Journal of Food Bioactives, ISSN 2637-8752 print, 2637-8779 online
Journal website www.isnff-jfb.com

Review

Volume 24, December 2023, pages 29-39

Potential role of nobiletin in Alzheimer’s disease

Figures

Figure 1.
Figure 1. The chemical structure of Flavonoid basic skeleton.
Figure 2.
Figure 2. The chemical structure of nobiletin.
Figure 3.
Figure 3. The chemical structure of 5-demethylnobiletin.
Figure 4.
Figure 4. Beneficial effects of nobiletin on Alzheimer’s disease features. Abbreviations: Aβ, amyloid-β.
Figure 5.
Figure 5. Mechanism of nobiletin on neuroprotection in Alzheimer’s disease. Notes: Nobiletin reduces APP production and Aβ deposition by downregulating AD-related genes (APP, BACE1, APoE). Nobiletin also activates the cAMP/PKA/ERK signaling cascade, which stimulates CREB phosphorylation and enhances the expression of learning-related genes. Nobiletin inhibits p-JNK and p-p38 production via the MAPK pathway, while suppressing caspase-3 and Bax activation as well as upregulation of Bcl-2 for the purpose of avoiding oxidative stress and improving cognitive impairment. Nobiletin reprograms the different circadian rhythms of gene expression in neurons, astrocytes and microglia, which in turn alleviates astrocyte hyperplasia and neuroinflammation, thereby improving Aβ pathology and recognition impairment. Abbreviations: APP, amyloid-β precursor protein; Aβ, amyloid-β; BACE1, β-Site amyloid precursor protein cleaving enzyme 1; APoE, Apolipoprotein E; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; ERK, extracellular signal-regulated kinases; CREB, cyclic-AMP-responsive-element-binding protein; p-JNK, Phosphorylated c-Jun aminoterminal kinase; MAPK, mitogen-activated protein kinases; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma-2; M, Microglia; A, Astrocyte; N, neuronal cell.

Tables

Table 1. Effect of nobiletin on AD animal models
 
ModelDosagesBehavioral test experimentEffectReferences
Aβ-infused rat10–50 mg/kgEight-arm radial maze testImprove learning and cognitive impairment caused by A1–40Matsuzaki et al., 2006
Olfactory-bulbectomy (OBX) mice50 mg/kgPassive avoidance testRescues Bulbectomy-Induced Cholinergic Neurodegeneration, while improving impaired memory in OBX miceNakajima et al., 2007
Olfactory-bulbectomy (OBX) mice50 mg/kgY-maze testRescue of memory deficits in olfactory bulbectomized mice with cholinergic neurodegenerationNagase et al., 2005
APP-SL 7-5 Tg mice10 mg/kgOpen-field testImproved memory deficits in amyloid precursor protein (APP) transgenic miceOnozuka et al., 2008
Female APP/PS1 mice0.10%Circadian activity and period measurement; noninvasive piezoelectric transducer sleep/wake recording; glucose tolerance and cold tolerance test; metabolic chamber analysisinhibited the synthesis of APP proteins and the deposition of Aβ in a circadian time-dependent mannerKim et al., 2021
Senescence-accelerated mouse prone 8 (SAMP8)10–50 mg/kgNovel object recognition test; Fear conditioning test; Elevated-plus maze testAmeliorated the learning and memory deficits, oxidative stress, and hyperphosphorylation of tau in aging as well as age-related neurodegenerative diseases such as ADNakajima et al., 2013
Triple transgenic mice model of AD (3XTg-AD)30 mg/kgOpen-field test; Locomotor activity test; Y-maze test; Novel object recognition test; Elevated-plus maze test; Passive avoidance test; Morris water maze testReversal of short-term memory and recognition memory impairment in 3XTg-AD miceNakajima et al., 2015

 

Table 2. Effect of nobiletin on cell models
 
ModelMechanismEffectReferences
HT22 cells by hydrogen peroxide-inducedinhibited the production of p-N-terminal kinase (p-JNK) and p-p38, while inhibiting caspase-3 and Bax activation and upregulating Bcl-2Inhibition of oxidative stress, protects the integrity of neuronsCho et al., 2015
PC12 cellsstimulates cyclic-AMP-responsive-element-binding protein (CREB) phosphorylation by activating the cAMP/PKA/ERK signaling cascade and increases cAMP-mediated dependent transcription in the presence of forskolinIncreases the expression of learning and memory-related genesNagase et al., 2005; Nakajima et al., 2007
Astrocytesreprogramming different circadian rhythms of gene expressionimprove Aβ pathology and recognition deficits, alleviates astrocyte proliferation and neuroinflammationWirianto et al., 2022