Abstract
Background: In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition.
Objective: This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis.
Methods: Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days.
Results: Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified.
Conclusion: In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.
Keywords: Sepsis, tryptophan-2, 3-dioxygenase, blood-brain barrier permeability, oxidative stress, cognitive impairment, catalase.
CNS & Neurological Disorders - Drug Targets
Title:Amelioration of Neurochemical Alteration and Memory and Depressive Behavior in Sepsis by Allopurinol, a Tryptophan 2,3-Dioxygenase Inhibitor
Volume: 23 Issue: 12
Author(s): Kiuanne Lino Lobo Metzker, Khiany Mathias, Richard Simon Machado, Sandra Bonfante, Larissa Joaquim, Marina Goulart da Silva, Guilherme Cabreira Daros, Elisa Mitkus Flores Lins, Fernanda Belle, Carolina Giassi Alano, Rafaela Tezza Matiola, Isabela da Silva Lemos, Lucinéia Gainski Danielski, Fernanda Frederico Gava, Rafael Mariano de Bitencourt, Franciane Bobinski, Emilio Luiz Streck, Gislaine Zilli Reus and Fabricia Petronilho*
Affiliation:
- Laboratory of Experimental Neurology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, SC, Brazil
Keywords: Sepsis, tryptophan-2, 3-dioxygenase, blood-brain barrier permeability, oxidative stress, cognitive impairment, catalase.
Abstract:
Background: In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition.
Objective: This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis.
Methods: Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days.
Results: Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified.
Conclusion: In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.
Export Options
About this article
Cite this article as:
Metzker Lino Lobo Kiuanne, Mathias Khiany, Machado Simon Richard, Bonfante Sandra, Joaquim Larissa, da Silva Goulart Marina, Daros Cabreira Guilherme, Lins Mitkus Flores Elisa, Belle Fernanda, Alano Giassi Carolina, Matiola Tezza Rafaela, Lemos da Silva Isabela, Danielski Gainski Lucinéia, Gava Frederico Fernanda, de Bitencourt Mariano Rafael, Bobinski Franciane, Streck Luiz Emilio, Reus Zilli Gislaine and Petronilho Fabricia*, Amelioration of Neurochemical Alteration and Memory and Depressive Behavior in Sepsis by Allopurinol, a Tryptophan 2,3-Dioxygenase Inhibitor, CNS & Neurological Disorders - Drug Targets 2024; 23 (12) . https://dx.doi.org/10.2174/0118715273282363240415045927
DOI https://dx.doi.org/10.2174/0118715273282363240415045927 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Heart and Brain Axis Targets in CNS Neurological Disorders
Recently there has been a surge of interest in delving deeper into the complex interplay between the heart and brain. This fascination stems from a growing recognition of the profound influence each organ holds over the other, particularly in the realm of central nervous system (CNS) neurological disorders. The purpose ...read more
Lifestyle Interventions to Prevent and Treat Cognitive Impairment and Dementia
More than 55 million people live with dementia worldwide. By 2050, the population affected by dementia will exceed 139 million individuals. Mild cognitive impairment (MCI) is a pre-dementia stage, also known as prodromal dementia, affecting older adults. MCI emerges years before the manifestation of dementia but can be avoidable and ...read more
Novel Treatments in Subarachnoid Hemorrhage
The current landscape of therapeutic strategies for subarachnoid hemorrhage (SAH), a significant adverse neurological event commonly resulting from the rupture of intracranial aneurysms, is rapidly evolving. Through an in-depth exploration of the natural history of SAH, historical treatment approaches, and emerging management modalities, the present work aims to provide a ...read more
Pathogenic Proteins in Neurodegenerative Diseases: From Mechanisms to Treatment Modalities
The primary objective of this thematic issue is to elucidate the molecular mechanisms by which pathogenic proteins contribute to neurodegenerative diseases and to highlight current and emerging therapeutic strategies aimed at mitigating their effects. By bringing together cutting-edge research and reviews, this issue aims to: 1.Enhance Understanding: Provide a comprehensive ...read more
![](/images/wayfinder.jpg)
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers