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Potential role of administration of menaquinone-4 and its chemically related compound for neuroinflammatory modulation

Wahyu Dwi Saputra 東北大学

2022.03.25

概要

In the aging society, which is not exclusively found in developed countries, neurodegeneration has become a recent health concern (Kalaria et al., 2008). Neurodegeneration is the condition within the central nervous system (CNS) in which the degenerative process contributes to the progressive loss of neuronal cells and subsequently leads to the CNS-associated cognitive or motoric decline. Alzheimer’s and Parkinson’s are the primary diseases strongly associated with the neurodegenerative condition called dementia. According to the current report, the number of dementia patients worldwide will be 65.7 million people by 2030. The increasing dementia prevalence is in line with the spike in dementia cost care (Prince et al., 2013). Thus, dementia has had a substantial global socio- economic impact. With this regard, understanding the dementia onset mechanism and its prevention remains elusive.

Generally, the human brain consists of two types of cells: neuron cells and glial cells. Neuron cells make up around 20% of the total brain cells. On the other hand, glial cells that fill the other 80% consist of four types of cells: oligodendrocytes, ependymal cells, astrocytes, and microglia (von Bartheld et al., 2016). The dysfunction of these cells, such as neuroinflammatory conditions, has been reported to contribute to dementia progression. Neuroinflammation is strongly associated with the over-activation of microglial cells (Streit et al., 2004). Microglia is the brain-resident macrophage-like cells that induce innate immunity over CNS. In the physiological environment, microglia are stated as resting cells. Furthermore, these cells can be transformed into different characteristics by specific stimuli. For example, under negative stimuli such as infection, excess oxidative stress, or injury, microglia are transformed to M1 type microglia, which express pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and other chemokines. On the contrary, the anti-inflammatory cytokines induce microglial transformation into M2 type microglia, which produce anti-inflammatory cytokines and repairing substances such as interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) (Cherry et al., 2014).

With regard to neuroinflammation, microglia are activated due to the occurrence of dangerous stimuli and produce pro-inflammatory cytokines to diminish these threats. Under transient stimulation, the production of cytokines is controllable. However, when the negative stimuli exist for an extended period, microglia undergo cycles of cytokines production uncontrollably, which further induces neuroinflammation (Mandrekar and Landreth, 2010). The excess levels of cytokines and chemokines due to the neuroinflammation are harmful and potentially cause neuronal cell defects and death, creating neurodegeneration (McGeer and McGeer, 2004). Lipopolysaccharide (LPS) is an endotoxin from the gram-negative bacteria, extensively studied as the potent microglial activator. The intraperitoneal injection of LPS induced neuroinflammation through microglial inflammation in animal-based experiment (Qin et al., 2007; Zhao et al., 2019). In addition, LPS injection-induced the nuclear factor κB (NF-κB) activation is responsible for transactivating pro-inflammatory cytokines and chemokines (Ifuku et al., 2012; Kang et al., 2019). Therefore, NF-κB is the potential target for inflammatory modulation.

In the viewpoint of prevention, daily food consumption containing bioactive compounds is recommended to maintain a healthy status. One promising bioactive compound is vitamin K. Vitamin K has been known for its roles in blood coagulation and bone metabolism. However, several studies recently reported that vitamin K modulates peripheral inflammation, steroidogenesis, and glucose metabolism (Ho et al., 2020; Ito et al., 2011; Ohsaki et al., 2010). In addition, vitamin K exists naturally in two forms: vitamin K1 (green- leafy vegetables) and vitamin K2 (fermented product). After consumption, same portion of vitamin K analogs are suggested to convert into menaquinone-4 (MK-4), a subtype of vitamin K2, in the organ by the UBIAD1 enzyme (Nakagawa et al., 2010). Recent studies reported that MK-4 is distributed in several animal organs, including the brain. Furthermore, MK-4 administration improved LPS-induced inflammation in microglial cell lines, albeit its molecular mechanism was unclear. Moreover, geranylgeraniol (GGOH) is the natural isoprenoid that shares a similar chemical structure with the side chain of MK-4. It is contained in edible grains, rice bran, and vegetable oils (Muraguchi et al., 2011; Ruiz- Aracama et al., 2017). The administration of GGOH has been evaluated to inhibit peripheral inflammation in cell and animal experiments (Giriwono et al., 2019, 2013).

This study mainly evaluated the molecular mechanisms of anti-inflammatory action by MK-4 and GGOH treatments on the LPS-induced inflammation in MG6 mouse microglial-derived cells. In addition, we sought whether the anti-inflammatory properties of MK-4 and GGOH are found not only in the peripheral inflammatory models but also in the CNS inflammatory scenario. We hope that these findings may place preliminary and basic understanding for future experiments in developing MK-4 and GGOH as nutrients and prodrugs for neuroinflammatory modulation.

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