduced ROS production, increased HO-1 protein levels independently of Nrf2, enhanced AMPK phosphorylation, and elevated protein levels of SIRT1 and PGC-1α.
	In vitro [46]	Glutamate-induced oxidative stress in HT22 cells	10 µM	Single pretreatment for 30 minutes before glutamate stimulation for 12 hours	ROS, DPPH radical scavenging, GCLM, NQO-1, Nrf2, and HO-1	Scavenged DPPH radicals, increased HO-1 expression, and decreased ROS production.
GC	In vitro [46]	Glutamate-induced oxidative stress in HT22 cells	10 µM	Single pretreatment for 30 minutes before glutamate stimulation for 12 hours	ROS, DPPH radical scavenging, GCLM, NQO-1, Nrf2, and HO-1	Scavenged DPPH radicals, decreased HO-1 expression, and ROS production.
GD	In vitro [46]	Glutamate-induced oxidative stress in HT22 cells	10 µM	Single pretreatment for 30 minutes before glutamate stimulation for 12 hours	DPPH radical scavenging, GCLM, NQO-1, Nrf2, and HO-1	Increased HO-1 expression.
Garciniafuran	In vitro [46]	Glutamate-induced oxidative stress in HT22 cells	10 µM	Single pretreatment for 30 minutes before glutamate stimulation for 12 hours	DPPH radical scavenging, GCLM, NQO-1, Nrf2, and HO-1	Increased HO-1 expression.

Fig. 2 Antioxidative and anti-inflammatory mechanisms of mangosteen and its xanthones.

Antioxidative effects

Mangosteen extract consistently demonstrated potent antioxidant effects across various studies, reinforcing its role in combating oxidative stress. In a study involving Sprague–Dawley rats with PD, daily administration of 30 and 60 mg/kg over 8 weeks significantly reduced ROS levels and increased Nrf2 expression, highlighting the extractʼs ability to enhance oxidative defence mechanisms [35]. Similarly, in vitro studies using primary cultured rat cortical cells exposed to oxidative insults like N-methyl-D-aspartic acid (NMDA), glutamate, and amyloid beta (Aβ) 25 – 35 revealed that mangosteen extract effectively inhibited ROS production and lipid peroxidation while scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals at various concentrations [37]. These antioxidant capabilities were further demonstrated in SK-N-SH cells, where the extract reduced hydrogen peroxide (H₂O₂)-induced ROS production, elevated the activity of antioxidant enzymes like catalase (CAT) and heme oxygenase-1 (HO-1), and continued to scavenge DPPH radicals [26]. Additionally, the extract decreased ROS production and scavenged DPPH radicals in primary cultures of cerebellar granule neurons exposed to 3-Nitropropionic acid (3-NP)-induced neurotoxicity, providing further evidence of its protective effects against oxidative damage [19]. Clinical trials involving AD patients also support these findings, where the extract decreased 4-hydroxy-2-nonenal (4-HNE) levels, a marker of lipid peroxidation, reinforcing its protective role [34]. Moreover, studies in 3×Tg-AD mice indicated that daily supplementation with the extract increased serum glutathione (GSH) levels, demonstrating sustained antioxidant effect with prolonged use [22]. Similar antioxidant effects were observed in Flinders Resistant Line rats [36] and ICR mice treated with lead acetate [40], where mangosteen extract effectively reduced malondialdehyde (MDA) levels, a marker of oxidative stress. Additionally, in rats with closed head injury, the extract not only reduced MDA levels but also increased superoxide dismutase (SOD) expression, indicating enhanced protection against oxidative stress in traumatic brain injury [24]. Finally, in SK-N-SH cells exposed to Aβ42-induced cytotoxicity, mangosteen extract significantly reduced ROS levels, further showcasing its broad-spectrum antioxidant properties across different models [33].

