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Exendin-4 treatment improves LPS-induced depressive-like behavior without affecting pro-inflammatory cytokines

Ventorp, Filip LU ; Bay-Richter, Cecilie LU ; Nagendra, Analise Sauro; Janelidze, Shorena LU ; Matsson, Viktor Sjödahl; Lipton, Jack; Nordström, Ulrika LU ; Westrin, Asa LU ; Brundin, Patrik LU and Brundin, Lena LU (2017) In Journal of Parkinson's Disease 7(2). p.263-273
Abstract

Background: 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. Objective: To investigate whether exendin-4 directly reduces inflammation in the brain following an... (More)

Background: 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. Objective: 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). Methods: Rats were administered LPS systemically and were treated with either 0.5 g/kg exendin-4 or saline vehicle injections over 5 days. Behavior was evaluated with forced swim test. We assayed TNF-and IL-1 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. Results: 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. Conclusion: 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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Brain, Cytokine, Depression, Dopamine, Exendin-4, Inflammation, Parkinson's disease
in
Journal of Parkinson's Disease
volume
7
issue
2
pages
11 pages
publisher
IOS Press
external identifiers
  • scopus:85019346078
  • wos:000401801600006
ISSN
1877-7171
DOI
10.3233/JPD-171068
language
English
LU publication?
yes
id
81ea3183-835e-40d3-b0be-3313c24c7537
date added to LUP
2017-08-18 13:19:15
date last changed
2018-05-20 04:36:36
@article{81ea3183-835e-40d3-b0be-3313c24c7537,
  abstract     = {<p>Background: 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. Objective: 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). Methods: Rats were administered LPS systemically and were treated with either 0.5 g/kg exendin-4 or saline vehicle injections over 5 days. Behavior was evaluated with forced swim test. We assayed TNF-and IL-1 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. Results: 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. Conclusion: 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.</p>},
  author       = {Ventorp, Filip and Bay-Richter, Cecilie and Nagendra, Analise Sauro and Janelidze, Shorena and Matsson, Viktor Sjödahl and Lipton, Jack and Nordström, Ulrika and Westrin, Asa and Brundin, Patrik and Brundin, Lena},
  issn         = {1877-7171},
  keyword      = {Brain,Cytokine,Depression,Dopamine,Exendin-4,Inflammation,Parkinson's disease},
  language     = {eng},
  number       = {2},
  pages        = {263--273},
  publisher    = {IOS Press},
  series       = {Journal of Parkinson's Disease},
  title        = {Exendin-4 treatment improves LPS-induced depressive-like behavior without affecting pro-inflammatory cytokines},
  url          = {http://dx.doi.org/10.3233/JPD-171068},
  volume       = {7},
  year         = {2017},
}