Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

Abstract

Background: Alzheimer's disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. Methods: The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis. Results: Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. Conclusions: Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the antiinflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

Zerumbone attenuates lipopolysaccharide-induced activation of BV-2 microglial cells via NF-κB signaling

“…Taken together, these results indicate that zerumbone can inhibit microglial activation. In a recent study by Li et al, zerumbone inhibited the production of NO and pro-inflammatory cytokines as well as amyloid β-induced activation in a LPS-treated murine microglia cell line (N9) and primary microglia [31]. Li et al reported zerumbone to be effective in an APP-PS1 transgenic mouse model of Alzheimer's disease [31].…”

Ginger, a Possible Candidate for the Treatment of Dementias?

“…Additionally, the effects of zerumbone were studied by Li et al [ 57 ] both in vivo and in vitro. In the in vivo experiment, transgenic APP/PSEN1 mice received daily gavage of zerumbone for 20 days.…”

Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease

“…As in previous studies, western blot analysis was carried out [9,24]. One part of the hippocampal tissue obtained from the experimental mice was lysed and homogenized using RIPA buffer containing 1% protease inhibitor cocktail and 2% PMSF.…”

“…The activation of chronic glial and the production of pro-inflammatory cytokine stimulate neurodegenerative, which are observed in AD patients and animal models [ 7 ]. Inflammation activated microglia and astrocytes produce tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) to exacerbate neuronal damage in several neurodegenerative diseases [ 8 , 9 ]. Activated microglia and astrocytes produce interleukin (IL)-6 and IL-1β to increase the level of amyloid-beta precursor protein (APP) and promote Aβ deposition in AD mice models [ 10 ].…”