α-M, a xanthone derived from mangosteen, has shown significant antioxidant effects across various oxidative stress conditions. In PC12 cells exposed to oxidative stress induced by cadmium, arsenic, and acrylamide, α-M at concentrations ranging from 1.25 to 5 µM effectively reduced ROS production [11]. In cases of acrylamide-induced oxidative stress in these cells, α-M also elevated GSH levels while decreasing MDA levels [18]. In SH-SY5Y cells, α-M mitigated oxidative damage caused by H₂O₂ [42], rotenone [20], and 1-methyl-4-phenylpyridinium (MPP+) [27] exposure by reducing ROS levels, enhancing the expression of key antioxidant enzymes such as CAT and SOD2, and upregulating regulatory proteins like sirtuin (SIRT) 1, SIRT3, and forkhead box O3a (FOXO3a), which are crucial for cellular defence mechanisms. The neuroprotective benefits of α-M extend to HT22 cells, where a 10 µM concentration significantly decreased glutamate-induced ROS production and upregulated HO-1 expression [46]. In primary cultures of cerebellar granule neurons, α-M mitigated oxidative stress caused by iodoacetate [41] and 3-NP [39], resulting in reduced ROS production and increased HO-1 protein levels and activity. In a study using rat brain synaptosomes P2 fractions, treatment with α-M at concentrations of 10, 25, and 50 µM for 1 hour led to a decrease in GSH levels, while simultaneously increasing glutathione peroxidase (GPx) activity [32]. This indicates that α-M may shift the redox balance towards the utilisation of GSH for GPx activity, highlighting a nuanced antioxidant mechanism in neuronal tissues. Moreover, α-M reduced lipid peroxidation in rat cortical slices and rat brain homogenates subjected to oxidative insults like ferrous sulphate, quinolinate, and 3-NP [31]. Additionally, in primary microglia cultures exposed to α-Synuclein, α-M significantly inhibited H₂O₂ production, highlighting its broad-spectrum antioxidant potential in neuroinflammatory conditions [21]. However, it is worth noting that in one study involving primary cultures of rat cortical cells exposed to H₂O₂-induced oxidative stress, α-M did not reduce ROS production, lipid peroxidation, or scavenge DPPH radicals [29]. Supporting these in vitro findings, in vivo studies have also shown the efficacy of α-M in reducing oxidative stress. In rats with immune activation-induced deficits, treatment with 20 mg/kg of α-M daily for 16 days significantly reduced lipid peroxidation [30]. In C57BL/6 mice with cuprizone-induced demyelination of the corpus callosum, daily administration of α-M at doses of 20, 40, and 80 mg/kg for 5 weeks effectively reduced MDA levels at all tested concentrations [13]. Male Wistar rats with chronic constriction injury-induced painful peripheral neuropathy, treated with α-M at 50 mg/kg daily for 2 weeks, exhibited reduced MDA levels and increased GSH levels [17]. Similarly, in Wistar rats with autism induced by propionic acid, daily administration of α-M at 100 and 200 mg/kg for 44 days resulted in decreased MDA levels and increased SOD and GSH levels [45]. In rat models of developmental neurotoxicity induced by abamectin, α-M restored oxidative stress markers to normal levels by reducing MDA levels while increasing GSH, glutathione S-transferase (GST), CAT, and SOD levels [23]. Furthermore, in vivo studies on Wistar rats with ALS induced by methylmercury and on Wistar rats with chronic constriction injury-induced neuropathy revealed that α-M not only reduced oxidative markers like MDA and lactate dehydrogenase (LDH) but also enhanced GSH and SOD levels, indicating a broad spectrum of antioxidant effects [43]. In rat cortical slices and the C. elegans CL2166 strain with Parkinsonʼs disease induced by 6-hydroxydopamine (6-OHDA), α-M treatment decreased lipid peroxidation and preserved GST-4 expression [15]. Additionally, scopolamine-induced amnesic Wistar rats treated with 50 mg/kg of α-M daily for 7 days showed reduced MDA levels [14], and in Sprague–Dawley rats with Parkinsonʼs disease induced by rotenone, administration of 10 mg/kg of α-M daily for 3 weeks resulted in reduced MDA levels and increased GSH levels, further reinforcing its antioxidant potential across various models [38].

