VU0360172 exerts anti-inflammatory effect on germinal matrix hemorrhage in neonatal rats via the mGluR5/PI3Kγ/PPARγ pathway

IF 2.1 4区医学 Q3 NEUROSCIENCES

Journal of Stroke & Cerebrovascular Diseases Pub Date : 2025-12-01 Epub Date: 2025-10-10 DOI:10.1016/j.jstrokecerebrovasdis.2025.108469

Xiaoya Wang , Jianwei Xu , Ying Liu , Qin Chen , Rongjie Liu , Qing Zhang , Ying Xiong , Zhanhui Feng , Qian Zheng , Lan Ye

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Abstract

Background

This study investigated the neuroprotective and anti-inflammatory effects of the mGluR5-specific positive allosteric modulator VU0360172 on germinal matrix hemorrhage (GMH) in neonatal rats, as well as the pharmacological mechanism pathway that may underlie this anti-inflammatory effect.

Methods

A GMH model was established by intracerebral injection of 0.3 U collagenase VII-S in 7-day-old Sprague-Dawley rats. Animals were randomly divided into the following seven groups: (1) Sham, (2) GMH, (3) GMH +VU0360712 (0.75 mg/kg), (4) GMH + VU0360712 (1.5 mg/kg), (5) GMH + VU0360712 (3.0 mg/kg), (6) GMH + VU0360172 (3.0 mg/kg) + MTEP (0.6 mg/kg), and (7) GMH + VU0360172 (3.0 mg/kg) + AS-605240 (1.8 mg/kg). Western blot analysis was conducted on samples collected at 0, 3, 12 and 24 h and 3 and 7 days post-surgery to observe the postoperative changes in metabotropic glutamate receptor 5 (mGluR5). The neuroprotective and anti-inflammatory effects of different doses of VU0360172 (0.75, 1.5, and 3.0 mg/kg) on GMH were evaluated through neurological behavior testing, brain water content, brain hemorrhage volume, hematoxylin and eosin staining, and ELISA. Finally, MTEP and AS-605240 as inhibitors, were administered to explore the inflammatory regulation and microglial polarization regulation of the mGluR5/PI3Kγ/PPARγ pathway.

Results

The results demonstrated that mGluR5 levels started to decline as early as 3 hours after GMH and reached a minimum at 24 hours. Compared with the GMH group, treatment with VU0360172 reduced improved neurological deficits, brain edema, and hemorrhage, reduced tissue loss and inflammatory cell infiltration, and alleviated the inflammatory response, with the middle and high doses showing particularly notable effects (P < 0.05). However, both MTEP and AS-605240 reversed the regulatory effects of VU0360172 on the mGluR5/PI3Kγ/PPARγ pathway. Significant reversals in the expression of key inflammatory factors and microglial markers were observed in the MTEP and AS-605240 groups compared to the high-dose VU0360172 group (P < 0.05).

Conclusion

VU3060172 has a neuroprotective effect and anti-inflammatory properties on the GMH mouse model. Its anti-inflammatory mechanism may be achieved by activating the mGluR5/PI3Kγ/PPARγ pathway to regulate microglial polarization.

查看原文本刊更多论文

VU0360172通过mGluR5/PI3Kγ/PPARγ通路对新生大鼠生发基质出血具有抗炎作用。

背景：本研究探讨mglur5特异性阳性变构调节剂VU0360172对新生大鼠生发基质出血（GMH）的神经保护和抗炎作用，并探讨其可能的药理机制途径。方法：采用0.3 U胶原酶VII-S脑内注射法建立7日龄sd大鼠GMH模型。动物随机分为以下七类:(1)虚假的,(2)GMH, (3) GMH + VU0360712(0.75毫克/公斤),(4)GMH + VU0360712(1.5毫克/公斤),(5)GMH + VU0360712(3.0毫克/公斤),(6)GMH + VU0360172(3.0毫克/公斤) + MTEP(0.6毫克/公斤)和(7)GMH + VU0360172(3.0毫克/公斤) + - 605240(1.8毫克/公斤)。对术后0、3、12、24 h及3、7 d采集的标本进行Western blot分析，观察术后代谢性谷氨酸受体5 （mGluR5）的变化。通过神经行为学测试、脑含水量、脑出血量、苏木精和伊红染色及ELISA检测，评价不同剂量（0.75、1.5、3.0 mg/kg） VU0360172对GMH的神经保护和抗炎作用。最后，给药MTEP和as -605240作为抑制剂，探讨mGluR5/PI3Kγ/PPARγ通路的炎症调节和小胶质细胞极化调节。结果：结果表明，mGluR5水平早在GMH后3小时开始下降，24小时达到最低。与GMH组相比，VU0360172治疗可改善神经功能缺损、脑水肿和出血，减少组织损失和炎症细胞浸润，减轻炎症反应，其中中、高剂量效果尤为显著(p结论：VU3060172对GMH小鼠模型具有神经保护作用和抗炎作用。其抗炎机制可能通过激活mGluR5/PI3Kγ/PPARγ通路调节小胶质细胞极化来实现。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Stroke & Cerebrovascular Diseases Medicine-Surgery

CiteScore

5.00

自引率

4.00%

发文量

583

审稿时长

62 days

期刊介绍： The Journal of Stroke & Cerebrovascular Diseases publishes original papers on basic and clinical science related to the fields of stroke and cerebrovascular diseases. The Journal also features review articles, controversies, methods and technical notes, selected case reports and other original articles of special nature. Its editorial mission is to focus on prevention and repair of cerebrovascular disease. Clinical papers emphasize medical and surgical aspects of stroke, clinical trials and design, epidemiology, stroke care delivery systems and outcomes, imaging sciences and rehabilitation of stroke. The Journal will be of special interest to specialists involved in caring for patients with cerebrovascular disease, including neurologists, neurosurgeons and cardiologists.