Research Progress on the Protective Role of Alpha-Mangostin in the Nervous System

α-Mangostin (α-MG) is a xanthone compound isolated from the pericarp of mangosteen (Garcinia mangostana L.), a plant belonging to the Clusiaceae family. As depicted in the figure below, pharmacological experiments have shown that α-MG possesses anticancer, anti-inflammatory, and neuroprotective properties. Among these, α-MG exhibits multi-target neuroprotective effects in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), depression, autism, vascular dementia, and schizophrenia by inhibiting inflammatory reactions, antioxidative stress, and neuronal apoptosis.

1. The delaying effect of α-mangostin on Alzheimer's disease (AD)

α-Mangostin, a small lipophilic molecule, is capable of entering the nervous system and is considered one of the potential candidate drugs for treating AD. α-Mangostin has demonstrated significant efficacy in various AD animal models, which is attributed to its actions against the pathophysiological mechanisms of AD.

① Inhibition of Aβ fibrils and their precursor fibrils formation. α-Mangostin can inhibit the production of Aβ. The salt bridge structure formed by the 23rd aspartic acid (Asp23) and the 28th lysine (Lys28) on the Aβ protein plays a crucial role in the formation of Aβ fibrils. Blocking the formation of this salt bridge can inhibit the formation of Aβ fibrils. The phenolic hydroxyl group on α-mangostin binds to Asp23 on the Aβ protein, preventing the formation of the salt bridge between Asp23 and Lys28, thus inhibiting the formation of Aβ fibrils.

② Reduction of Aβ protein aggregation. α-Mangostin can also reduce Aβ-induced neurotoxicity by inhibiting Aβ aggregation. Molecular docking dynamic simulation results show that α-mangostin "fits into" a concave pocket-like region in the Aβ protein, enhancing the hydrophobic interaction between the 19th phenylalanine (Phe19) on the Aβ protein and the benzene ring on α-mangostin. This promotes the formation of hydrogen bonds between the 16th lysine (Lys 16), 22nd glutamic acid (Glu22), and 23rd aspartic acid (Asp23) on the Aβ protein and the phenolic hydroxyl groups on α-mangostin, stabilizing its conformation and interfering with the aggregation between Aβ proteins. Dot blot assay results demonstrate that α-mangostin reduces the number of Aβ protein dimers and trimers in a concentration-dependent manner. Transmission electron microscopy observations and ThT fluorescence experiments both confirm that α-mangostin can block the aggregation of Aβ monomers into protofibrils and disassemble already aggregated protofibrils.

③ Alleviation of inflammatory damage. α-Mangostin antagonizes microglial cell-mediated inflammatory damage by regulating the activation state and cellular behavior of microglia. It can increase the survival rate of primary hippocampal neurons under inflammatory conditions, improve the reduced expression of microtubule-associated protein 2 (MAP2), which is crucial for regulating neuronal dendrite growth in the hippocampus and cerebral cortex, and alleviate dendrite damage in neuronal cells.

④ Anti-neuronal apoptosis. Soluble Aβ oligomers can lead to axonal dystrophy, dendritic degeneration, and damage. 1 nmol/L of oligomerized Aβ1-40 and Aβ1-42 proteins can respectively reduce the total synaptic length and the number of branching points. However, when these two oligomerized proteins are cultured with 5 nmol/L of α-mangostin for 24 hours, both the total synaptic length and the number of branching points increase significantly. The deposition of Aβ, the phosphorylation of tau protein, and the production of inflammatory factors can directly mediate neurotoxicity, and can also trigger massive neuronal apoptosis by activating enzymes involved in the apoptosis process, such as caspase-3/9. In addition to preventing neuronal apoptosis by reducing Aβ production and aggregation, increasing its uptake and degradation, antagonizing inflammatory damage, and reducing ROS production, α-mangostin can also exert anti-apoptotic effects by increasing the activity and expression of heme oxygenase (HO)-1 in a metabolic inhibition model of primary rat neuronal cells induced by iodoacetate. As a cell-protective protein, the overexpression of HO-1 has been shown to inhibit apoptosis in model cells. Moreover, Garcinia mangostana pericarp extract containing α-mangostin also has the effect of reducing Aβ-induced increases in caspase-3 activity.

2. The Effects of α-Mangostin on Parkinson's Disease (PD)

The characteristic pathological changes in PD are the appearance of Lewy bodies and Lewy neuritis, where α-synuclein (α-Syn), particularly its phosphorylated form, serves as a major pathological marker and pathogenic factor. The synthesis and accumulation of α-Syn contribute to the formation of Lewy bodies and the degeneration of dopaminergic neurons. In PD patients, there is a significant increase in the concentrations of inflammatory factors, ROS, and iNOS in the cerebrospinal fluid. In various in vitro and in vivo models of PD, α-mangostin exerts its pharmacological effects through multiple targets, including antioxidant and anti-inflammatory effects.