γ-M has demonstrated significant antioxidant properties across various in vitro models, showcasing its potential to mitigate oxidative stress. In BV2 microglia cells exposed to Aβ42 oligomers, pretreatment with γ-M at concentrations of 1 and 5 µM for 2 hours followed by 24-hour exposure to the oligomers resulted in a substantial reduction in ROS production and downregulated cyclooxygenase-2 (COX-2) [28]. In HT22 hippocampal neurons subjected to glutamate-induced cytotoxicity, γ-M significantly reduced ROS levels and stimulated HO-1 expression across a range of 2.5 to 10 µM [12]. Additionally, another study using the same cell line and glutamate-induced model found that pretreatment with γ-M at 10 µM effectively scavenged DPPH radicals, decreased ROS production, and modulated HO-1 expression [46]. In rat cortical cells exposed to H₂O₂, γ-M, at concentrations ranging from 0.3 to 30 µM, significantly reduced ROS production, scavenged DPPH radicals, and inhibited lipid peroxidation, underscoring its potent antioxidative capabilities [29]. Furthermore, SH-SY5Y cells treated with 6-OHDA showed that γ-M at concentrations of 0.5, 1, and 2.5 µM significantly reduced ROS production, indicating its neuroprotective potential against dopaminergic cell damage [25].

In male B6C3 mice induced by Doxorubicin-Adriamycin (20 mg/kg), a single dose of 200 mg/kg body weight of xanthone significantly reduced Doxorubicin-induced increases in protein carbonyls, 3-nitrotyrosine (3-NT), and 4-HNE, highlighting its antioxidant properties [44]. Mangostanaxanthone IC (MX-IC), administered at 30 mg/kg daily for three weeks in Swiss albino mice with sporadic AD, reduced levels of MDA and H₂O₂ while increasing GSH levels and decreasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity [10]. Gartanin exhibited protective effects against glutamate-induced oxidative stress in HT22 hippocampal neuronal cells by significantly reducing ROS production and increasing HO-1 protein levels, independently of Nrf2 [16]. It also enhanced AMP-activated protein kinase (AMPK) phosphorylation and elevated SIRT1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) levels, indicating a broad antioxidative mechanism. A similar antioxidative was observed with gartanin in glutamate-stressed HT22 cells, where it reduced effects ROS production and scavenged DPPH radicals [46]. Garcinone D (GD) [46] and garciniafuran [46], tested at 10 µM in the same oxidative stress model using HT22 cells, increased HO-1 expression, highlighting the role of mangosteen-derived compounds in bolstering cellular antioxidant defences. In contrast, while garcinone C (GC) decreased HO-1 expression, it remained effective in reducing ROS production and scavenging DPPH radicals [46].

 

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Anti-inflammatory effects

Mangosteen extract exhibited significant anti-inflammatory effects across various models, consistently demonstrating its potential to modulate inflammatory responses. In a study involving Wistar rats with obesity induced by a high-fat diet, daily administration of 400 mg/kg for 6 weeks led to a substantial reduction in pro-inflammatory cytokines interleukin (IL)-6 and IL-12, highlighting its ability to counteract diet-induced inflammation [48]. These findings were further supported by research in Sprague–Dawley rats with Parkinsonʼs disease, where the extract similarly lowered levels of tumour necrosis factor alpha (TNF-α), IL-1β, and IL-6, reinforcing its broad anti-inflammatory properties across different disease models [35]. Further evidence comes from studies on pregnant female Sprague–Dawley rats and their male pups exposed to lipopolysaccharide (LPS)-induced immune activation, where a daily dose of 50 mg/kg of mangosteen extract significantly reduced levels of IL-6 and TNF-α, confirming its efficacy in reducing inflammation triggered by immune challenges [30]. The anti-inflammatory effects of mangosteen extract were also validated in 3×Tg-AD mice, where the extract significantly decreased levels of IL-6, phosphorylated p38 mitogen-activated protein kinase (MAPK), and COX-2 expression, underlining its role in downregulating key inflammatory pathways [22].

