Research progress on the mechanism of action of hesperetin in cerebral ischemia: a narrative review

Abstract

Background and objective: Ischemic cerebrovascular disease is one of the main diseases threatening human health and survival and is a commonly occurring disease in neurology. Due to its high disability rate, ischemic cerebrovascular disease is one of the most important diseases to be prevented and treated at present. The risk factors of cerebral ischemia include atherosclerosis, hypertension, hyperlipidemia, and blood viscosity caused by thrombocytosis. After cerebral ischemia, cerebral ischemia-reperfusion injury may be induced by oxidative stress (OS), inflammatory reaction, nitric oxide damage, apoptosis, excitatory amino acid toxicity, calcium (Ca²⁺) overload, and other mechanisms. Hesperidin is a flavanone compound and is a key component in citrus plants. It is a kind of traditional Chinese medicine extract with high levels of Pericarpium, shell, fruit, and green peel. In recent years, Hesperidin has received great attention, compelling evidence has indicated Hesperidin plays a beneficial role in cerebral ischemia.

Methods: We conducted a literature search for published manuscripts hesperidin in ischemia/reperfusion up to December 2021 in common English databases (i.e., PubMed, EMBASE, Web of Science, SpringerLink, Wiley, Cochrane Library) and Chinese databases [Chinese BioMedical Literature Service System (CBM), WANFANG database, China Knowledge Resource Integrated Database (CNKI)].

Key content and findings: In this article, we reviewed the mechanisms of action of hesperidin in the treatment of cerebral ischemia, including antioxidant stress, anti-inflammatory reaction, anti-atherosclerosis, anti-thrombosis, anti-apoptosis, and nitric oxide regulation.

Conclusions: In this narrative review, Hesperidin exhibits antioxidant stress, anti-platelet aggregation, vasodilation, anti-atherosclerotic, anti-inflammatory, anti-apoptotic, hypolipidemic, anti-tumor, cardiovascular protection, and nitric oxide-release regulatory properties Such a comprehension of the recent progress of hesperidin will help identify biomarkers for diagnosis and therapeutic targets to cerebral ischemia.

Keywords: Hesperetin; apoptosis; atherosclerosis; cerebral ischemia-reperfusion injury; oxidative stress (OS).

Figure 1

Causes of ischemia-reperfusion injury. The pathogenesis of cerebral ischemia-reperfusion injury includes OS, inflammatory reaction, nitric oxide injury, apoptosis, excitatory amino acid toxicity, Ca²⁺ overload, etc. NO, nitric oxide; OS, oxidative stress.

Figure 2

Hydrolysis of hesperidin to produce hesperetin.

Figure 3

Anti-oxidative stress and anti-apoptosis of hesperetin. LPS induces ROS production, resulting in oxidant/antioxidant imbalance and OS. LPS promotes OS by inducing the production of LPO and ROS. LPS also down-regulated the expression of Nrf-2, HO-1 and anti-apoptotic Bcl-2, while increased significantly the expression of JNK/Bax and cleaved Caspase-3. Hesperetin could inhibit the expression of LPO and ROS and promote the expression of Nrf-2 and HO-1, while promoted Bcl-2 protein levels and prevents LPS-induced neuron apoptosis by reducing the expression of JNK/Bax and Caspase-3, indicating that hesperetin exerts anti-oxidative stress and anti-apoptosis. LPS, lipopolysaccharide; ROS, reactive oxygen species; OS, oxidative stress; LPO, lipid peroxidation; Nrf-2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; Bcl-2, B cell lymphoma-2; JNK, c-Jun N-terminal kinase; Bax, Bcl-2 associated X protein.

Figure 4

Anti-atherosclerosis of hesperetin. Hesperetin can enhance the expression of macrophage lipid transporter adenosine triphosphate binding transporter A1, inhibit macrophage infiltration in the plaque site, and reduce foam cell formation in the plaque area, inhibit the expression and secretion of TNF-α and MCP-1 inflammatory factors, thereby inhibiting the inflammatory reaction and reducing or delaying the progression of atherosclerosis. Hesperetin also exerts an anti-atherosclerotic effect by inhibiting PDGF-bb-induced proliferation of rat aortic VSMCs through G(0)/G(1) blockade. TNF-α, tumor necrosis factor-α; MCP-1, monocyte chemoattractant protein-1; VSMCs, vascular smooth muscle cells.

Figure 5

Anti-inflammation of hesperetin. LPS treatment increases the expression of inflammatory mediators, such as p-NF-κB, TNF-α, and IL-1β, which are involved in cerebral ischemia. Hesperetin significantly reduces the expression level of p-NF-κB and markedly reduces the expression levels of TNF-α and IL-1β cytokines. MAPKs, including the ERK1/2, JNK, and p38 MAPK, are important upstream regulators of inflammatory cytokines, which could stimulate by LPS. Hesperetin can significantly inhibit the phosphorylation of ERK1/2 and p38 MAPK after LPS treatment. The effect of hesperetin on neuroinflammation is notably mediated by the inhibition of NF-κB and MAPKs signaling. LPS, lipopolysaccharide; p-NF-κB, phosphorylation nuclear factor κB; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β; MAPKs, Mitogen activated protein kinases; ERK1/2, extracellular signal-regulated kinase 1/2.

Figure 6

Anti-thrombosis of hesperetin. Hesperetin can inhibit platelet aggregation induced by collagen and arachidonic acid, and the cellular mechanism of hesperetin’s antiplatelet activity is mainly mediated by inhibition of PLC-2 phosphorylation and cyclooxygenase-1 activity. This beneficial characteristic of hesperetin is critical in thrombosis. PLC-2, phospholipase C-2.

Figure 7

Anti-hyperlipidemia of hesperetin. Hesperetin reduces blood lipid by reducing the transcription of ACAT-2 mRNA in Hep G2 cells and reducing the synthesis carrier protein, while reduces the bioavailability of assembled lipids for carrier protein-bound lipoproteins, thereby improving the transport capacity of cholesterol in the blood. Hesperetin also affected the synthesis and esterification of cholesterol, which is represented by reducing the activities of HMG-CoA reductase and ACAT enzymes. The anti-hyperlipidemia effects of hesperetin are achieved in three ways: (I) reducing the activity of ATAC1 and ATAC2; (II) selectively reducing the expression of ATAC2; and (III) reducing the activity of the triglyceride transfer protein. ACAT-2, acyl coenzyme cholesterol acyltransferase-2; mRNA, messenger ribonucleic acid; Hep, hepatocyte; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A.

Figure 8

NO damage and function of hesperetin. The NO that is produced is neurotoxic, which is generally due to the overexpression of iNOS. Hesperetin could inhibit the expression of iNOS and exert the neuroprotective effect. NO, nitric oxide; iNOS, inducible nitric oxide synthase.