Abstract
Sepsis-associated encephalopathy (SAE), a neurological dysfunction caused by sepsis, is the most common complication among septic ICU patients. Given the major role of inflammation in the pathophysiology of sepsis-induced anxiety, an extreme and early manifestation of SAE, the present study examined whether tannic acid, as an anti-inflammatory agent, has anxiolytic effects in cecal ligation and puncture (CLP)-induced sepsis. Forty male Wistar rats were assigned to four groups: (1) sham; (2) sham + tannic acid; (3) sepsis and (4) sepsis + tannic acid. Sepsis was induced by cecal ligation and puncture model. Animals in the sham + tannic acid and sepsis + tannic acid groups received tannic acid (20 mg/kg, i.p.), 6, 12, and 18 h after the sepsis induction. Twenty-four hours after the sepsis induction, systolic blood pressure and sepsis score were assessed. Anxiety-related behaviors were evaluated using elevated plus-maze and dark–light transition tests. Moreover, inflammatory markers (TNF-α and IL-6) and oxidative stress parameters (MDA and SOD) were measured in the brain tissue while protein levels (GABAA receptors and IL-1β) were assessed in the hippocampus. Administration of tannic acid significantly improved sepsis score and hypotension induced by sepsis. Anxiety-related behaviors showed a significant decrease in the sepsis + tannic acid group compared to the sepsis group. Tannic acid caused a significant decrease in the brain inflammatory markers and a remarkable improvement in the brain oxidative status compared to the septic rats. Tannic acid prevented animals from decreasing GABAA receptors and increasing IL-1β protein levels in the hippocampus compared to the sepsis group. This study indicated that tannic acid mitigated anxiety-related behaviors through decreasing inflammation and oxidative stress and positively modifying IL-1β/GABAA receptor pathway. Therefore, tannic acid shows promise as an efficacious treatment for comorbid anxiety in septic patients.
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This research was supported by a grant (no. 98–01-139–41863) from Tehran University of Medical Sciences.
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M.R designed the study and edited the manuscript, F.K performed experiments and wrote the manuscript, G.A performed Western Blotting technique, K.L wrote the manuscript and prepared the figures, and F.A performed experiments.
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Highlights
• Sepsis-associated encephalopathy (SAE) is defined as an acute brain dysfunction secondary to sepsis without overt infection of the central nervous system and is characterized by neurological symptoms of varying severity, from sickness behavior and delirium to coma. Anxiety is a manifestation of sickness behavior caused by sepsis, which based on the available evidence, occurs significantly in 47% of the patients.
• The present study demonstrated that anxiety comorbidity with sepsis may occur due to increased inflammation and oxidative stress in the brain, and negative modifying IL-1β/GABAA receptor pathway in the hippocampus.
• Treatment with tannic acid was able to ameliorate all the mentioned parameters almost close to the levels measured before the induction of sepsis. Therefore, tannic acid administration may be considered as a potential therapeutic strategy in the context of comorbid anxiety during sepsis. However, further investigations are needed to elucidate the exact mechanisms underlying the beneficial effects of tannic acid.
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Ranjbaran, M., Kianian, F., Ashabi, G. et al. Beneficial effects of tannic acid on comorbid anxiety in cecal ligation and puncture-induced sepsis in rats and potential underlying mechanisms. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1019–1030 (2023). https://doi.org/10.1007/s00210-022-02374-5
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DOI: https://doi.org/10.1007/s00210-022-02374-5