TY - JOUR
T1 - Exendin-4 treatment improves LPS-induced depressive-like behavior without affecting pro-inflammatory cytokines
AU - Ventorp, Filip
AU - Bay-Richter, Cecilie
AU - Nagendra, Analise Sauro
AU - Janelidze, Shorena
AU - Matsson, Viktor Sjödahl
AU - Lipton, Jack
AU - Nordström, Ulrika
AU - Westrin, Asa
AU - Brundin, Patrik
AU - Brundin, Lena
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Brain
KW - Cytokine
KW - Depression
KW - Dopamine
KW - Exendin-4
KW - Inflammation
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=85019346078&partnerID=8YFLogxK
U2 - 10.3233/JPD-171068
DO - 10.3233/JPD-171068
M3 - Article
C2 - 28387682
AN - SCOPUS:85019346078
SN - 1877-7171
VL - 7
SP - 263
EP - 273
JO - Journal of Parkinson's Disease
JF - Journal of Parkinson's Disease
IS - 2
ER -