Kim Tae Jung, Kim Young-Ju, Park Soo-Hyun, Kim Youngjoon, Ko Sang-Bae
Department of Neurology, Seoul National University College of Medicine, Seoul, Korea; Department of Critical Care Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Department of Neurology, Seoul National University College of Medicine, Seoul, Korea.
Mol Cell Neurosci. 2025 Sep;134:104030. doi: 10.1016/j.mcn.2025.104030. Epub 2025 Jul 10.
Lobeglitazone, an oral antidiabetic medication, acts as a peroxisome proliferator-activated receptor γ (PPARγ) agonist and demonstrates neuroprotective effects. This study investigated beneficial effects and mechanisms of lobeglitazone treatment in an experimental intracerebral hemorrhage (ICH) rat model. ICH was induced in the left striatum of Sprague-Dawley rats by administration of 0.6 units of collagenase type IV. Rats with ICH were assigned randomly to three treatment groups: (1) control group, (2) lobeglitazone 2 mg/kg, and (3) lobeglitazone 4 mg/kg (N = 6, in each group). Medications were administered orally for 3 days following ICH. Outcomes were measured based on brain edema on the third day after ICH. Behavioral outcomes were evaluated on days 1, 3, 6, and 13 following ICH utilizing the modified neurological severity score (mNSS). On the third day after ICH, inflammatory cytokines were evaluated using western blotting, and inflammatory cells were examined through immunohistochemistry. Administration of lobeglitazone at a dosage of 4 mg/kg reduced brain edema significantly (15 %) in comparison to the control and 2 mg/kg (7 %) groups. Moreover, lobeglitazone administration at a dosage of 4 mg/kg suppressed infiltration of macrophages and neutrophils in perihematomal areas. Expression of several inflammatory cytokines, including interleukin-1 beta (IL-1b), extracellular signal-regulated kinase (ERK), and cyclooxygenase-2 (COX2) were also reduced. Regarding functional outcomes, a high dose of lobeglitazone (4 mg/kg) improved the mNSS significantly on days 3 and 13 after ICH. The results suggest that lobeglitazone, a PPARγ agonist, has potential neuroprotective effects on ICH by modulating brain edema and brain inflammation via IL-1β-ERK-COX-2 pathway inhibition.
罗格列酮是一种口服抗糖尿病药物，作为过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，具有神经保护作用。本研究在实验性脑出血（ICH）大鼠模型中研究了罗格列酮治疗的有益效果和机制。通过注射0.6单位IV型胶原酶在Sprague-Dawley大鼠的左侧纹状体诱导脑出血。将脑出血大鼠随机分为三个治疗组：（1）对照组，（2）2mg/kg罗格列酮组，和（3）4mg/kg罗格列酮组（每组N = 6）。脑出血后口服给药3天。根据脑出血后第三天的脑水肿情况测量结果。在脑出血后第1、3、6和13天利用改良神经功能缺损评分（mNSS）评估行为结果。在脑出血后第三天，使用蛋白质印迹法评估炎性细胞因子，并通过免疫组织化学检查炎性细胞。与对照组和2mg/kg（7%）组相比，4mg/kg剂量的罗格列酮给药显著降低了脑水肿（15%）。此外，4mg/kg剂量的罗格列酮给药抑制了血肿周围区域巨噬细胞和中性粒细胞的浸润。包括白细胞介素-1β（IL-1b）、细胞外信号调节激酶（ERK）和环氧化酶-2（COX2）在内的几种炎性细胞因子的表达也降低了。关于功能结果，高剂量罗格列酮（4mg/kg）在脑出血后第3天和第13天显著改善了mNSS。结果表明，PPARγ激动剂罗格列酮通过抑制IL-1β-ERK-COX-2途径调节脑水肿和脑炎症，对脑出血具有潜在的神经保护作用。
