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Nat Commun:脑部特异性抑制mTORC1帮助治疗酒精成瘾

2021-07-28 haibei MedSci原创

在临床上使用的mTORC1抑制剂是治疗AUD有希望的治疗药物。然而,长期抑制外周组织的mTORC1会产生不良的副作用,这限制了它们在治疗AUD方面的潜在用途。

酒精使用障碍(AUD)的特点是不顾不良后果,强迫性地摄入酒精。AUD的存在很普遍,影响10-15%的人口,可以造成重大的医疗、社会和经济负担。事实上,AUD是最普遍的精神健康疾病之一,2001年至2013年期间,美国AUD的诊断发生率增加了35%。

不幸的是,针对AUD的药物治疗选择有限。目前只有三种药物,纳曲酮、阿坎酸和双硫仑,被美国食品和药物管理局(FDA)批准为治疗AUD的药物。因此,我们有必要开发更多的有效药物,以缓解酗酒、成瘾和复发等表型。

对啮齿类动物的研究表明,mTORC1在重度酒精摄入、成瘾和复发等表型背后的机制中起着关键作用。已知mTORC1是一个多蛋白复合物,包含丝氨酸/苏氨酸蛋白激酶mTOR以及适应蛋白(包括Raptor、Deptor和mLST8)。mTORC1被生长因子、氨基酸和氧气激活,并在脂质生成、葡萄糖平衡、蛋白质翻译和自噬中发挥作用。

已有的研究显示,mTORC1的过度激活与多种病理状态有关,如胰岛素抵抗和癌症。在中枢神经系统(CNS),mTORC1可以被神经递质和神经调节剂激活,如谷氨酸和BDNF。

在临床上使用的mTORC1抑制剂是治疗AUD有希望的治疗药物。然而,长期抑制外周组织的mTORC1会产生不良的副作用,这限制了它们在治疗AUD方面的潜在用途。

为了克服这些限制,最近,研究人员设计了一种二元药物策略,即用mTORC1抑制剂RapaLink-1和一种小分子(RapaBlock)一起治疗雄性小鼠,以保护外周组织中的mTORC1活性

策略的示意图

该研究结果表明,虽然RapaLink-1的给药阻断了肝脏中mTORC1的激活,但RapaBlock消除了Rapalink-1的抑制作用。RapaBlock还可以防止长期抑制mTORC1所产生的不良副作用

RapaBlock有效预防了RapaLink-1依赖性的体重减轻、葡萄糖不耐受和肝脏毒性

重要的是,RapaLink-1和RapaBlock的共同给药抑制了酒精依赖性mTORC1在横状隔核中的激活,并削弱了对酒精的需求和饮用

 

原始出处:

Yann Ehinger et al. Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice. Nature Communications (2021). 

 

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    2021-11-02 liye789132251
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    2021-08-05 liuli5079
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    2021-12-18 carrotlyl

    aws的情况确实要多关注

    0

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