Exploring the mechanism of Panax notoginseng saponin in inhibiting the inflammatory response of microglia in cerebral ischemia based on network pharmacology

Abstract

With the increasing global population and aging demographic, the incidence of stroke is rising. Among these, ischemic stroke (IS), also known as cerebral ischemia, constitutes over 80% of all stroke cases. This condition is characterized by an acute cerebrovascular disease caused by the blockage and interruption of the brain's blood supply, resulting in localized tissue ischemia, oxygen, and glucose deficiency, ultimately leading to the death of nerve cells and tissue necrosis [1,2]. "Vascular recanalization and the restoration of cerebral blood flow" are the primary clinical treatment objectives and are achieved through the intravenous administration of drugs such as tissue plasminogen activator or through surgical thrombectomy. These interventions not only restore the delivery of oxygen and glucose to the affected cerebral area but also help prevent the expansion of the infarcted region. However, the restoration of reperfusion cerebral blood flow similarly exposes the infarct area to peripheral immune cells, triggering the activation of the immune response and inflammation-induced injury [3]. Research indicates that IS elicits a robust inflammatory response, with neuroinflammation playing a crucial role in the secondary neurodegeneration process following stroke. Neuroinflammatory responses are initiated and perpetuated through injury cascades that include the release of inflammatory mediators, the migration and recruitment of white blood cells across the blood-brain barrier, and the impairment of endothelial nitric oxide synthase. These mechanisms collectively promote the activation of pro-inflammatory genes, which in turn activate microglia (MG) and exacerbate ischemic damage and neurological dysfunction [4]. MG are resident immune cells of the central nervous system (CNS). Its function is akin to that of macrophages, serving as the first line of defense against injuries within the central nervous system. Under typical conditions, brain microglia participate in immune surveillance and defense against infectious agents. However, in the pathogenesis of neurodegenerative diseases such as IS, MG are activated by various stimuli. Once activated, MG are known to release numerous proinflammatory or cytotoxic factors, such as inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and reactive oxygen species (ROS). These factors initiate the neuroinflammatory response, exacerbate inflammation, intensify damage to brain tissue and neurons, and significantly hinder the repair of brain injuries and neurogenesis [5,6]. Therefore, inhibiting the activation of microglia and reducing the inflammatory response in the central nervous system are crucial for minimizing brain damage caused by IS and are vital for developing effective prevention and treatment strategies. In recent years, certain natural compounds extracted from traditional drug formulations have shown high therapeutic potential in protecting the brain from cerebral ischemic injury. These compounds reduce the neuroinflammatory response and apoptosis following stroke. Traditional Chinese herbal medicine (TCHM) and its constituent herbs feature a multiplicity of components, targets, and pathways owing to their complex formulations and therapeutic principles, making them promising sources for developing effective treatments for IS. Panax notoginseng saponin (PNS), as the principal bioactive component of Panax notoginseng, is extensively utilized in the prevention and treatment of cardiovascular and cerebrovascular diseases. Its pharmacological benefits include dissipating blood stasis, promoting hemostasis, alleviating swelling and pain, regulating energy metabolism disorders, balancing ion metabolism, and reducing and accelerating the clearance of free radicals [7]. Research indicates that PNS mitigates apoptosis by maintaining mitochondrial homeostasis, enhancing the integrity of the blood‒brain barrier (BBB), augmenting cerebral blood supply, and fostering the differentiation of neural stem cells and proliferation of hippocampal neurons. In addition, PNS offers neuroprotection against focal cerebral I/R injury in rats by reducing brain edema, upregulating the expression of the heat shock protein HSP70, and downregulating the expression of transferrin [8,9]. Additionally, PNS has been reported to enhance the recovery of neurogenesis and neurological function in cerebral embolism induced by microspheres and to reduce sepsis-induced acute kidney injury by suppressing inflammation [10]. However, the mechanism by which PNS targets IS has not been fully elucidated. In this study, we investigated the anti-inflammatory effects of PNS on IS and identified potential target pathways that could inhibit microglia-mediated inflammatory response.

1. Introduction

With the increasing global population and aging demographic, the incidence of stroke is rising. Among these, ischemic stroke (IS), also known as cerebral ischemia, constitutes over 80% of all stroke cases. This condition is characterized by an acute cerebrovascular disease caused by the blockage and interruption of the brain's blood supply, resulting in localized tissue ischemia, oxygen, and glucose deficiency, ultimately leading to the death of nerve cells and tissue necrosis [1,2].

Vascular recanalization and the restoration of cerebral blood flow are the primary clinical treatment objectives and are achieved through the intravenous administration of drugs such as tissue plasminogen activator or through surgical thrombectomy. These interventions not only restore the delivery of oxygen and glucose to the affected cerebral area but also help prevent the expansion of the infarcted region. However, the restoration of reperfusion cerebral blood flow similarly exposes the infarct area to peripheral immune cells, triggering the activation of the immune response and inflammation-induced injury [3].

Research indicates that IS elicits a robust inflammatory response, with neuroinflammation playing a crucial role in the secondary neurodegeneration process following stroke. Neuroinflammatory responses are initiated and perpetuated through injury cascades that include the release of inflammatory mediators, the migration and recruitment of white blood cells across the blood-brain barrier, and the impairment of endothelial nitric oxide synthase. These mechanisms collectively promote the activation of pro-inflammatory genes, which in turn activate microglia (MG) and exacerbate ischemic damage and neurological dysfunction [4].