Novel insight into the therapeutical potential of flavonoids from traditional Chinese medicine against cerebral ischemia/reperfusion injury

Abstract

Cerebral ischemia/reperfusion injury (CIRI) is a major contributor to poor prognosis of ischemic stroke. Flavonoids are a broad family of plant polyphenols which are abundant in traditional Chinese medicine (TCM) and have beneficial effects on several diseases including ischemic stroke. Accumulating studies have indicated that flavonoids derived from herbal TCM are effective in alleviating CIRI after ischemic stroke in vitro or in vivo, and exhibit favourable therapeutical potential. Herein, we systematically review the classification, metabolic absorption, neuroprotective efficacy, and mechanisms of TCM flavonoids against CIRI. The literature suggest that flavonoids exert potential medicinal functions including suppressing excitotoxicity, Ca²⁺ overloading, oxidative stress, inflammation, thrombin's cellular toxicity, different types of programmed cell deaths, and protecting the blood-brain barrier, as well as promoting neurogenesis in the recovery stage following ischemic stroke. Furthermore, we identified certain matters that should be taken into account in future research, as well as proposed difficulties and opportunities in transforming TCM-derived flavonoids into medications or functional foods for the treatment or prevention of CIRI. Overall, in this review we aim to provide novel ideas for the identification of new prospective medication candidates for the therapeutic strategy against ischemic stroke.

Keywords: cerebral ischemia/reperfusion injury (CIRI); flavonoid; ischemic stroke; neuroprotection; traditional Chinese medicine (TCM).

FIGURE 1

The fate of botanical medicine flavonoids in vivo. Upon gastrointestinal absorption, botanical medicine flavonoids undergo renal and fecal excretion, eliminating them from the body. Once absorbed by the small and large intestines, these bioactive compounds enter the systemic circulation, exerting their therapeutic potential on specific molecular targets within the human body, thus alleviating CIRI.

FIGURE 2

The neuroprotective efficacy of Chinese herbal medicine flavonoids. The botanical medicine flavonoids play a neuroprotective role by decreasing excitotoxicity, Ca²⁺ overloading, oxidative stress, inflammation, thrombin toxicity, and cell deaths, and protecting BBB and neurogenesis.

FIGURE 3

The signalling pathways and targets of botanical medicine flavonoids against CIRI-induced autophagy. Botanical medicine flavonoids alleviate CIRI-induced autophagy by upregulating LC3, LC3-Ⅱ, ULK1, AMPK, p-Akt, mTOR, Beclin1 and LC3-Ⅱ/LC3-Ⅰ ratio and downregulating LC3-Ⅱ/LC3-Ⅰ ratio, Beclin-1 through mediating the PI3K/Akt/mTOR pathway and AMPK-mTOR-ULK1 signalling pathway.

FIGURE 4

The signalling pathways and targets of botanical medicine flavonoids against CIRI-induced PANoptosis and ferroptosis. The inhibitory effect of botanical medicine flavonoids on PANoptosis and ferroptosis can potentially alleviate CIRI. Botanical medicine flavonoids play a neuroprotective role through increasing necroptosis-associated proteins (RIPK1, RIPK3, and MLKL/p-MLKL), thus alleviating CIRI. Chinese herbal medicine flavonoids repair CIRI-induced pyroptosis by down-regulating the expressions of NLRP3, ASC, cleaved caspase-1, IL-1β, IL-18, and GSDMD N-terminus. Botanical medicine flavonoids alleviate CIRI-induced apoptosis by downregulating Bax/Bcl-2, Bax, FADD, caspase-3, and Bcl-2. Moreover, Chinese herbal medicine flavonoids alleviate CIRI-induced ferroptosis by upregulating the SLC7A11 and GPX4.