FLZ attenuates learning and memory deficits via suppressing neuroinflammation induced by LPS in mice

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder in which neuroinflammation plays an important role. FLZ is a novel synthetic derivative of natural squamosamide. Previous studies demonstrated that FLZ had neuroprotective effects on AD models and showed strong anti-inflammatory property in Parkinson's disease models. However, whether the neuroprotective effects of FLZ on AD are associated with its anti-inflammatory property is still not fully elucidated. In this study, we aimed to investigate the ability of FLZ in modulating inflammation. The results showed that FLZ significantly improved memory deficits and alleviated neuronal damage as well as neuronal loss in the hippocampus of mice intracerebroventricular injected with lipopolysaccharide (LPS). Mechanistic studies revealed that the neuroprotective effects of FLZ were due to the suppression of neuroinflammation induced by LPS, as indicated by inactivation of astrocytes and microglia, reduced production of tumor necrosis factor-α, interleukin-1β, and nitric oxide, as well as decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase. The beneficial effects of FLZ on AD were further supported by the finding that FLZ attenuated β-amyloid production through inhibiting β-amyloid precursor protein cleaving enzyme 1 expression. These results suggested that anti-inflammatory agent could be useful for the treatment of AD.

Targeting neuroinflammation in Alzheimer’s disease

“…The hope is to get satisfactory results from clinical studies with compounds that have been successful in vitro, ex vivo, and/or in vivo experiments, such as the administration of molecules like acetylpuerarin,138 edaravone,139 palmitoylethanolamide,38 N -[2-(4-hydroxyphenyl)ethyl]-2-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-hydroxyphenyl) acrylamide (compound FLZ),140 oleuropeinaglycone,141 oridonin,142 protocatechuic acid,143 resveratrol,110 rutin,144 or immunotherapies145,146 and vaccinations 147…”

Nuclear factor‐kappa B: Glucocorticoid‐induced leucine zipper interface analogs suppress pathology in an Alzheimer's disease model

“…It has been well documented that peripherally injected LPS induce a variety of central effects. Multiple injections of LPS increase the number of F4/80+, CD11b+, or Iba1-+ cells and induce morphological changes characteristic of activated microglia in the CNS [31] , [36] , [41] , [42] . We observed that the mice induced neuroinflammation and treated with GA-1 or GA-2 exhibited reduced Iba1+ microglial cells and GFAP+ astroglial cells in the hippocampus as compared with that in the hippocampus of mice treated with CP or left untreated ( Figs.…”

“…Any perturbation of this balance that leads to more severe and persistent neuroinflammatory cycle could promote neurodegeneration culminating in clinical disease. Central or systemic LPS administration has been shown to increase the number of glial cells, upregulate proinflammatory cytokines in the brain, and eventually precipitate dopaminergic neurotoxicity [13,22,41,49]. Culture medium of LPS‐stimulated microglia cells enhanced NF‐κB p65 signaling and downregulated Bcl‐2 expression in neuronal cells.…”

Acetaminophen metabolites p-aminophenol and AM404 inhibit microglial activation

“…Elevated nitric oxide (NO) released by astrocytes and microglia during neurodegenerative disease is both necessary and sufficient to induce primary microglial phagocytosis of neurons and leads to neurotoxic effects resulting from perturbed mitochondrial respiration [6][7][8] . Down-regulation of inducible nitric oxide synthase (iNOS) in AD-model mice, and subsequent decrease in NO, has been associated with rescue of cognitive function, reduction in Ab and NFT load, decreased glial activation, and attenuated neuronal loss [9][10][11] . As dysregulated activation of microglia resulting from inflammatory insult has been closely associated with AD brain regions exhibiting extensive deterioration, Ab deposition, and markers of NO-mediated protein damage [8,12,13] , it has been suggested that reducing microglial activation may be an effective means of treating neurodegenerative diseases.…”