Anti-neuroinflammatory Activity of a Novel Cannabinoid Derivative by Inhibiting the NF-κB Signaling Pathway in Lipopolysaccharide-Induced BV-2 Microglial Cells

Abstract

Abstract. Microglial-mediated neuroinflammation has recently been implicated as one of the important mechanisms responsible for the progression of neurodegenerative diseases. Activated microglia cells produce various neurotoxic factors that are harmful to neurons. Therefore, suppression of the inflammatory response elicited by activated microglia is considered a potential therapeutic target for neurodegenerative diseases. The cannabinoid (CB) system is widespread in the central nervous system and is very crucial for modulating a spectrum of neurophysiological functions such as pain, appetite, and cognition. In the present study, we synthesized and investigated a novel CB derivative (CD-101) for its ability to suppress lipopolysaccharide (LPS)-mediated activation of BV-2 microglial cells and subsequent release of various inflammatory mediators. CD-101 significantly inhibited the production of inflammatory markers such as nitric oxide, cyclooxygenase-2, and pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. The anti-neuroinflammatory effect of this novel cannabinoid derivative occurred by inhibiting p38MAPK phosphorylation and by decreasing nuclear translocation of p65 subunit of nuclear factor kappa-B in LPS-stimulated BV-2 microglial cells. These results suggest that the use of the cannabinoid derivative CD-101 might be a potential therapeutic target against neuroinflammatory disorders.

1-O-Tigloyl-1-O-deacetyl-nimbolinin B Inhibits LPS-Stimulated Inflammatory Responses by Suppressing NF-κB and JNK Activation in Microglia Cells

“…The transcription factor NF-kB is a key regulator of various genes such as iNOS, COX-2, TNF-a, and IL-1b involved in the inflammatory responses (32,33,48). It has been well studied that the NF-kB activation results in the phosphorylation, ubiquitination, and proteasomemediated degradation of IkB proteins followed by translocation from the cytoplasm to nucleus (49,50).…”

Xanthoceraside Inhibits Pro-inflammatory Cytokine Expression in Aβ25–35/IFN-γ–Stimulated Microglia Through the TLR2 Receptor, MyD88, Nuclear Factor-κB, and Mitogen-Activated Protein Kinase Signaling Pathways

“…Experimental data indicated that XB husk extract significantly improves the learning and memory dysfunction in rats after bilateral occlusion of the common carotid arteries (13). Xanthoceraside could also alleviate the amyloid b [25][26][27][28][29][30][31][32][33][34][35] (Ab [25][26][27][28][29][30][31][32][33][34][35] )-induced impairment of spatial memory and oxidative stress in mice (14). Our previous study also demonstrated the anti-inflammatory effects of xanthoceraside in mice by down-regulating the expression of inducible NO synthase (iNOS) and nitrotyrosine levels in the hippocampus and by up-regulating IL-4 mRNA expression (15).…”

“…DMEM, MEM and fetal bovine serum (FBS) were obtained from GIBCO (Carlsbad, CA, USA). Poly-d-lysine, 3-(4,5-dimetrylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), DMSO, and Ab [25][26][27][28][29][30][31][32][33][34][35] were purchased from Sigma (St. Louis, MO, USA). IFN-g was purchased from Peprotech (Rocky Hill, NJ, USA).…”

“…Hashioka et al (9) stated in their paper that a great increase (about 10-fold) in TNF-a accumulation is induced in primary cultured rat microglia after exposure to Ab [25][26][27][28][29][30][31][32][33][34][35] plus IFN-g at 37°C for 24 h; therefore the experiments were performed after 24-h incubation with Ab [25][26][27][28][29][30][31][32][33][34][35] plus IFN-g. In our preliminary experiments, we found that Ab [25][26][27][28][29][30][31][32][33][34][35] plus IFN-g induced the increases in IL-1b, TNF-a, and NO expression in microglia after 24 h without affecting the cell viability of microglia, while pretreatment with xanthoceraside for 16 h suppressed the release of IL-1b, TNF-a, and NO in a concentrationdependent manner.…”

“…However, the molecular mechanism underlying its anti-inflammatory action remains unclear. In the present study, we attempted to determine the effects of xanthoceraside on the production of pro-inflammatory mediators in amyloid b [25][26][27][28][29][30][31][32][33][34][35] ) / interferon-g (IFN-g)-stimulated microglia. Our results indicated that xanthoceraside (0.01 and 0.1 mM) significantly inhibited the release of nitric oxide (NO) and pro-inflammatory cytokines interleukin-1b and tumor necrosis factor-a in a concentration-dependent manner.…”