Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery

Abstract

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO^-), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.

Figure 1

Schematic illustrating the involvement of RNS/caveolin-1/MMPs in mediating the ischemic brain injury and the natural compounds regulating related targets. Upon cerebral ischemia, reduction of caveolin-1 (CAV-1) activates nitric oxide synthase (NOS) and overproduces NO. NO is accumulated and down-regulates CAV-1 expression in ischemic brains, which further activates NOS and forms a feedback interaction to amplify the detrimental signals. MMPs activity is negatively regulated by CAV-1, and loss of CAV-1 leads to higher activity of MMPs. In addition, NO reacts with O₂⁻ to generate ONOO⁻. ONOO⁻ is highly toxic and could also activate MMPs. Active MMPs cleave tight junction proteins, including occludin, claudin, and ZO-1, leading to blood-brain barrier damage. Calycosin or Calycosin-7-O-β-D-glucoside targets on CAV-1 (Ref 125), NO (Ref 124,125,130), and MMPs (Ref 125,127,128); M charantia polysaccharide targets on NO (Ref 45) and ONOO⁻ (Ref 45); Baicalin targets on NO (Ref 150,151), ONOO⁻ (Ref 46,59,151), and MMPs (Ref 46,152,153); Chlorogenic acid targets on CAV-1 (Ref 181), NO (Ref 173), ONOO⁻ (Ref 168,169,170,171), and MMPs (172, 175, 176); lutein targets on ONOO⁻ (Ref 182); lycopene targets on ONOO⁻ (Ref 187,188,189). Ref, reference.

Figure 2

Calycosin-7-O-β-D-glucoside.

Figure 3

Baicalin.

Figure 4

Chlorogenic acid.

Figure 5

Lutein.

Figure 6

Lycopene.