Role of ginseng in the neurovascular unit of neuroinflammatory diseases focused on the blood-brain barrier

Abstract

Ginseng has long been considered as an herbal medicine. Recent data suggest that ginseng has anti-inflammatory properties and can improve learning- and memory-related function in the central nervous system (CNS) following the development of CNS neuroinflammatory diseases such as Alzheimer's disease, cerebral ischemia, and other neurological disorders. In this review, we discuss the role of ginseng in the neurovascular unit, which is composed of endothelial cells surrounded by astrocytes, pericytes, microglia, neural stem cells, oligodendrocytes, and neurons, especially their blood-brain barrier maintenance, anti-inflammatory effects and regenerative functions. In addition, cell-cell communication enhanced by ginseng may be attributed to regeneration via induction of neurogenesis and angiogenesis in CNS diseases. Thus, ginseng may have therapeutic potential to exert cognitive improvement in neuroinflammatory diseases such as stroke, traumatic brain injury, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

Keywords: central nervous system; ginseng; neuroinflammation; neurovascular unit; regeneration.

Graphical abstract

Fig. 1

Schematic figure demonstrates the possible therapeutic mechanisms of ginseng and ginsenosides. At the early phase of central nervous system (CNS) injury, ginseng/ginsenosides may facilitate neuroprotection through anti-inflammatory effects. Then, at the late phase of CNS injury, ginseng/ginsenosides-mediated recovery of cellular communication may enhance the formation of functional neural circuit through regeneration, such as angiogenesis, neurogenesis, and synaptogenesis.

Fig. 2

Blood-brain barrier (BBB) integrity is maintained by ginseng/ginsenosides following central nervous system (CNS) injury. The neurovascular unit refers to functional coupling of brain endothelia with other local cells (e.g. pericytes, astrocytes, microglia, neural stem cells, and neurons) and the extracellular matrix. Endothelial tight junctions and integral proteins are involved in regulation of paracellular permeability. Following CNS injury, expression patterns - including site and level - of tight junction and integral proteins become altered. Damaged endothelia exhibit markedly increased NF-κB activation, leading to infiltration of monocytes into the brain parenchyma, where they become activated macrophages. Additionally, concomitant disruption of functional cellular associations is accompanied by breakdown of BBB integrity. Damaged brain parenchyma exhibits activated astrocytes and M1-polarized microglia, apoptotic pericytes, and neurotransmitter-degraded neurons. Abbreviations: JAM, junction adhesion molecule; ZO-1, zonula occluden-1; AF6, afadin 6; VE-cadherin, vascular endothelial cadherin; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells.

Fig. 3

Mitochondrial reactive oxygen species (ROS) triggers neuroinflammation, and this effect is suppressed by ginseng/ginsenosides. (A) At the healthy synapses, mitochondria are packed in presynaptic terminal, synaptic vesicles are clustered at presynaptic release sites (active zone), and transmitter receptors are clustered in the postsynaptic membrane. Nerve terminals are coated with processes of oligodendrocytes. (B) At the neurodegenerating synapses, damaged mitochondria produce ROS and synaptic vesicles are reduced in presynaptic terminal, leading to less transmitter receptors in the postsynaptic membrane. (C) Mitochondrial ROS and neurotoxic materials can exacerbate neuronal functions by inducing inflammation cascades. Ginseng/ginsenosides can block both the NF-κB signaling and excessive mitochondrial ROS generation, which can reduce the production of pro-IL-1β, pro-IL18, and inactive NLRP3. Then, NLRP3-ASC-pro-caspase-1 complex is further processed, and active caspase-1 cleaves pro-IL-1β and pro-IL-18 into mature form of IL-1β and IL-18, respectively. Then, those inflammatory cytokines are released. Abbreviations: IL, interleukin; NLRP3, NOD-, LRR- and pyrin domain-containing 3; ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase recruitment domain-containing protein.

Fig. 4

Possible therapeutic mechanism of ginseng/ginsenosides is the induction of cellular network in neurovascular unit. Ginseng/ginsenosides possess multifaceted repair mechanisms including anti-inflammation through BBB protection and inhibition of NF-κB signaling and oxidative stress, and induction of healthy mitochondria. In addition, ginseng/ginsenosides play important roles in the protection of blood-brain barrier, inhibition of apoptosis, and enhancement of cellular interactions. Consequently, functional neural circuit may be partly restored by ginseng-mediated glia-neuron and vessel-neuron communications, leading to angiogenesis, neurogenesis, synaptogenesis, and remyelination. In conclusion, ginseng and ginsenosides can contribute to cognitive repair in cases of neurovascular inflammatory diseases.