7-(4-Hydroxyphenyl)-1-phenyl-4<i>E</i>-hepten-3-one, a Diarylheptanoid from <i>Alpinia officinarum</i>, Protects Neurons against Amyloid-β Induced Toxicity

Abstract

Amyloid-β (Aβ) is one of the major causative agents of Alzheimer's disease (AD), the most common neurodegenerative disorder characterized by progressive cognitive impairment. While effective drugs for AD are currently limited, identifying anti-Aβ compounds from natural products has been shown as a promising strategy which may lead to breakthroughs for new drug candidate discovery. We have previously reported that 7-(4-hydroxyphenyl)-1-phenyl-4E-hepten-3-one (AO-1), a diarylheptanoid extracted from the plant Alpinia officinarum, has strong effects on neuronal differentiation and neurite outgrowth in vitro and in vivo. The present study further uncovers that AO-1 exerts neuroprotective effects against the neurotoxicity caused by Aβ. Under the damage of Aβ oligomers, the major pathological forms of Aβ, dendrites of neurons become atrophic and simplified, but such impairments were substantially alleviated by AO-1 treatment. Moreover, AO-1 reduced apoptotic levels and oxidative stress triggered by Aβ. Further analysis showed that the anticaspase and dendrite protective effects of AO-1 were dependent on activation of phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways. These findings collectively identify AO-1 as a beneficial compound to ameliorate the deleterious effects of Aβ on dendrite integrity and cell survival, and may provide new insights on drug discovery of AD.Key words Alzheimer's disease (AD); amyloid-β (Aβ); dendrite; mammalian target of rapamycin (mTOR); neuroprotection; phosphatidylinositol 3-kinase (PI3K) Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly which is characterized by progressive cognitive decline and movement dysfunction. Being a disease with extremely complex etiology, the accumulation of amyloid-β (Aβ) peptides is believed as a main pathogenic event that directly causes neurodegeneration. 1-3)Aβ peptides, which are normally constituted by 40-42 amino acids, are released by the aberrant cleavage of amyloid precursor protein (APP) and deposit at synapses. Aβ peptides are the major component of the senile plaques observed in AD brain. Moreover, soluble oligomers formed by aggregation of monomeric Aβ42 (1-42 a.a.) peptides are the most pathogenic forms during early progression of AD. The damaging effects of Aβ42 includes synapse loss, neurite dystrophy and dendritic simplification.4,5) Thus, one of the current efforts for drug development against AD is to generate platforms that aim at antagonizing the devastating effects of Aβ oligomers. Such approaches have been proven promising for therapeutic design and drug discovery of AD. [6][7][8] A variety of compounds derived from natural sources have been identified effective for counteracting Aβ-induced neurotoxicity.9,10) Such anti-Aβ activities could be achieved through several ways. For instance, Aβ production or aggregation is prevented, or Aβ clearance is accelerated. Moreover, Aβ-induced signaling pathways could be blocked or downregulated. A great number of natural compou...

Evaluation of Phytochemical, Antioxidant, and Memory-Enhancing Activity of Garuga pinnata Roxb. Bark and Bryophyllum pinnatum (Lam) Oken. Leaves

“…They also notably protected hippocampal HT22 cells from glutamate insult-induced neurotoxicity. Overall, diarylheptanoids may mitigate memory deficiency by activating the BDNF–CREB pathway and inhibit neuronal cell death to prevent neurodegeneration [ 43 , 44 ]. Besides, leaves of B. pinnatum and bark of G. pinnata were reported to present potent anti-inflammatory nonsteroidal derivatives [ 10 ], phytosterols, triterpenoids, alkaloids, glycosides, polyphenol, β -amyrin structure, and so on [ 34 , 35 , 45 , 46 ].…”

A natural diarylheptanoid protects cortical neurons against oxygen–glucose deprivation-induced autophagy and apoptosis

“…We have shown that AO‐2 reduces the levels of phosphor‐p38 MAPK, a signalling molecule that leads to inflammatory responses . Indeed, accumulating evidence indicates diarylheptanoids has anti‐inflammatory roles . It would be thus of interest to examine whether AO‐2 also inhibits OGD‐induced neuroinflammation in glial cells such as microglia.…”

Therapeutic potential of Zingiberaceae in Alzheimer's disease

“…2). Huang et al (2016) showed that the compound 7-(4-hydroxyphenyl)-1-phenyl-4E-hepten-3-one, a diarylheptanoid extracted from 95% ethanolic extract of A. officinarum rhizome, presents effects on neuronal differentiation and neurite outgrowth in vitro. 7-(4-hydroxyphenyl)-1-phenyl-4E-hepten-3-one (0.5-10 μM) had neuroprotective effects against the neurotoxicity caused by Aβ, attenuated the damage of Aβ oligomers, and reduced apoptotic levels and oxidative stress triggered by Aβ.…”