Hesperidin attenuates learning and memory deficits in APP/PS1 mice through activation of Akt/Nrf2 signaling and inhibition of RAGE/NF-κB signaling

Hong, Yan; An, Zhuoling

doi:10.1007/s12272-015-0662-z

Cited by 78 publications

(41 citation statements)

References 33 publications

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“…It is known that Nrf2 is compromised by age [109,110] and downregulated in AD [111], deficits replicated in different animal models [112,113]. Notably, our data indicate that Aβ challenge did not translate in a concomitant activation of Nrf2 and its downstream antioxidant response elements in spite of eliciting a severe ROS production in neuronal cells, findings consistent with the Nrf2 downregulation coexisting with the amply documented oxidative stress reported in AD [111,114].…”

Section: Discussionsupporting

confidence: 77%

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

2020

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Background: Mounting evidence points to a crucial role of amyloid-β (Aβ) in the pathophysiology of Alzheimer's disease (AD), a disorder in which brain glucose hypometabolism, downregulation of central elements of phosphorylation pathways, reduced ATP levels, and enhanced oxidative damage coexist, and sometimes precede, synaptic alterations and clinical manifestations. Since the brain has limited energy storage capacity, mitochondria play essential roles in maintaining the high levels of energy demand, but, as major consumers of oxygen, these organelles are also the most important generators of reactive oxygen species (ROS). Thus, it is not surprising that mitochondrial dysfunction is tightly linked to synaptic loss and AD pathophysiology. In spite of their relevance, the mechanistic links among ROS homeostasis, metabolic alterations, and cell bioenergetics, particularly in relation to Aβ, still remain elusive. Methods: We have used classic biochemical and immunocytochemical approaches together with the evaluation of real-time changes in global energy metabolism in a Seahorse Metabolic Analyzer to provide insights into the detrimental role of oligAβ in SH-SY5Y and primary neurons testing their pharmacologic protection by small molecules.Results: Our findings indicate that oligomeric Aβ induces a dramatic increase in ROS production and severely affects neuronal metabolism and bioenergetics. Assessment of global energy metabolism in real time demonstrated Aβ-mediated reduction in oxygen consumption affecting basal and maximal respiration and causing decreased ATP production. Pharmacologic targeting of Aβ-challenged neurons with a set of small molecules of known antioxidant and cytoprotective activity prevented the metabolic/bioenergetic changes induced by the peptide, fully restoring mitochondrial function while inducing an antioxidant response that counterbalanced the ROS production. Search for a mechanistic link among the protective small molecules tested identified the transcription factor Nrf2compromised by age and downregulated in AD and transgenic models-as their main target and the PI3K/GSK-3 axis as the central pathway through which the compounds elicit their Aβ protective action. Conclusions:Our study provides insights into the complex molecular mechanisms triggered by oligAβ which profoundly affect mitochondrial performance and argues for the inclusion of small molecules targeting the PI3K/ GSK-3 axis and Nrf2-mediated pathways as part of the current or future combinatorial therapies.

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Section: Discussionsupporting

confidence: 77%

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

2020

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“…Moreover, several HMGB1 inhibition approaches, including TTP488, sRAGE-mesenchymal stem cells (MSCs), FPS-ZM1, matrine, pentamidine, hesperidin, and linguizhugan, have revealed promising outcomes in experimental AD models mainly by inhibiting RAGE expression, decreasing production of Aβ, reducing Aβ deposition, oxidative stress, and inflammatory cytokines, while improving spatial learning and memory (Table 2) [113][114][115][116][117][118].…”

Section: Effects Of Rage Inhibition In Admentioning

confidence: 99%

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Paudel

Angelopoulou

Piperi

et al. 2020

Cells

179

128

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.

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“…Suppressing NF-κB activity attenuates pain and inflammation in rats with osteoarthritis (25). Hesperidin has been reported to suppress oxidative stress and inflammation via activation of the protein kinase B/nuclear factor erythroid 2-related factor 2 signaling pathway, inhibition of the receptor for advanced glycation end products/NF-κB signaling pathway and further confers neuroprotection (26). In the current study, it was revealed that hesperidin significantly inhibited NF-κB activity in IL-1β-stimulated human OA chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Hesperidin protects against IL‑1β‑induced inflammation in human osteoarthritis chondrocytes

Chen

Xie

et al. 2018

Exp Ther Med

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Hesperidin is a vitamin P flavonoid compound primarily present in citrus fruits, which possesses an anti-inflammatory effect. The functional role of hesperidin in interleukin (IL)-1β-stimulated human osteoarthritis (OA) chondrocytes is still unknown. In the present study, anti-inflammatory effects of hesperidin in IL-1β-stimulated chondrocytes were investigated. The results demonstrated that hesperidin treatment markedly decreased nitric oxide and prostaglandin E2 production and markedly downregulated inducible nitric oxide synthase and cyclooxygenase-2 expression in IL-1β-stimulated OA chondrocytes. In addition, hesperidin markedly reduced IL-1β-induced matrix metalloproteinase (MMP)-3 and MMP-13 expression in human OA chondrocytes. Furthermore, hesperidin markedly decreased the activation of nuclear factor (NF)-κB in human OA chondrocytes. In conclusion, it was revealed for the first time that hesperidin inhibited inflammatory responses in IL-1β-stimulated human chondrocytes, potentially through inhibiting the activation of the NF-κB signaling pathway. These data suggest that hesperidin may be a potential agent for the treatment of OA.

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Hesperidin attenuates learning and memory deficits in APP/PS1 mice through activation of Akt/Nrf2 signaling and inhibition of RAGE/NF-κB signaling

Cited by 78 publications

References 33 publications

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

Hesperidin protects against IL‑1β‑induced inflammation in human osteoarthritis chondrocytes

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