Spatial metabolomics reveals the effects of Acanthopanax senticosus on region-specific alterations in neurotransmitters and metabolites levels in the brains of α-syn transgenic Parkinson's disease model mice.

Abstract

Background: Acanthopanax senticosus (Rupr. et. Maxim.) Harms (ASH), a widely used traditional Chinese herbal medicine, possesses various therapeutic effects, such as the ability to tonify the spleen and kidney, strengthen muscles and bones, and promote consciousness and nerve relaxation. Previous research has indicated its good efficacy in treating Parkinson's disease (PD). We aimed to investigate the effects of ASH on changes in neurotransmitter and metabolite levels within the brain tissue of α-synuclein (α-syn) transgenic mice with PD. Additionally, we sought to explore the potential mechanisms by which ASH treats PD and the targets of action of ASH. α-Syn transgenic mice were chosen as a suitable model of PD. Hematoxylin‒eosin (HE) staining was used to detect changes in neurons in the substantia nigra. Immunohistochemistry (IHC) was performed to measure tyrosine hydroxylase (TH) activity in the substantia nigra and the areal density of α-syn in the striatum. Moreover, we measured the pole climbing time and autonomous activity to assess motor ability. Nontargeted matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was used to investigate changes in neurotransmitter levels in each brain region of the mice and further identify the regions in which ASH exerts its effects. ASH reduced the climbing time and increased the number of autonomous movements in PD model mice. HE staining, along with IHC, indicated that ASH interfered with the accumulation of α-syn, increased TH activity, and mitigated neuronal damage. The MALDI-MSI results revealed that ASH could significantly increase dopamine (DA) levels in brain tissue by increasing the levels of 3-methoxytyramine (3-MT) in the striatum and cerebral cortex, acetylcholine (Ach) in the substantia nigra pars compacta (SNc), γ-amino butyric acid (GABA) in the hippocampus (Hip), and 3,4-dihydroxyphenylglycol (DOPEG) in the globus pallidus interna/substantia nigra reticulata (Gpi/SNr) complex, while decreasing 5-HIAA levels in the Hip, cerebral cortex, and striatum. Additionally, the behavioral correlation analysis suggested that the SNc may be a crucial region for the ability of ASH to ameliorate behavioral dysfunction in PD model mice. ASH can regulate DA release by modulating the metabolism of neurotransmitters in brain tissue, particularly in the SNc, thereby influencing the basal ganglia circuit and alleviating the symptoms of PD, and monoamine oxidase (MAO) plays a vital role throughout this metabolic process.