Role of Imaging Modalities and N-Acetylcysteine Treatment in Sepsis-Associated Encephalopathy

Abstract

Sepsis-associated encephalopathy is a severe systemic infection complication. Although early stages involve pathophysiological changes, detection using conventional imaging is challenging. Glutamate chemical exchange saturation transfer and diffusion kurtosis imaging can noninvasively investigate cellular and molecular events in early disease stages using magnetic resonance imaging (MRI). N-Acetylcysteine, an antioxidant and precursor of glutathione, regulates neurotransmitter glutamate metabolism and participates in neuroinflammation. We investigated the protective role of n-acetylcysteine in sepsis-associated encephalopathy using a rat model and monitored changes in brain using magnetic resonance (MR) molecular imaging. Bacterial lipopolysaccharide was injected intraperitoneally to induce a sepsis-associated encephalopathy model. Behavioral performance was assessed using the open-field test. Tumor necrosis factor α and glutathione levels were detected biochemically. Imaging was performed using a 7.0-T MRI scanner. Protein expression, cellular damage, and changes in blood–brain barrier permeability were assessed using western blotting, pathological staining, and Evans blue staining, respectively. Lipopolysaccharide-induced rats showed reduced anxiety and depression after treatment with n-acetylcysteine. MR molecular imaging can identify pathological processes at different disease stages. Furthermore, rats treated with n-acetylcysteine showed increased glutathione levels and decreased tumor necrosis factor α, suggesting enhanced antioxidant capacity and inhibition of inflammatory processes, respectively. Western blot analysis showed reduced expression of nuclear factor kappa B (p50) protein after treatment, suggesting that n-acetylcysteine inhibits inflammation via this signaling pathway. Finally, n-acetylcysteine-treated rats showed reduced cellular damage by pathology and reduced extravasation of their blood–brain barrier by Evans Blue staining. Thus, n-acetylcysteine might be a therapeutic option for sepsis-associated encephalopathy and other neuroinflammatory diseases. Furthermore, noninvasive “dynamic visual monitoring” of physiological and pathological changes related to sepsis-associated encephalopathy was achieved using MR molecular imaging for the first time, providing a more sensitive imaging basis for early diagnosis, identification, and prognosis.

N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress

“…Due to the multiple interactions between the ER stress pathway and the inflammatory response, the underlying mechanisms by which NAC plays a role in sepsis-induced muscle atrophy deserve further investigation. As mentioned previously, NAC is a potential H2S-releasing donor [18,23]. Ferlito et al elucidated that H2S inhibits CHOP expression and improves survival in septic mice [45].…”

“…N-acetylcysteine (NAC), a precursor of glutathione (GSH), has anti-inflammatory, antioxidant, and cytoprotection properties, and it is deacetylated intracellularly to form L-cysteine and acts as potential H2S-releasing donor [18][19][20]. NAC protects against sepsisassociated encephalopathy, septic acute lung injury, and septic acute kidney injury, and its mechanism of action is related to anti-inflammatory, antioxidant, and anti-apoptotic functions [21][22][23]. Recently, a study found that NAC prevented skeletal muscle atrophy in diabetes [24].…”