Oral administration of methysticin improves cognitive deficits in a mouse model of Alzheimer's disease

Abstract

IntroductionThere is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an anti-inflammatory transcription factor that regulates the oxidative stress defense. Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ)-induced oxidative stress in vitro by Nrf2 pathway activation. Here, we tested an in vivo kavalactone treatment in a mouse model of AD.MethodsThe kavalactone methysticin was administered once a week for a period of 6 months to 6 month old transgenic APP/Psen1 mice by oral gavage. Nrf2 pathway activation was measured by methysticin treatment of ARE-luciferase mice, by qPCR of Nrf2-target genes and immunohistochemical detection of Nrf2. Aβ burden was analyzed by CongoRed staining, immunofluorescent detection and ELISA. Neuroinflammation was assessed by immunohistochemical stainings for microglia and astrocytes. Pro-inflammatory cytokines in the hippocampus was determined by Luminex multi-plex assays. The hippocampal oxidative damage was detected by oxyblot technique and immunohistochemical staining against DT3 and 4-HNE. The cognitive ability of mice was evaluated using Morris water maze.ResultsMethysticin treatment activated the Nrf2 pathway in the hippocampus and cortex of mice. The Aβ deposition in brains of methysticin-treated APP/Psen1 mice was not altered compared to untreated mice. However, methysticin treatment significantly reduced microgliosis, astrogliosis and secretion of the pro-inflammatory cytokines TNF-α and IL-17A. In addition, the oxidative damage of hippocampi from APP/Psen1 mice was reduced by methysticin treatment. Most importantly, methysticin treatment significantly attenuated the long-term memory decline of APP/Psen1 mice.ConclusionIn summary, these findings show that methysticin administration activates the Nrf2 pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD. Therefore, kavalactones might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.

The role of Nrf2 signaling in counteracting neurodegenerative diseases

“…Oral administration of the kavalactone methysticin (Fig. ) activated the Nrf2 pathway in the hippocampus and cortex of AD (APP/Psen1) mice . This treatment reduced microgliosis, astrogliosis, and the secretion of the proinflammatory cytokines TNF‐α and IL‐17A, as well as oxidative damage.…”

Salidroside Attenuates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8 (SAMP8) and Modulating Inflammation on the Gut-brain Axis

“…Low-grade systemic inflammation was observed in the serum of SAMP8, whereas salidroside was able to decreased the levels of proinflammatory cytokines, IL-1α, IL-6, IL-17A and IL-12. Notably, the elevated levels of these four proinflammatory cytokines are reported to be involved in the subsequent cognitive decline or pathology of AD [37][38][39][40] . Primarily based on murine models, Th1 cells significantly accelerates markers of Alzheimer's disease [41] , and Th17 cells have also been described to induced severe fluctuation in neuronal intracellular Ca(2+) concentration, causing neuronal damage and neuroinflammation in vivo imaging experiments [42] .…”

Extracts and Essential Oils from Medicinal Plants and Their Neuroprotective Effect

“…Several studies have investigated the action of Piper methysticum in experimental models of neurodegenerative diseases, specifically in AD, demonstrating the neuroprotective effect of this herbal medicine [15][16][17].…”

“…Recent studies, such as Fragoulis et al have shown that one of the possible explanations for the action of piper mechanism in AD is associated with the activation of the erythroid2-related nuclear factor (NrF2) [15].…”