# 5-Hydroxytryptophan, a Precursor for Serotonin Synthesis, Alleviated Cognitive Dysfunction in a Mouse Model of Sepsis-Associated Encephalopathy

## TL;DR

This study shows that 5-HTP, a serotonin precursor, can improve cognitive issues in a mouse model of sepsis-related brain dysfunction.

## Contribution

The study is the first to investigate 5-HTP's effects on sepsis-associated encephalopathy and its potential clinical relevance.

## Key findings

- A 10 mg/kg dose of 5-HTP improved cognitive dysfunction in sepsis-induced mice.
- Higher 5-HTP doses worsened cognitive function and increased mortality in sepsis models.
- The cognitive benefits of 5-HTP were reversed by a 5-HT1A receptor antagonist.

## Abstract

Background: Patients with sepsis-associated encephalopathy (SAE) present with cognitive impairments. Serotonergic neurotransmission plays a critical role in regulating cognitive processes, and its dysfunction may contribute to SAE-related deficits. However, the effect of 5-hydroxytryptophan (5-HTP), a direct serotonin precursor, on SAE has not been investigated. We hypothesized that 5-HTP could alleviate cognitive dysfunction in SAE. Methods: The SAE mouse model was induced via intraperitoneal administration of lipopolysaccharide (LPS, 10 mg/kg). Cognitive function and locomotor activity were assessed using the Barnes maze, novel object recognition test, and open-field test to evaluate the effects of 5-hydroxytryptophan (5-HTP). Additionally, WAY100635, a selective 5-HT1A receptor antagonist, was co-administered with 5-HTP to investigate the potential mechanisms underlying its effects on SAE-related cognitive dysfunction. The effects of 5-HTP and WAY100635 on cognition and motor activity were also investigated in healthy mice. Results: LPS-induced sepsis caused a learning deficit. A dose of 10 mg/kg 5-HTP improved cognitive dysfunction, whereas doses of 25 and 100 mg/kg worsened cognitive dysfunction. Moreover, 100 mg/kg 5-HTP increased mortality in SAE mouse models. Neither 5-HTP (10 mg/kg) nor WAY100635 (1 mg/kg) alone exerted a significant impact on the locomotor activity or cognitive function of healthy mice. The cognition-enhancing effect of 5-HTP (10 mg/kg) was reversed by WAY100635 (1 mg/kg). Conclusions: improvement in cognitive dysfunction by 5-HTP suggests that serotonergic transmission plays a role in the pathophysiology of SAE, and 5-HTP, an over-the-counter supplement approved for human use, may hold clinical potential for the prevention and treatment of SAE.