Abstract
Background: Pharmacological research results showed that total flavonoids of Chuju (TFCJ) could be used to treat acute myocardial ischemia and myocardial ischemia-reperfusion injury. In this study, we explored the protective effect of TFCJ on ischemic stroke (IS) in the IS rat model. We hypothesized that TFCJ might exert its neuroprotective effects by suppressing apoptosis and oxidative stress that are closely related to PI3K/Akt/mTOR signaling pathway.Method: TFCJ (10, 20, and 40 mg/kg) was administered for 7 days. Rats (260 ± 20 g) were subjected to middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for 24 h. The neuroprotective effect of TFCJ was substantiated in terms of neurological deficits, oxidative stress (superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde), pathomorphological changes (HE staining and TUNEL staining), and neurobehavioral functions in the rats. Then, we employed network pharmacology to reveal the potential mechanism of TFCJ against IS. Western blot was used to determine the levels of PI3K/AKT/mTOR pathway proteins. The expression of BCL-2, BAX, and cleaved-Caspase-3 was also measured by Western blots and RT-PCR.Results: The histopathological assessment showed that TFCJ reduced MCAO-induced brain damage. Besides, TFCJ exerted a protective role in MCAO rats by alleviating cell apoptosis and oxidative stress. Network pharmacology showed that TFCJ might be used against IS through the PI3K/AKT signaling pathway. TFCJ reduced cell apoptosis and oxidative stress by increasing the level of p-AKT and p-mTOR in MCAO rats, while the effect of TFCJ was significantly reversed when applying LY294002 (PI3k inhibitor).Conclusion: These results indicated that TFCJ might decrease oxidative stress and apoptosis that are closely related to PI3K/Akt/mTOR pathway in IS. TFCJ is a promising authentic traditional Chinese medicine for the management of IS.
Highlights
Stroke is a common disease characterized by a decreased or blockage in the brain’s blood supply, which accounted for 11.59% of all deaths in 2019 (GBD 2019 Demographics Collaborators, 2020)
The neurological deficit scores in the middle cerebral artery occlusion (MCAO) group were higher than that in the sham group (Figure 1A, ##P < 0.01); the neurological deficits in the rats pre-treated with total flavonoids of Chuju (TFCJ) (10, 20, and 40 mg·kg−1) were significantly lower than those in the MCAO group; the neurological deficit scores in the Xuesaitong group significantly decreased compared to the MCAO group (Figure 1B, ∗∗P < 0.01)
Cerebral infarct area in three dose groups of TFCJ was much lower than MCAO group (Figure 1B, ∗∗P < 0.01)
Summary
Stroke is a common disease characterized by a decreased or blockage in the brain’s blood supply, which accounted for 11.59% of all deaths in 2019 (GBD 2019 Demographics Collaborators, 2020). In the United States, every year more than 795,000 people suffer a stroke, 610,000 of these being first or new cases (GBD 2019 Demographics Collaborators, 2020). In the United States, about 87% of all strokes are ischemic strokes (GBD 2019 Demographics Collaborators, 2020). While existing drugs can protect against free radical damage, thrombolytic drugs, antiplatelet aggregation drugs, anti-inflammatory drugs, and anticoagulants (Carvalhal et al, 2019; Kanazawa et al, 2019; Liu et al, 2019), they have been associated with serious side effects and have a single mechanism of action (Allegaert et al, 2010; Ma et al, 2016; Polderman et al, 2018), which limits their clinical application (Ren et al, 2017). We explored the protective effect of TFCJ on ischemic stroke (IS) in the IS rat model. We hypothesized that TFCJ might exert its neuroprotective effects by suppressing apoptosis and oxidative stress that are closely related to PI3K/Akt/mTOR signaling pathway
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