α-M has demonstrated substantial anti-inflammatory effects, particularly through its ability to lower pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 across various models. For instance, in LPS-induced inflammation in female C57BL/6 J mice [49] and pregnant Sprague–Dawley rats [30], α-M significantly reduced IL-6 levels, along with COX-2 and translocator protein (TSPO) expression, highlighting its potential to modulate inflammation both at the cellular and molecular levels. Supporting these findings, a study involving Sprague–Dawley rats with maternal immune activation induced by LPS showed that α-M, administered at 20 mg/kg daily for 16 days, effectively reduced levels of pro-inflammatory cytokines IL-6, indicating its role in mitigating immune activation-induced inflammation [30]. Further evidence of α-Mʼs anti-inflammatory potential comes from studies on male Wistar rats with chronic constriction injury-induced painful peripheral neuropathy, where treatment with α-M at 50 mg/kg daily for 2 weeks resulted in reduced levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), IL-1β, matrix metallopeptidase 2 (MMP-2), COX-2, TNF-α, and toll-like receptor 4 (TLR-4) [17]. Similarly, in C57BL/6 mice with cuprizone-induced demyelination, treatment with α-M at 80 mg/kg reduced levels of TNF-α [13]. Additionally, Wistar rats with methylmercury-induced amyotrophic lateral sclerosis (ALS) treated with α-M at 100 and 200 mg/kg daily for three weeks showed decreased levels of TNF-α, IL-1β, NO, and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) [43]. In vitro studies have further corroborated these anti-inflammatory properties. For example, primary microglia cultures exposed to α-Synuclein exhibited reduced production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, along with the suppression of iNOS expression, NF-κB activation, and NO production when treated with α-M [21]. α-M also mitigated the developmental neurotoxicity of abamectin in rats by reducing NO production to normal levels [23]. Furthermore, in LPS-stimulated male C57BL/6 mice, BV2 microglial cells, and primary hippocampal neurons, α-M inhibited the production of TNF-α, IL-6, and NO, as well as the expression of iNOS and key signalling molecules involved in the inflammatory response, such as TLR-4, myeloid differentiation primary response 88 (MyD88), transforming growth factor-beta-activated kinase 1 (TAK1), and NF-κB [47]. The anti-inflammatory effects of α-M are also evident in Wistar rats with autism induced by propionic acid, where daily administration of α-M at 100 and 200 mg/kg for 44 days led to decreased levels of TNF-α, IL-1β, and NO [45]. Lastly, in Sprague–Dawley rats with Parkinsonʼs disease induced by rotenone, α-M administered at 10 mg/kg daily for 3 weeks resulted in reduced NO levels, further substantiating its anti-inflammatory efficacy [38].

γ-M has also shown potent anti-inflammatory effects. In BV2 microglia cells exposed to Aβ42 oligomers, γ-M not only reduced NO production but also downregulated the expression of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. It further decreased the levels of iNOS and inhibited the phosphorylation of MAPK and c-Jun N-terminal kinase (JNK) [28]. Similarly, in the HT22 hippocampal neuron model of glutamate-induced cytotoxicity, γ-M effectively inhibited MAPK phosphorylation, further supporting its anti-inflammatory properties [12]. In an in vivo study, xanthone reduced inflammation in male B6C3 mice induced with Doxorubicin-Adriamycin. A single dose of 200 mg/kg body weight significantly decreased TNF-α, iNOS, and NO production, demonstrating its anti-inflammatory effects [44]. Additionally, MX-IC treatment in Swiss albino mice with sporadic AD led to a reduction in inflammatory cytokines TNF-α and IL-6 [10].

Collectively, these studies demonstrate that xanthones from mangosteen possess significant antioxidative and anti-inflammatory effects, making them promising candidates for managing conditions characterised by oxidative stress and inflammation.

 

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Quality assessment

Most of the included studies (28 out of 40) were rated as having a low risk of bias across all key domains, indicating a high level of methodological rigor. However, 12 studies were rated as having a high risk of bias in certain domains. The primary issues identified were related to inadequate randomisation (6 studies), failure to disclose conflicts of interest (8 studies), and one study that inaccurately labelled its intervention, referring to xanthone (purchased from Sigma-Aldrich) as “xanthone derivatives” throughout the study. Despite these variations in study quality, the majority of the studies provided robust evidence that supports the main findings of this review. The impact of the high-risk studies on the overall conclusions was considered minimal, as sensitivity analysis showed consistent results when these studies were excluded.

