Beneficial effects of tannic acid on comorbid anxiety in cecal ligation and puncture-induced sepsis in rats and potential underlying mechanisms

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 in ammation in the pathophysiology of sepsis-induced anxiety, an extreme and early manifestation of SAE, the present study examined whether tannic acid, as an anti-in ammatory 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, in ammatory markers (TNF-α and IL-6), oxidative stress parameters (MDA and SOD) and protein levels (GABAA receptors and IL-1β) were measured in the brain tissue samples.Administration of tannic acid signi cantly improved sepsis score and hypotension which induced by sepsis. Anxiety-related behaviors showed a signi cant decrease in the Sepsis + Tannic acid group compared to the Sepsis group. Tannic acid caused a signi cant decrease in the brain in ammatory 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 brain tissue samples compared to the Sepsis group. This study indicated that tannic acid mitigated anxietyrelated behaviors through decreasing in ammation and oxidative stress and positive modifying IL-1β/GABAA receptors pathway. Therefore, tannic acid shows promise as an e cacious treatment for comorbid anxiety in septic patients. HighlightsSepsis-associated encephalopathy (SAE) is de ned 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 signi cantly in 47% of the patients.The present study demonstrated that anxiety comorbidity with sepsis may occur due to increased in ammation and oxidative stress in the brain, and negative modifying IL-1β/GABAA receptors 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 bene cial effects of tannic acid.

Post-sepsis psychiatric disorder: Pathophysiology, prevention, and treatment

“…For instance, mice exhibit anxiety- and depression-like behaviors one month after intraperitoneal injection of lipopolysaccharide (LPS), concomitant with an increase in the expression of the inducible nitric oxide synthase (iNos) gene and oxidative stress markers in the hippocampus and prefrontal cortex [ 33 ]. Similarly, rats display marked anxiolytic behavior following CLP, accompanied by an increase in malondialdehyde content and a significant decrease in superoxide dismutase activity [ 34 ]. The mechanisms involved in how oxidative stress contributes to post-sepsis psychiatric disorder are not clear.…”

“…Neurotransmitters such as gamma amino butyric acid (GABA), dopamine, norepinephrine, glutamate, and acetylcholine have been reported to be abnormally expressed during sepsis [ 45 ], suggesting that they may be involved in post-sepsis psychiatric disorder. One study noted that the anxiety-like behavior seen in rats after CLP was correlated with the activation of the IL-1β/GABA type A receptor (GABAAR) pathway in the hippocampus [ 34 ]. Meanwhile, a different study found that post-sepsis anxiety is associated with a decrease in the expression of 5-hydroxytryptamine 1A receptor (5-HT1AR) and an increase in that of 5-HT2AR [ 46 ].…”

Research Progress of Macromolecules in the Prevention and Treatment of Sepsis

“…Tannic acid is a polyphenolic compound with both anti-inflammatory and anxiolytic properties. In sepsis, tannic acid can regulate blood pressure; reduce the expression of TNF-α, IL-6, IL-1 β and MDA in the brain tissue; upregulate the expression of γ-aminobutyric acid sub-type A receptors in the hippocampus; reduce inflammation and oxidative stress in patients with sepsis; decrease inflammation and oxidative stress in CLP rats; and improve anxiety-related behaviors in SAE rats [ 77 ].…”