Ventorp Filip, Bay-Richter Cecilie, Nagendra Analise Sauro, Janelidze Shorena, Matsson Viktor Sjödahl, Lipton Jack, Nordström Ulrika, Westrin Åsa, Brundin Patrik, Brundin Lena
Division of Psychiatry, Lund University, Lund, Sweden.
Department of Clinical Medicine, Aarhus University, Arhus, Denmark.
J Parkinsons Dis. 2017;7(2):263-273. doi: 10.3233/JPD-171068.
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.
艾塞那肽-4是胰高血糖素样肽-1（GLP-1）受体的肽激动剂，目前正处于帕金森病潜在疾病修饰疗法的临床试验阶段。鉴于此，了解艾塞那肽-4在大脑中的潜在作用模式非常重要。艾塞那肽-4具有神经保护作用，并且有人提出它具有直接抗炎作用，认为这是其减少神经退行性变的一种方式。然而，先前的研究集中在涉及神经退行性变和炎症的动物模型上，因此，观察到的炎症减少也有可能是神经退行性变减少的继发结果。
研究在涉及神经炎症但不涉及神经退行性变的损伤（即全身注射脂多糖（LPS））后，艾塞那肽-4是否能直接减轻大脑炎症。
给大鼠全身注射LPS，并在5天内用0.5μg/kg艾塞那肽-4或生理盐水进行注射治疗。用强迫游泳试验评估行为。我们使用qPCR检测脑脊液中TNF-α和IL-1β水平以及纹状体、海马体和皮质组织中细胞因子mRNA表达。我们使用高效液相色谱法测定脑单胺类物质。最后，我们从大鼠中分离出原代脑小胶质细胞，并在艾塞那肽-4处理和LPS刺激后测量细胞因子产生情况。
艾塞那肽-4治疗对大脑中的细胞因子mRNA表达、脑脊液中的细胞因子水平或培养的小胶质细胞产生的细胞因子没有影响，尽管纹状体多巴胺有增加的趋势。重要的是，艾塞那肽-4在LPS注射后24小时显著预防了抑郁样行为，表明该药物作用于大脑中的一个靶点。抑郁样行为与纹状体中多巴胺代谢改变有关。
我们未检测到艾塞那肽-4的任何抗炎作用。在先前探索艾塞那肽-4对涉及神经退行性变的脑损伤影响的研究中，观察到的炎症减少可能是神经元死亡减轻的继发结果。我们的结果表明，艾塞那肽-4对行为的影响可能是由于对多巴胺合成或代谢的影响。
