title: Exendin-4 Treatment Improves LPS-Induced Depressive-Like Behavior Without Affecting Pro-Inflammatory Cytokines.
abstract: Exendin-4 is a peptide agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently in clinical trials as a potential disease-modifying therapy for Parkinson's disease. In light of this, it is important to understand potential modes of action of exendin-4 in the brain. Exendin-4 is neuroprotective and has been proposed to be directly anti-inflammatory, and that this is one way it reduces neurodegeneration. However, prior studies have focused on animal models involving both neurodegeneration and inflammation, therefore, it is also possible that the observed decreased inflammation is secondary to reduced neurodegeneration.
  
  
  
  To investigate whether exendin-4 directly reduces inflammation in the brain following an insult that involves neuroinflammation but not neurodegeneration, namely systemic administration of lipopolysaccharide (LPS).
  
  
  
  Rats were administered LPS systemically and were treated with either 0.5 μg/kg exendin-4 or saline vehicle injections over 5 days. Behavior was evaluated with forced swim test. We assayed TNF-α and IL-1β levels in cerebrospinal fluid and cytokine mRNA expression in striatal, hippocampal and cortical tissues using qPCR. We determined brain monoamines using high-performance liquid chromatography. Finally, we isolated primary brain microglia from rats and measured cytokine production after exendin-4 treatment and LPS stimulation.
  
  
  
  Exendin-4 treatment did not affect cytokine mRNA expression in brain, cytokine levels in cerebrospinal fluid or cytokine production from cultured microglia, although there was a trend towards increased striatal dopamine. Importantly, exendin-4 significantly prevented depressive-like behavior at 24 hours after LPS injection, indicating that the drug engaged a target in the brain. Depressive-like behavior was associated with altered dopamine turnover in the striatum.
  
  
  
  We did not detect any anti-inflammatory effects of exendin-4. In previous studies exploring the effects of exendin-4 on brain insults involving neurodegeneration, observations of reduced inflammation might have been secondary to mitigation of neuronal death. Our results indicate that the effects of exendin-4 on behavior may be due to effects on dopamine synthesis or metabolism.
authors.affiliation: Division of Psychiatry, Lund University, Lund, Sweden.
authors.forename: Filip
authors.initials: F
authors.lastname: Ventorp
authors.affiliation: Department of Clinical Medicine, Aarhus University, Arhus, Denmark.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Bay-Richter
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Analise Sauro
authors.initials: AS
authors.lastname: Nagendra
authors.affiliation: Division of Psychiatry, Lund University, Lund, Sweden.
authors.forename: Shorena
authors.initials: S
authors.lastname: Janelidze
authors.affiliation: Division of Psychiatry, Lund University, Lund, Sweden.
authors.forename: Viktor Sjödahl
authors.initials: VS
authors.lastname: Matsson
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Lipton
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Nordström
authors.affiliation: Division of Psychiatry, Lund University, Lund, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Westrin
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Brundin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000978:Antiparkinson Agents / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003863:Depression / Q000139:chemically induced / Q000517:prevention & control*; D004660:Encephalitis / Q000517:prevention & control*; D000077270:Exenatide; D055809:Illness Behavior; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage*; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D000893:Anti-Inflammatory Agents; D000978:Antiparkinson Agents; D016207:Cytokines; C000594089:IL1B protein, rat; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D014688:Venoms; D000077270:Exenatide
keywords: Brain; Exendin-4; Parkinson’s disease; cytokine; depression; dopamine; inflammation