Department of Anesthesiology, Pain and Perioperative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People's Republic of China; Henan Province International Joint Laboratory of Pain, Cognition and Emotion, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People's Republic of China.
Department of Anesthesiology, Pain and Perioperative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People's Republic of China; Henan Province International Joint Laboratory of Pain, Cognition and Emotion, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People's Republic of China.
Int Immunopharmacol. 2023 Nov;124(Pt B):110991. doi: 10.1016/j.intimp.2023.110991. Epub 2023 Sep 27.
Thalamic pain frequently occurs after stroke and is a challenging clinical issue. However, the mechanisms underlying thalamic pain remain unclear. Neuroinflammation is a key determining factor in the occurrence and maintenance of hemorrhage-induced thalamic pain. Pioglitazone is an agonist of peroxisome proliferator-activated receptor gamma (PPARγ) and shows anti-inflammatory effects in multiple diseases. The present work focused on exploring whether PPARγ is related to hemorrhage-induced thalamic pain.
Immunostaining was conducted to analyze the cellular localization of PPARγ and co-localization was evaluated with NeuN, ionized calcium-binding adapter molecular 1 (IBA1), and glia fibrillary acidic protein (GFAP). Western blot analyses were used to evaluate MyD88, pNF-κB/NF-κB, pSTAT6/STAT6, IL-1β, TNF-α, iNOS, Arg-1, IL-4, IL-6, and IL-10 expression. Behavioral tests in mice were conducted to evaluate continuous pain hypersensitivity.
We found that pioglitazone appeared to mitigate the contralateral hemorrhage-induced thalamic pain while inhibiting inflammatory responses. Additionally, Pioglitazone induced phosphorylation of STAT6 and suppressed the phosphorylation NF-κB in our model of thalamic pain. These effects could be partially reversed with the PPARγ antagonist GW9662.
The PPARγ agonist pioglitazone can mitigate mechanical allodynia by suppressing the NF-κB inflammasome while activating the STAT6 signal pathway, which are well-known to be associated with inflammation.
丘脑痛常发生于卒中后，是一个具有挑战性的临床问题。然而，丘脑痛的发病机制尚不清楚。神经炎症是导致出血性丘脑痛发生和维持的关键决定因素。吡格列酮是过氧化物酶体增殖物激活受体 γ（PPARγ）的激动剂，在多种疾病中具有抗炎作用。本研究旨在探讨 PPARγ 是否与出血性丘脑痛有关。
免疫组化分析 PPARγ 的细胞定位，并与神经元特异性核蛋白（NeuN）、离子钙结合衔接分子 1（IBA1）和胶质纤维酸性蛋白（GFAP）进行共定位分析。Western blot 分析用于评估髓样分化因子 88（MyD88）、磷酸化核因子-κB（pNF-κB）/核因子-κB（NF-κB）、磷酸化信号转导子和转录激活子 6（pSTAT6）/信号转导子和转录激活子 6（STAT6）、白细胞介素 1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、诱导型一氧化氮合酶（iNOS）、精氨酸酶 1（Arg-1）、白细胞介素 4（IL-4）、白细胞介素 6（IL-6）和白细胞介素 10（IL-10）的表达。采用小鼠行为学测试评估持续性疼痛过敏。
我们发现吡格列酮似乎可以减轻对侧脑出血引起的丘脑痛，同时抑制炎症反应。此外，吡格列酮在我们的丘脑痛模型中诱导 STAT6 磷酸化并抑制 NF-κB 的磷酸化。这些作用可以用 PPARγ 拮抗剂 GW9662 部分逆转。
PPARγ 激动剂吡格列酮通过抑制 NF-κB 炎性小体，同时激活 STAT6 信号通路，减轻机械性痛觉过敏，该信号通路与炎症有关。
