Inhibitors of Microglial Neurotoxicity: Focus on Natural Products

Dong Kug Choi, Sushruta Koppula, Kyoungho Suk
2011 Molecules  
Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation. Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors
more » ... ts-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed. Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels. OPEN ACCESS more efficacious at ameliorating microglia-associated neurodegenerative and neuroinflammatory diseases. In the following sections, we will focus on popular and important natural products and their active constituents as well as their anti-inflammatory activities based on inhibiting microglial activation. Ginsenosides from Panax ginseng Ginseng, part of the Araliaceae family and species in the genus Panax, is found throughout the world. The name Panax means "all healing," which describes the traditional belief that ginseng has properties to heal all aspects of the body. Ginseng is prepared and used in several ways: as fresh ginseng (sliced and eaten, or brewed in a tea), white ginseng (peeled and dried), or red ginseng (peeled, steamed, and dried). Traditional medicine suggests that red ginseng is the most potent, but modern research has shown that all forms have many beneficial properties [18] [19] [20] . Mechanisms include inhibition of DNA damage [21] , induction of cancer cell apoptosis [22] , and inhibition of cell proliferation [23] . Ginseng has been proved to possess potent chemotherapeutic effects. Ginseng and its active components significantly decrease several types of cancers in the pharynx, stomach, liver, pancreas, and colon [24] [25] . There is abundant evidence that ginseng has potent effects on key players in the inflammatory cascade. Ginseng extracts and total saponins significantly suppress NF-κB and MAP kinase activities, which are upstream signaling molecules in inflammation. The ginsenosides Rh2, Rh3 and compound K significantly inhibit lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and cytokine expressions, thereby proving their beneficial effect in various neuroinflammatory diseases. Another recent study revealed that American ginseng selectively inhibits the expression of iNOS via suppression of the STAT cascade in inflamed macrophages [26] . Ginseng also inhibits the LPSinduced tumor necrosis factor alpha (TNF-α) and other pro-inflammatory cytokines produced by cultured macrophages [27] . Recent studies by Park et al. showed the beneficial effect of ginseng extract and total saponins on microglial activation in co-cultured murine BV-2 microglia and B35 rat neuroblastoma cells [28] . The single compound ginsenoside Rg3 ( Figure 1A ) inhibited phorbol ester-induced cyclooxygenase-2 (COX-2) and NF-κB induction [29] . Studies also revealed that ginsan, a polysaccharide extracted from P. ginseng, inhibits the p38 MAP kinase pathway and NF-κB in vitro, and the pro-inflammatory cytokines in vivo [30] . BST204, a fermented ginseng extract, can inhibit iNOS expression and subsequent nitric oxide (NO) production from LPS-stimulated RAW264.7 murine macrophages. Ginsenoside Rg3 was also reported to attenuate neuroinflammation in the coculture of mouse primary dopaminergic neurons and glia. The anti-inflammatory effects of ginsenoside were demonstrated by a reduction in NO formation and PGE 2 synthesis and involve interference with iNOS and COX-2 expression, making the molecule useful in treating or preventing various neuroinflammatory diseases including PD [31] . Various forms of ginseng have ubiquitous properties to stop inflammation via microglia-mediated mechanisms. Furthermore, intravenous infusion of ginsenoside derivative Rb1 prevented the ischemic neuronal death, and it passed through blood-brain
doi:10.3390/molecules16021021 pmid:21350391 fatcat:q3itxjg425dfzk4zzixmhpkxqm