Ginseng gintonin, aging societies, and geriatric brain diseases

Abstract

Background: A dramatic increase in aging populations and low birth rates rapidly drive aging societies and increase aging-associated neurodegenerative diseases. However, functional food or medicinal formulations to prevent geriatric brain disorders are not readily available. Panax ginseng is a candidate, since ginseng has long-been consumed as a rejuvenating agent. However, the underlying molecular mechanisms and the components of ginseng that are responsible for brain rejuvenation and human longevity are unknown. Accumulating evidence shows that gintonin is a candidate for the anti-aging ingredient of ginseng, especially in brain senescence.

Methods: Gintonin, a glycolipoprotein complex, contains three lipid-derived G protein-coupled receptor ligands: lysophosphatidic acids (LPAs), lysophosphatidylinositols (LPIs), and linoleic acid (LA). LPA, LPI, and LA act on six LPA receptor subtypes, GPR55, and GPR40, respectively. These G protein-coupled receptors are distributed within the nervous and non-nervous systems of the human body.

Results: Gintonin-enriched fraction (GEF) exhibits anti-brain senescence and effects against disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Oral administration of gintonin in animal models of d-galactose-induced brain aging, AD, HD, and PD restored cognitive and motor functions. The underlying molecular mechanisms of gintonin-mediated anti-brain aging and anti-neurodegenerative diseases include neurogenesis, autophagy stimulation, anti-apoptosis, anti-oxidative stress, and anti-inflammatory activities. This review describes the characteristics of gintonin and GEF, and how gintonin exerts its effects on brain aging and brain associated-neurodegenerative diseases.

Conclusion: Finally, we describe how GEF can be applied to improve the quality of life of senior citizens in aging societies.

Keywords: Brain aging; Gintonin; Neurodegenerative diseases; Panax ginseng; Rejuvenation.

Fig. 1

The chemical structures of four main bioactive components of gintonin. Gintonin was prepared from Panax ginseng root. LPAs was proved as the main functional ingredients of gintonin. Gintonin LPAs act as exogenous ligand for G protein-coupled LPA receptors. Recently, gintonin LPI and linoleic acid was also proved as a ligand of GPR40 and GPR55.

Fig. 2

Signal transduction of ginseng gintonin on the mammalian cell plasma membrane via LPA receptors, GPR40, and GPR55. Gintonin activates LPA GPCRs, GPR40 and GPR55, respectively, which can lead to intracellular responses through the regulations of ion channels and receptors. In nervous system, gintonin-mediated signaling transduction pathway can be also coupled to neurotransmitter (i.e., acetylcholine, dopamine, norepinephrine, and serotonin) release for intercellular communications and to stimulations of BDNF and VEGF releases. The released neurotransmitters and neurotrophic factors further regulate their respective receptors to exhibit ginseng gintonin-mediated in vivo biological effects. Thus, in vivo biological effects of ginseng gintonin might be achieved via LPA receptors, GPR40, and/or GPR55 and indirectly via activations of respective receptors by ligands released by gintonin treatment. ACh, acetylcholine; DA, dopamine; NE, norepinephrine; 5-HT, serotonin.

Fig. 3

Effects of gintonin and GEF on geriatric brain diseases. Long-term oral administration of ginseng gintonin attenuates geriatric brain diseases. The common mode of action of gintonin against neurodegenerative diseases is LPA receptors activation and anti-apoptosis, anti-inflammation, anti-oxidative stress, and autophagic stimulations. GPR40 and GPR55 might be involved in geriatric brain diseases but not yet clearly demonstrated as much as LPA and LPA1 receptor. HTT, huntingtin.

Fig. 4

Signaling pathway for gintonin-mediated autophagic influx via LPA1 receptor. Gintonin stimulates astrocytic autophagy via down-streams of autophagic processes. Stimulations of autophagy flux by gintonin might play a role for housekeeper by cleaning brain toxic wastes such as Aβ, α-synuclein, HTT and others, although it requires more studies to show that gintonin-mediated astrocytic autophagy is coupled to in vivo anti-neurodegenerative diseases.