Abstract
Ischemic brain injury impacts cardiac dysfunction depending on the part of the brain affected, with a manifestation of irregular blood pressure, arrhythmia, and heart failure. Generally called brain–heart syndrome in traditional Chinese medicine, few mechanistic understanding and treatment options are available at present. We hypothesize that considering the established efficacy for both ischemic stroke and myocardial infarction (MI), Danhong injection (DHI), a multicomponent Chinese patent medicine, may have a dual pharmacological potential for treating the brain–heart syndrome caused by cerebral ischemic stroke through its multi-targeted mechanisms. We investigated the role of DHI in the setting of brain–heart syndrome and determined the mechanism by which it regulates this process. We induced Ischemia/Reperfusion in Wistar rats and administered intravenous dose of DHI twice daily for 14 days. We assessed the neurological state, infarct volume, CT scan, arterial blood pressure, heart rhythm, and the hemodynamics. We harvested the brain and heart tissues for immunohistochemistry and western blot analyses. Our data show that DHI exerts potent anti-stroke effects (infarct volume reduction: ∗∗p < 0.01 and ∗∗∗p < 0.001 vs. vehicle. Neurological deficit correction: ∗p < 0.05 and ∗∗∗p < 0.001 vs. vehicle), and effectively reversed the abnormal arterial pressure (∗p < 0.05 vs. vehicle) and heart rhythm (∗∗p < 0.01 vs. vehicle). The phenotype of this brain–heart syndrome is strikingly similar to those of MI model. Quantitative assessment of hemodynamic in cardiac functionality revealed a positive uniformity in the PV-loop after administration with DHI and valsartan in the latter. Immunohistochemistry and western blot results showed the inhibitory effect of DHI on the β-adrenergic pathway as well as protein kinase C epsilon (PKCε) (∗∗p < 0.01 vs. model). Our data showed the underlying mechanisms of the brain–heart interaction and offer the first evidence that DHI targets the adrenergic pathway to modulate cardiac function in the setting of brain–heart syndrome. This study has made a novel discovery for proper application of the multi-target DHI and could serve as a therapeutic option in the setting of brain–heart syndrome.
Highlights
Stroke and heart disease are the leading cause of disability and death in adults worldwide, there is no effective treatment for acute ischemic stroke apart from thrombolytic agents
We show that the multi-targeting Danhong injection (DHI) reversed cardiac abnormality via the β-adrenergic pathway, by suppressing the high level of the β-adrenergic expression in a rat model of brain–heart syndrome caused by Cerebral ischemic/reperfusion injury (CI/RI) similar to myocardial infarction (MI) and that the local β-adrenergic receptors (β-ARs) signaling pathway is critical for cardiac protection after cerebral ischemic stroke
Our present findings show that neurologic impact of CI/RI on the heart caused the critical reduction of Heart Rate (HR) in correlation with arrhythmia and PV-loops which were all ameliorated by DHI (Figures 3, 4D) (Laowattana et al, 2006; Doehner et al, 2018)
Summary
Stroke and heart disease are the leading cause of disability and death in adults worldwide, there is no effective treatment for acute ischemic stroke apart from thrombolytic agents. Neurological association between acute Cerebral ischemic/reperfusion injury (CI/RI), cardiac autonomic imbalance, and MI has been extensively studied in recent years (Palma and Benarroch, 2014), and authors showed that brain and heart are intrinsically connected through the neuroaxis and neuroendocrine system (Levy and Martin, 1984; Ishikawa et al, 2013). Heart, and kidney interacts sequel to CI/RI, and cause long-lasting disruptive effect on the cardiovascular autonomic regulatory system resulting in cardiac dysfunction due to impaired function of the sympathetic and parasympathetic tone mediated by norepinephrine and acting via β-adrenergic receptors (β-ARs) (Ishikawa et al, 2013; Palma and Benarroch, 2014; Silvani et al, 2016). Heart failure (HF), as well as CI/RI-induced HF, is linked with the β-AR levels in the human ventricular myocardium
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