Yasin Nasra, Veenman Leo, Caballero Beatriz, Zeineh Nidal, Gonzalez-Blanco Laura, Weizman Abraham, Gavish Moshe
The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Department of Morphology and Cell Biology, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain.
Int J Mol Sci. 2025 May 19;26(10):4854. doi: 10.3390/ijms26104854.
In this study, we assessed the ability of 2-Cl-MGV-1 (2-chlorophenyl quinazolin-4-yl, dimethyl carbamate), a ligand of the 18 kDa mitochondrial translocator protein (TSPO), to mitigate brain damage in a mouse model of traumatic brain injury (TBI). TSPO is important for arresting the death of neurons and glia and counteracting microglial activation, and it provides anti-inflammatory activity, promotes regeneration (including neurons), and contributes to angiogenesis. We assessed the minimal dose of the TSPO ligand 2-Cl-MGV-1 that attenuates the magnitude of brain damage as well as the time window following TBI in which the treatment is effective. We found that 7.5 mg/kg of 2-Cl-MGV-1 can reduce the impact of the TBI as assessed by magnetic resonance imaging (MRI). We also found that 2-Cl-MGV-1 improved motor performance as observed in a treadmill test (80.9% fewer shocks needed and 40.7% more distance covered, both < 0.05), and reduced anatomical brain damage (by 86.5%, < 0.05), cell death (by 75.0%, < 0.001), and microglial inflammatory response (by 50.2%, < 0.01). The treatment also increased expression of neuronal markers NeuN and β3-tubulin (30.0%, < 0.01; 36.0%, < 0.01, respectively). The time window in which we found the treatment to be effective was 3-11 h after TBI. Our study suggests that agents active at the TSPO can significantly attenuate the outcome of TBI, including in the structural, cellular, and neuro-behavioral dimensions. The mechanisms involved in the attenuation of brain damage following TBI may be related to a decrease in cell death and to anti-inflammatory activity. TSPO seems to be a novel target for the development of agents aimed at the suppression of neurodegenerative processes.
在本研究中，我们评估了18 kDa线粒体转位蛋白（TSPO）的配体2 - 氯 - MGV - 1（2 - 氯苯基喹唑啉 - 4 - 基，二甲基氨基甲酸酯）减轻创伤性脑损伤（TBI）小鼠模型脑损伤的能力。TSPO对于阻止神经元和神经胶质细胞死亡以及对抗小胶质细胞活化很重要，它具有抗炎活性，促进再生（包括神经元），并有助于血管生成。我们评估了减轻脑损伤程度的TSPO配体2 - 氯 - MGV - 1的最小剂量以及TBI后治疗有效的时间窗。我们发现，通过磁共振成像（MRI）评估，7.5 mg/kg的2 - 氯 - MGV - 1可以减轻TBI的影响。我们还发现，在跑步机测试中，2 - 氯 - MGV - 1改善了运动性能（所需电击减少80.9%，行走距离增加40.7%，两者均P < 0.05），并减少了解剖学脑损伤（减少86.5%，P < 0.05）、细胞死亡（减少75.0%，P < 0.001）和小胶质细胞炎症反应（减少50.2%，P < 0.01）。该治疗还增加了神经元标志物NeuN和β3 - 微管蛋白的表达（分别增加30.0%，P < 0.01；36.0%，P < 0.01）。我们发现治疗有效的时间窗是TBI后3 - 11小时。我们的研究表明，作用于TSPO的药物可以显著减轻TBI的后果，包括在结构、细胞和神经行为方面。TBI后脑损伤减轻所涉及的机制可能与细胞死亡减少和抗炎活性有关。TSPO似乎是开发旨在抑制神经退行性过程的药物的新靶点。
