Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity.
Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity.
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DOI：
10.1093/brain/awad293
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发表时间：
2024-01-04
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影响因子：
--
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中风导致局部神经断开和全脑神经元网络功能障碍，从而导致神经功能缺损。除了缺血性中风的超急性期之外，还没有临床批准的药物治疗可以减轻感觉运动障碍。中风后的功能恢复涉及新的或替代的神经元回路的形成，包括现有的神经连接。 5 型代谢型谷氨酸受体 (mGluR5) 已被证明可以调节大脑可塑性和功能，是中风以外神经系统疾病的治疗靶点。我们研究了 mGluR5 是否影响局灶性缺血的功能恢复和网络重组啮齿动物模型。通过多项行为测试，我们观察到，从中风后 2 或 10 天开始，使用 mGluR5 负变构调节剂 (NAM)（MTEP、非诺安和 AFQ056）治疗 12 天，可恢复失去的感觉运动功能，且不会缩小梗塞面积。开始治疗后数小时内即可明显恢复，并在随后的 12 天内取得进展。与野生型小鼠相比，mGluR5 敲除小鼠中，正变构调节剂 VU0360172 激活 mGluR5 会阻止恢复，并加速恢复。中风后，丰富环境的多感觉刺激增强了恢复，但 VU0360172 阻止了这一结果，这意味着 mGluR5 在丰富环境介导的恢复中发挥作用。此外，与单独的 MTEP 或富集环境相比，MTEP 处理与富集环境外壳相结合提供了额外的恢复增强。使用光学内在信号成像，我们观察到中风后全脑静息态功能连接的破坏，而对侧感觉运动和双侧视觉皮层不同区域的 mGluR5 抑制可以防止这种破坏。中风后，小鼠和中风患者组织样本中的 mGluR5 蛋白水平没有变化。我们得出的结论是，中风后促进感觉运动功能的神经元回路受到 mGluR5 依赖性适应不良可塑性机制的抑制，而 mGluR5 抑制可恢复该机制。 mGluR5 NAM 联合康复训练的急性中风后治疗可能代表一种新型的急性中风后治疗。哈康等人。研究表明，代谢型谷氨酸受体 5 (mGluR5 NAM) 的负变构调节剂可以恢复局灶性缺血啮齿动物模型中失去的感觉运动功能和功能连接。与康复训练相结合，mGluR5 NAM 可能代表一种新型的急性中风后治疗方法。
Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172 and accelerated in mGluR5 knock-out mice compared with wild-type mice. After stroke, multisensory stimulation by enriched environments enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in enriched environment-mediated recovery. Additionally, MTEP treatment in conjunction with enriched environment housing provided an additive recovery enhancement compared to either MTEP or enriched environment alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy. Hakon et al. show that negative allosteric modulators of metabotropic glutamate receptor 5 (mGluR5 NAMs) restore lost sensorimotor function and functional connectivity in rodent models of focal ischaemia. Combined with rehabilitative training, mGluR5 NAMs may represent a novel post-acute stroke therapy.
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针对5型代谢型谷氨酸受体：神经退行性疾病的潜在治疗策略？
影响因子：
5.6
作者：
Budgett, Rebecca F.;Bakker, Geor;Sergeev, Eugenia;Bennett, Kirstie A.;Bradley, Sophie J.
通讯作者：
Bradley, Sophie J.
影响因子：
3.5
作者：
Carey, Leeanne M.;Matyas, Thomas A.
通讯作者：
Matyas, Thomas A.
影响因子：
3.7
作者：
Felleman, Daniel J.;Van Essen, David C.
通讯作者：
Van Essen, David C.
影响因子：
5.3
作者：
Carmichael ST;Kathirvelu B;Schweppe CA;Nie EH
通讯作者：
Nie EH
DOI：
10.1093/cercor/bhx298
发表时间：
2018-01-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Bauer AQ;Kraft AW;Baxter GA;Wright PW;Reisman MD;Bice AR;Park JJ;Bruchas MR;Snyder AZ;Lee JM;Culver JP
通讯作者：
Culver JP