 

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Discussion

In concordance with the growing popularity of natural products research, mangosteen, its various crude extracts, and its purified bioactives have demonstrated great promise in solving or attenuating many medical complications like bacterial infections [54], [55], cancer [56], [57], and neurodegenerative diseases [58]. Collective studies delineated in this systematic review revealed the potential of mangosteen crude extracts, as well as its purified chemical compounds, in performing neuroprotection and resolving neurodegenerative diseases, mainly by tackling oxidative stress and inflammation.

Oxidative stress and inflammation have been the main culprits that exacerbate both acute and chronic neurodegenerative processes, like acute brain injury and AD [59]. The reviewed studies indicated that mangosteen and its xanthones mitigate oxidative damage by enhancing endogenous antioxidative processes, like increased glutathione and superoxide dismutase levels, to reduce ROS production. While ROS production is an essential part of the cellular natural processes, especially redox signalling [60], [61], dysregulation of ROS production and elimination has been implicated in aiding the progression of many neurodegenerative diseases by excessively inducing apoptosis and necrosis of neurons [62]. In diseased nervous systems like AD, a deficit of functional reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (Complex I of Electron Transport Chain) in the mitochondria abnormally accumulates ROS [63], [64]; the chemical radicals inflict lethal modifications to cellular macromolecules like mitochondrial DNA damage, as well as undesired protein and lipid peroxidation, which lead to cytotoxic aggregation of the dysfunctional macromolecules [65], [66].

The collective studies indicated that the neuroprotective effects of the mangosteen extract and its purified bioactive compounds may be exerted through the downregulation of pro-oxidative factors like SOD1, SOD2, and Nrf2, as well as the upregulation of antioxidative and anti-inflammatory factors like several interleukins, iNOS, and TNF-α. Xanthones, the major class of bioactive constituent in mangosteen, and their derivatives, have been reported to confer important antioxidative functions in many natural processes in plants to protect from oxidative damage [67], [68]. Moreover, collective studies summarised herewith also reported that crude extracts and other components of mangosteen like MX-IC and α-M increase serum concentration of GSH. GSH is an antioxidative agent in stabilising the cellular redox states, which eliminates ROS by being oxidised into GSH disulfide [69], and neurodegenerative diseases often observe a decrease in serum GSH concentration [70], [71].

Moreover, reviewed studies also indicated that mangosteen and its xanthones alleviate neuroinflammation. The effects of neuroinflammation on promoting the progression of neurodegenerative diseases were also well-documented. Pathological neuroinflammation was often tied to activated microglia. Upon Aβ-induced neuroinflammation, TLR-4 senses Aβ and in turn activates NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in microglia to convert them into the pro-inflammatory M1 phenotype [72], which eventually leads to the vicious cycle of inflammatory cascades by the production of proinflammatory cytokines [73]. Other products of activated microglia like Cathepsin B mediates apoptotic events by damaging extracellular matrix of neurons, which further exacerbates the inflamed environment [74].

The anti-inflammatory properties of xanthones have been reported to harbour potential for ameliorating many other conditions like skin inflammatory diseases [75], diabetes [76], and cancer [77], [78]. Xanthones attenuate many inflammatory pathways like MAPK, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), and NF-κB, while downregulating the expression of pro-inflammatory cytokines like IL-6 and TNF-α [75], [78].

In addition, the implications of oxidative stress and inflammation in nervous systems are often intertwined. With the neuroinflammatory simulation of Aβ and ROS, microglia and astrocytes are not only activated to propagate the inflammatory cascade but also to produce more ROS [79]. Cellular environment with excessive copper exhibits higher ROS in BV2 microglia, which activates the NF-κB pathway to result in inflammatory response and, subsequently, pyroptosis of dopaminergic neurons [80].

