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An-Gong-Niu-Huang-Wan (AGNHW) regulates cerebral blood flow by improving cerebrovascular reactivity and microcirculation disturbances after stroke

ABSTRACT: Our previous work has proved that successful brain repair requires the restoration of cerebrovascular regulation and effective management of cerebral blood flow. An-Gong-Niu-Huang-Wan (AGNHW) has been used in the treatment of ischemic stroke for over 220 years, but its effect on cerebral blood flow regulation has not been reported. In this study, distal middle cerebral artery occlusion (dMCAO) mice were used to uncover whether AGNHW has a role in regulating cerebral blood flow after ischemic stroke, and the underlying mechanisms. The results showed that AGNHW significantly reduced infarct volume, oxidative stress and inflammatory response, alleviated ischemic injury and promoted functional recovery after cerebral ischemia. AGNHW improved the hypoperfusion state in the ischemic cortex, cerebrovascular reactivity, and the velocity and flux of red blood cells in the capillaries. Furthermore, AGNHW improved endothelium-dependent microcirculation disorders, as evidenced by regulating the expression of genes related to cerebrovascular function and endothelium-dependent vasoactive mediators. In conclusion, AGNHW improved cerebral blood flow in ischemic cortex after stroke. This effect was achieved by the regulation of cerebrovascular response to hypoperfusion, cerebrovascular reactivity and endothelium-dependent microcirculation disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE253928 | GEO | 2024/12/24

REPOSITORIES: GEO

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Project description:Stroke remains a major leading cause of death and disability worldwide. Despite continuous advances, the identification of key molecular signatures of ischemic stroke within the hyper-acute phase of the disease is still of primary interest for a real translational research on stroke diagnosis, prognosis and treatment. High-throughput - omics technologies are enabling large-scale studies on stroke pathology at different molecular levels. Data integration resulting from these -omics approaches is becoming crucial to unravel the interactions among all different molecular elements and highly contribute to interpret all findings in a complex biological context. Here, we have used advanced data integration methods for multi-level joint analysis of transcriptomics and proteomics datasets depicted from the mouse brain 2h after cerebral ischemia. By modeling network-like correlation structures, we identified a set of differentially expressed genes and proteins by ischemia with a relevant association in stroke pathology. The ischemia-induced deregulation of 10 of these inter-correlated elements was successfully verified in a new cohort of ischemic mice, and changes in their expression pattern were also evaluated at a later time-point after cerebral ischemia. Of those, CLDN20, GADD45G, RGS2, BAG5 and CTNND2 were highlighted and evaluated as potential blood biomarkers of cerebral ischemia in blood samples from ischemic and sham-control mice and from ischemic strokes and other patients presenting stroke-mimicking conditions. Our findings indicated that CTNND2 and GADD45G levels in blood within the first hours after ischemic stroke might be potentially useful to discriminate ischemic strokes from mimics and to predict patients’ poor outcome after stroke, respectively. In summary, we have here used for the first time an integrative approach to elucidate by means of biostatistical tools key elements of the initial stages of the stroke pathophysiology, highlighting new outstanding proteins that might be further considered as blood biomarkers of ischemic stroke.

Project description:Stroke remains a major leading cause of death and disability worldwide. Despite continuous advances, the identification of key molecular signatures of ischemic stroke within the hyper-acute phase of the disease is still of primary interest for a real translational research on stroke diagnosis, prognosis and treatment. High-throughput -omics technologies are enabling large-scale studies on stroke pathology at different molecular levels. Data integration resulting from these -omics approaches is becoming crucial to unravel the interactions among all different molecular elements and highly contribute to interpret all findings in a complex biological context. Here, we have used advanced data integration methods for multi-level joint analysis of transcriptomics and proteomics datasets depicted from the mouse brain 2h after cerebral ischemia. By modeling net-like correlation structures, we identified a set of differentially expressed genes and proteins with a relevant association in stroke pathology. The ischemia-induced deregulation of 10 of these inter-correlated elements was successfully verified in a new cohort of ischemic mice and changes in their expression pattern were also evaluated at a later time-point after cerebral ischemia. Of those, CLDN20, GADD45G, RGS2, BAG5 and CTNND2 were highlighted as potential candidates as blood biomarkers of cerebral ischemia and hence they were evaluated in blood samples from ischemic and sham-control mice and in ischemic strokes and patients presenting stroke-mimicking conditions. Our findings indicated that CTNND2 and GADD45G levels in blood within the first hours after ischemic stroke might be potentially useful to discriminate ischemic strokes from mimics and to predict patients’ poor outcome after stroke, respectively. In summary, we have here used for the first time an integrative approach that enabled us to elucidate by means of biostatistical tools key elements of the initial stages of the stroke pathophysiology and highlight new outstanding proteins that might be further considered as blood biomarkers of ischemic stroke.

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An-Gong-Niu-Huang-Wan (AGNHW) regulates cerebral blood flow by improving cerebrovascular reactivity and microcirculation disturbances after stroke

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