Abstract
BackgroundIt is known that amyloid-β peptide (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Interaction between Aβ and the receptor for advanced glycation end products (RAGE) has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism.MethodsMice received an intracerebroventricular fusion of Aβ25-35. Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform.ResultsOur results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ25-35-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ1-42 production and scavenging intracellular reactive oxygen species (ROS). However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly depressed the activation of p38 mitogen-activated protein kinase (MAPK)-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways and the downstream nuclear factor κB (NFκB) inflammatory response subsequent to Aβ-RAGE interaction. In addition, pinocembrin significantly alleviated mitochondrial dysfunction through improving mitochondrial membrane potential and inhibiting mitochondrial oxidative stress, and regulated mitochondrion-mediated apoptosis by restoration of B cell lymphoma 2 (Bcl-2) and cytochrome c and inactivation of caspase 3 and caspase 9.ConclusionsPinocembrin was shown to infer cognitive improvement and neuronal protection in AD models. The mechanisms of action of the compound were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD.
Highlights
It is known that amyloid-b peptide (Ab) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD)
Pinocembrin inhibited receptor for advanced glycation end products (RAGE)-induced p38 mitogen-activated protein kinases (p38MAPK) and stress-activated protein kinase (SAPK)/ Jun N-terminal kinase (JNK) pathways of APPsw cells, not p44/42 mitogen-activated protein kinase (MAPK) in the presence of copper Oral pinocembrin treatment ameliorated the spatial learning and memory deficits against Ab25-35-induced toxicity Spatial learning was initiated on the third day of pinocembrin treatment and assessed by the time required to find the hidden platform
There was a significant treatment effect (F(3,44) = 16.68; P < 0.001) on the escape latency, and subsequent comparisons further suggested that 20 mg/kg and 40 mg/kg pinocembrin treatment reduced the escape latency in comparison to the Ab25-35 group (20 mg/kg, P< 0.01; 40 mg/kg pinocembrin, P< 0.001) during the 5-day acquisition training, which demonstrated that pinocembrin was effective in attenuating spatial learning deficits in Ab25-35-treated mice
Summary
It is known that amyloid-b peptide (Ab) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Ab-induced toxicity and explored its potential mechanism. Increased intracellular Ab levels could further facilitate opening of the mitochondrial permeability transition pores [6]. This indicates that Ab can directly disrupt mitochondrial function, reduce energy metabolism and contribute to the mitochondrion-dependent apoptosis
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