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Neuroprotective effect of apo-9'-fucoxanthinone against cerebral ischemia injury by targeting the PI3K/AKT/GSK-3β
Yu Qi1, Shuhua Tang2, Shengjie Jin1
1School of Traditional Chinese Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Abstract:
Neuronal loss in cerebral ischemia primarily results from the combined effects of inflammatory responses and programmed cell death. Currently, there is an urgent need for potent neuroprotectants targeting both inflammatory and apoptotic responses for the treatment of ischemic stroke. Marine natural products are a vital source of novel drug candidates. Apo-9'-fucoxanthinone (APO-9'), a degradation product of fucoxanthin derived from marine brown algae, is known for its substantial anti-inflammatory effects, yet its neuroprotective action has not been clearly defined. In this study, the neuroprotective effects of APO-9' in alleviating cerebral ischemia injury and the underlying mechanism were primarily explored with the aid of tandem mass tag-based quantitative proteomics. APO-9' was found to markedly decrease the levels of inflammation factors by suppressing the IKK/IκB/NF-κB pathway in lipopolysaccharide (LPS)-induced BV2 cells. It also attenuated apoptotic responses in both LPS-induced BV2 cells and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced SH-SY5Y cells. These neuroprotective effects of APO-9' were linked to the activation of the PI3K/AKT pathway. Intraperitoneal injection of APO-9' in a MCAO mouse model showed significant cerebral protection against ischemia. The involvements of the IKK/IκB/NF-κB and PI3K/AKT/GSK-3β pathways were also confirmed in its alleviation of cerebral ischemia in vivo. This study established that APO-9' exerted neuroprotection against cerebral ischemia by inhibiting inflammatory and apoptotic cascades via the IKK/IκB/NF-κB and PI3K/AKT/GSK-3β signaling pathways.
Insights
Apo-9'-fucoxanthinone, derived from marine algae, offers neuroprotection against cerebral ischemia by reducing inflammation and apoptosis. It targets key signaling pathways, demonstrating significant therapeutic potential for stroke treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Marine Natural Products Chemistry
Background:
- Cerebral ischemia causes neuronal loss via inflammation and apoptosis, necessitating novel neuroprotective agents.
- Marine natural products are a promising source for drug discovery, with fucoxanthin derivatives showing anti-inflammatory properties.
- The neuroprotective potential of Apo-9 extquotesingle-fucoxanthinone (APO-9 extquotesingle), a fucoxanthin degradation product, remains largely undefined.
Purpose of the Study:
- To investigate the neuroprotective effects of APO-9 extquotesingle against cerebral ischemia.
- To elucidate the underlying molecular mechanisms involving inflammatory and apoptotic pathways.
- To evaluate APO-9 extquotesingle efficacy in a mouse model of ischemic stroke.
Main Methods:
- Tandem mass tag-based quantitative proteomics was employed to analyze molecular changes.
- In vitro studies utilized lipopolysaccharide (LPS)-induced BV2 cells and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced SH-SY5Y cells.
- In vivo studies involved a middle cerebral artery occlusion (MCAO) mouse model with intraperitoneal APO-9 extquotesingle administration.
Main Results:
- APO-9 extquotesingle suppressed inflammatory factors by inhibiting the IKK/IκB/NF-κB pathway in LPS-induced BV2 cells.
- APO-9 extquotesingle attenuated apoptotic responses in both LPS-induced BV2 and OGD/R-induced SH-SY5Y cells, linked to PI3K/AKT pathway activation.
- In vivo, APO-9 extquotesingle demonstrated significant cerebral protection in the MCAO mouse model, confirming pathway involvement.
Conclusions:
- APO-9 extquotesingle exerts significant neuroprotection against cerebral ischemia.
- The mechanism involves the inhibition of inflammatory and apoptotic cascades via the IKK/IκB/NF-κB and PI3K/AKT/GSK-3β signaling pathways.
- APO-9 extquotesingle represents a potential therapeutic candidate for treating ischemic stroke.
