Neuroinflammatory Mechanisms of Adult Sepsis-Associated Encephalopathy: Implications for Blood-Brain Barrier Disruption and Oxidative Stress

Abstract

Sepsis is a syndrome of life-threatening acute organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) refers to the diffuse brain dysfunction observed in sepsis cases, clinically characterized by a spectrum of neuropsychiatric manifestations ranging from delirium to coma. SAE is independently associated with increased short-term mortality and long-term neurological abnormalities, with currently no effective preventive or treatment strategies. The pathogenesis is intricate, involving disruptions in neurotransmitters, blood-brain barrier (BBB) breakdown, abnormal brain signal transmission, and oxidative stress, among others. These mechanisms interact or act in conjunction, contributing to the complexity of SAE. Scholars worldwide have made significant strides in understanding the pathogenesis of SAE, offering new perspectives for diagnosis and treatment. This review synthesizes recent mechanistic breakthroughs and clinical evidence to guide future research directions, particularly in targeting BBB restoration and oxidative stress.

Keywords: blood–brain barrier; microcirculation; mitochondrial disorders; neurotransmitters; oxidative stress; sepsis-related encephalopathy; signaling.

Figure 1

The pathogenesis of septic encephalopathy. During sepsis, inflammatory mediators such as IL-1β, TNF-α, and complement C5a reach the brain, causing an increase in BBB permeability and more harmful substances to enter the CNS, further aggravating neuroinflammation. At the same time, the release of large amounts of cytokines leads to neurotransmitter imbalance as well as abnormal brain signaling, causing patients to develop symptoms such as delirium. Systemic inflammation due to sepsis causes vasodilatation and extravasation of body fluids, and collective hypovolemia, resulting in inadequate blood supply to the brain and microcirculatory disturbances. The burst of neuroinflammation increases metabolic and energy demands, causing oxidative stress and mitochondrial dysfunction, ultimately leading to apoptosis. Changes in intracellular ion concentrations in neuronal cells appear to play an important role in septic encephalopathy (by Figdraw www.figdraw.com accessed on 6 July 2024).

Figure 2

BBB destruction and oxidative stress lead to SAE. Excessive immune response during sepsis leads to the accumulation of cytokines such as IL-6, TNF-α, and IL-1β in serum, which synergistically increase BBB permeability by activating endothelial cells to produce reactive oxygen species and nitric oxide. Inflammatory factors infiltrating the brain parenchyma activate astrocytes and microglia, triggering a cascading inflammatory response that exacerbates BBB injury. Meanwhile, together with ROS, this induces oxidative stress, leading to mitochondrial dysfunction and insufficient ATP synthesis. This metabolic disorder triggers an imbalance between the reduction in anti-apoptotic factors and the increase in pro-apoptotic factors, which ultimately drives the apoptotic process (by Figdraw).