Glucagon-like peptide-1 receptor agonist Exendin-4 improves neurological outcomes by attenuating TBI- induced inflammatory responses and MAPK activation in rats.

Abstract

Traumatic brain injury (TBI) can be exacerbated and prolonged for months or even years by chronic inflammatory processes with long-term consequences on neurodegeneration and neurological impairment. However, there are no clear pharmacological therapies of benefit to manage neurological dysfunctions, which, relating to the molecular mechanisms underlying the behavioral deficits after TBI, have yet to be fully identified. Recently, a glucagon-like peptide 1 (GLP-1) agonist, Exendin-4, was approved not only for the treatment of type 2 diabetes mellitus, but it also played a neurotrophic role in various CNS neurological diseases. In this study, we evaluated the neuroprotective effects of Exendin-4 on neurological outcome, cerebral blood flow, neurodegeneration, and inflammatory responses by utilizing a cortical contusion impact injury (CCI) model in rats. We found that TBI rats displayed neurological impairments, neurodegeneration, reduction of cerebral blood flow, and inflammatory responses, while Exendin-4 promoted neurological, cognitive, and cerebral blood flow recovery and attenuated neural degeneration and inflammatory cytokines after TBI. Furthermore, Exendin-4 treatment significantly diminished the TBI-induced overexpression of TNFα and IL-1β, as well as phosphorylation of p38 and ERK1/2. These data suggest a strong beneficial action of the glucagon-like peptide-1 receptor agonist Exendin-4 in improving neurological outcomes by attenuating inflammatory responses induced by traumatic brain injury, which is of therapeutic potential for TBI.

• Authors: Jun Zhang, Tailong Yi, Shixiang Cheng, Sai Zhang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 86 Pg. 106715 (Sep 2020) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 32570036 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Glucagon-Like Peptide-1 Receptor
• IL1B protein, mouse
• Interleukin-1beta
• Neuroprotective Agents
• Tnf protein, mouse
• Tumor Necrosis Factor-alpha
• Exenatide
• Mapk1 protein, mouse
• Mapk3 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Behavior, Animal (drug effects)
• Brain Injuries, Traumatic (complications, drug therapy, pathology)
• Cerebrovascular Circulation (drug effects)
• Cognition (drug effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme Activation
• Exenatide (pharmacology, therapeutic use)
• Glucagon-Like Peptide-1 Receptor (agonists)
• Inflammation (drug therapy, etiology)
• Interleukin-1beta (metabolism)
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neuroglia (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Tumor Necrosis Factor-alpha (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)