In an α-Syn-induced BV2 microglial cell model of PD in vitro, α-mangostin can concentration-dependently inhibit the production of IL-1β, IL-6, and TNF-α as well as the activation of the NF-κB pathway. In a rotenone-induced PD model using human neuroblastoma SH-SY5Y cells, α-mangostin can reverse the excessive production of ROS and mitochondrial dysfunction induced by rotenone. α-Mangostin can also inhibit α-Syn-induced morphological changes in BV2 cells in vitro, reduce the production of oxidative stress markers such as nitric oxide, iNOS, and H2O2, and its effects are related to the regulation of NADPH oxidase-1 (NOX-1) activity. In a 1-methyl-4-phenylpyridinium ion (MPP+)-induced oxidative stress model using SH-SY5Y cells, α-mangostin can effectively inhibit the production of ROS.

α-Mangostin can also antagonize neurotoxicity induced directly by α-Syn and indirectly mediated by microglia. Media rich in neurotoxic substances produced after α-Syn activates microglia, co-culture systems of α-Syn-microglia, and direct stimulation by α-Syn can significantly reduce the ability and activity of primary SD rat midbrain neurons to uptake dopamine. However, α-mangostin can significantly antagonize these effects and protect neurons, especially dopaminergic neurons. The p53-Bcl-2 pathway is an important signaling transduction pathway in the process of apoptosis. p53 can directly induce the transcription of the pro-apoptotic protein Bax, and can also directly or indirectly inhibit the activity of Bcl-2, thereby antagonizing the anti-apoptotic effect of Bcl-2. α-Mangostin can produce anti-apoptotic effects by reducing p53 expression, thus reducing apoptosis in SH-SY5Y cells.

In in vivo models, α-mangostin can significantly improve disease manifestations. In a rotenone-induced PD rat model, α-mangostin treatment improved motor function and cognitive memory impairment in rats. The levels of nitrite and malondialdehyde (MDA), which indicate the level of oxidative stress in the rat striatum, were significantly reduced, potentially related to the increase in glutathione levels caused by α-mangostin. α-Mangostin also restored hyperphosphorylated α-Syn and reversed the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain.

3. The Effects of α-Mangostin on Other Central Nervous System Diseases

In other disease models, α-mangostin has also demonstrated significant neuroprotective effects at multiple targets. In the tail suspension test model of depression in mice, compared to the use of selective 5-hydroxytryptamine (5-HT) reuptake inhibitors such as fluoxetine and tianeptine alone, α-mangostin alone or combined with the aforementioned drugs significantly shortened the immobility period of mice. α-Mangostin can also increase the levels of dopamine, γ-aminobutyric acid (GABA), and 5-HT in the brain tissues of the aforementioned mouse models, suggesting that its antidepressant effects may be mediated by the dopaminergic, GABAergic, and serotonergic systems.

In the autism model induced by propionic acid injection into the cerebral ventricle of Wistar rats, α-mangostin can reverse the weight loss caused by autism, improve activity disorders, spatial memory disorders, muscle coordination, and depression-like symptoms in a dose-dependent manner. It can normalize the elevated extracellular regulated protein kinases and myelin basic protein in the brain tissue of the model rats. Additionally, α-mangostin can antagonize the increases in Cas-3 and Bax and the decrease in Bcl-2 levels in the brain tissue caused by the model, thereby improving neuronal apoptosis and demyelination. It can also increase the levels of dopamine, 5-HT, and cholinergic neurotransmitters in the brain tissue of the model and lower the neurotoxic concentration of glutamic acid. Furthermore, α-mangostin can reverse the increases in inflammatory factors such as TNF-α and IL-1β as well as the elevations in oxidative stress factors like cholinesterase and lactate dehydrogenase in the brain tissue of the model. Additionally, α-M can also alleviate the damage such as hippocampal and cortical swelling, and brain atrophy in the autism model rats.

In the model of chronic cerebral hypoperfusion induced by bilateral ligation of the common carotid arteries in SD rats, α-mangostin can improve the impairment of spatial memory caused by this condition. In the model of ischemia-reperfusion injury after occlusion and reperfusion of the common carotid arteries in SD rats, α-mangostin can dose-dependently reduce the neurobehavioral injury score, improve neuronal survival, lower the concentration of inflammatory factors in the brain tissue, and decrease the expression of NF-κB-related proteins and apoptosis-related proteins.

The multi-target pharmacological properties exhibited by α-mangostin in neuroprotection, such as antagonism and inhibition of core pathogenic factors like Aβ and α-Syn, as well as the blocking, regulation, and improvement of various pathological manifestations and processes like neuroinflammatory injury, oxidative stress injury, and neuronal apoptosis, suggest that α-mangostin or its structural derivatives may be of significant importance in alleviating or even blocking the progression of diseases like AD and PD. It holds promising applications in the treatment of central nervous system diseases and neuroprotection.

References:

[1] Dong Yanhao, Zeng Qianlong, Lu Qian, Gao Jie, Zhao Lanxue, Hu Xiaoyu, Qiu Yu. Research Progress on the Neuroprotective Effects of α-Mangostin [J]. Chinese Journal of New Drugs and Clinical Remedies, 2022, 41(06): 321-326. DOI: 10.14109/j.cnki.xyylc.2022.06.01.

[2] Cao Juan, Zhang Chaofeng. Research Progress on the Pharmacological Effects and Molecular Mechanisms of α-Mangostin [J]. Medicine Frontiers, 2018, (Issue 20).

[3] Wang Zhuoqun, Hu Ping, Yu Shaowen. Research Progress on the Bioactivities and Pharmacological Effects of α-Mangostin [J]. China Pharmacy, 2014, 25(19): 1808-1811.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.