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.

Role of Caveolin-1 in Diabetes and Its Complications

“…With respect to ischemic stroke, several natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide, chlorogenic acid, lutein, and lycopene, have shown potential for targeting the RNS/CAV1/MMP signaling pathway (see the review in [212] and references therein).…”

Discussion on rationality of administration of Angong Niuhuang Pills from pharmacological and toxicological perspectives

“…Nitric oxide (NO) is an important second messenger with multiple functions involved in the control of vasomotor tone, vascular homeostasis, neuronal, and immunological functions [16]. Low concentration of NO considered as protective to brain vasculature by inducing vasodilatation and improving blood flow to penumbra [17,18]. However, during the ischemia-reperfusion stage, the activation of iNOS leads to the excessive release of NO, which causes the reaction of NO to superoxide (O2-) generating peroxynitrite radicals (ONOO-) and exacerbation of brain ischemia-and reperfusion-injury damage [17,[19][20][21].…”

“…Low concentration of NO considered as protective to brain vasculature by inducing vasodilatation and improving blood flow to penumbra [17,18]. However, during the ischemia-reperfusion stage, the activation of iNOS leads to the excessive release of NO, which causes the reaction of NO to superoxide (O2-) generating peroxynitrite radicals (ONOO-) and exacerbation of brain ischemia-and reperfusion-injury damage [17,[19][20][21]. ANP down-regulated the level of brain tissue and serum, suggest that ANP could also inhibit NO generation, decrease the negative effect of NO to nerve system.…”

Therapeutic effects of different treatment periods against ischemic stroke and toxicology study of Angong Niuhuang Pill in rats

“…Nitric oxide (NO) is an important second messenger with multiple functions involved in the control of vasomotor tone, vascular homeostasis, neuronal, and immunological functions [16]. Low concentration of NO considered as protective to brain vasculature by inducing vasodilatation and improving blood flow to penumbra [17,18]. However, during the ischemia-reperfusion stage, the activation of iNOS leads to the excessive release of NO, which causes the reaction of NO to superoxide (O 2-) generating peroxynitrite radicals (ONOO -) and exacerbation of brain ischemia and reperfusion injury damage [17,[19][20][21].…”