Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.
Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.
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DOI：
10.1371/journal.pone.0021108
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Suzumura A
中科院分区：
文献类型：
--
作者：
Takeuchi H;Mizoguchi H;Doi Y;Jin S;Noda M;Liang J;Li H;Zhou Y;Mori R;Yasuoka S;Li E;Parajuli B;Kawanokuchi J;Sonobe Y;Sato J;Yamanaka K;Sobue G;Mizuno T;Suzumura A
激活的小胶质细胞释放谷氨酸诱导兴奋性毒性神经元死亡，这可能导致神经退行性疾病（包括肌萎缩侧索硬化症和阿尔茨海默病）中的非细胞自主神经元死亡。虽然阻断谷氨酸受体和抑制小胶质细胞激活是这些神经退行性疾病的治疗候选药物，但谷氨酸受体阻滞剂也会干扰生理和必需的谷氨酸信号，而小胶质细胞激活抑制剂抑制了小胶质细胞的神经毒性/神经保护作用，几乎不影响疾病的进展。我们之前已经证明，激活的小胶质细胞通过间隙连接半通道特异性地释放大量谷氨酸。因此，阻断间隙连接半通道可能对神经退行性疾病的治疗有潜在的益处。在本研究中，我们制备了一种基于甘草次酸的新型血脑屏障可渗透间隙连接半通道阻滞剂。我们发现，药物阻断间隙连接半通道可抑制激活小胶质细胞过量释放谷氨酸，而不产生明显的毒性。在肌萎缩性侧索硬化症小鼠模型中，阻断间隙连接半通道可显著抑制携带G93A或G37R突变的人超氧化物歧化酶1转基因小鼠脊髓神经元丢失，延长存活时间。此外，在表达K595N和M596L突变的人淀粉样蛋白前体蛋白和A264E突变的早老素1的双转基因小鼠作为阿尔茨海默病小鼠模型中，阻断间隙连接半通道在不改变淀粉样蛋白β沉积的情况下也显著改善了记忆障碍。我们的研究结果表明，间隙连接半通道阻滞剂可能是一种新的治疗策略，可以特异性靶向神经毒性小胶质细胞，并预防各种神经退行性疾病中小胶质细胞介导的神经元死亡。
Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.
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影响因子：
2.9
作者：
Jin, Shijie;Kawanokuchi, Jun;Suzumura, Akio
通讯作者：
Suzumura, Akio
影响因子：
4.8
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
通讯作者：
Klein, William L.
影响因子：
3.5
作者：
Haughey, NJ;Mattson, MP
通讯作者：
Mattson, MP
影响因子：
5.3
作者：
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通讯作者：
Vickers, JC
影响因子：
4.7
作者：
Barger, SW;Basile, AS
通讯作者：
Basile, AS