Limitations and prospects

The neuroprotective properties of mangosteen and its bioactives have been studied for decades, and many showed promising results in both in vitro and in vivo experiments. Despite that, research gaps in this area remain prominent. In this section, we discuss the limitations and prospect the future directions as it moves towards clinical application.

Among the mangosteen xanthones, α-M has been extensively studied, followed by y-M. However, the anti-inflammatory and antioxidative properties of other bioactive xanthones like MX-IC, gartanin, GC, GD, and garciniafuran were understudied. Different derivatives of the garcinones exhibited antioxidative and anti-inflammatory capabilities in attempting to solve osteoporosis, hepatitis, and intestinal pathologies [81], [82], [83]. Moreover, in our study, we suggested that GD suppressed Aβ aggregation in vitro and in vivo [84]. Moving forward, how the suppression of Aβ aggregation could be related to its antioxidative and anti-inflammatory properties could be studied. However, researchers have suggested that oxidative stress precedes Aβ aggregation; therefore, the suppression of Aβ aggregation could be attributed by the antioxidative effect of GD. Moreover, many have only studied the sole effect of each purified bioactive. Synergistic effects from co-administration of various combinations of the purified bioactives, as well as combination with conventional drugs, could be investigated further to enhance the anti-inflammatory and antioxidative properties. For instance, a popular natural flavonoid, quercetin, has manifested synergistic enhancements of its bioactivities when combined with small molecule agents like curcumin [85].

In addition to testing the bioactivity of the purified compounds, the chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the compounds should be investigated, especially in vivo [86]. However, research has shown that xanthones are more water-soluble and confer better bioavailability compared to vitamin E [40]. Moreover, several chemical modifications on xanthones have been suggested to enable higher bioavailability, like minimisation of its particle size and improvement on its polarity [87], [88]. This is particularly important in tackling neurological conditions, of which the bioactives should be able to pass through the blood–brain barrier [89], [90]. In addition, other drug delivery optimisations, especially using nanoparticles, could be explored. Several attempts were performed to ameliorate the poor penetration of xanthones through the blood–brain barrier. Encapsulation of α-M with poly(ethylene glycol)-polylactide (PEG-PLA) nanoparticles enhanced its biodistribution in brain and liver [91]. Similarly, encapsulation of an artificially derived xanthone with poly(ethylene glycol)-polycaprolactone (PEG-PCL) polymersomes have exhibited improvement in transferring across the blood–brain barrier [92].

Additionally, despite the extensive number of studies showing promise on the bioactivities of mangosteen-derived xanthones in vivo and in vitro, its clinical applicability remains underexplored, with only the mangosteen extract having progressed to clinical trial to date [34], [58]. However, with the increasing promise of mangosteen and its bioactive compounds in various medicinal applications including cancer [56], more clinical trials on the anti-inflammatory and antioxidative neuroprotective properties of the purified compounds are needed to validate these findings and assess their safety [93]. Along with these promising effects on neuroprotection, several challenges in clinical translation, especially of those aforementioned such as bioavailability and long-term safety, must be addressed prior to or during clinical trials. In addition, other clinical applicability challenges like dosage optimisation and potentially unwanted drug interactions will be resolved through clinical trials.

 

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Conclusions

Oxidative stress and uncontrolled inflammation are the main drivers that exacerbate neurodegenerative diseases like AD. In this systematic review, collective studies demonstrated that mangosteen crude extract and its purified compounds showed promising antioxidative and anti-inflammatory properties in conferring neuroprotective effects against neurological stress during diseases. Although research gaps in this field were prominent, the emerging popularity of natural products should drive the mangosteen-derived xanthones further into drug development, as well as into clinical applications.

Data availability

Data will be made available on request.

 

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Contributorsʼ Statement

Hin Yee Thew: Conceptualization, Methodology, Investigation, Visualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Yong Chiang Tan: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Yong Sze Ong & Bey Hing Goh: Supervision, Writing – review & editing. Kooi Yeong Khaw: Conceptualization, Methodology, Supervision, Project administration; Funding acquisition, Data curation, Formal analysis, Validation, Writing – review & editing.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 21 January 2025

Accepted after revision: 20 June 2025

Article published online:
22 August 2025