PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?
PDE10A Inhibitors-Clinical Failure or Window Into Antipsychotic Drug Action?
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PDE10A抑制剂 - 临床上的衰竭或抗精神病药作用的窗口？
DOI：
10.3389/fnins.2020.600178
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发表时间：
2020
影响因子：
4.3
通讯作者：
Schmidt CJ
中科院分区：
文献类型：
--
作者：
Menniti FS;Chappie TA;Schmidt CJ
PDE10A是使cAMP和cGMP失活的磷酸二酯酶，是一种独特的信号分子，在纹状体中型多刺神经元中高度且几乎完全表达。这些神经元动态地整合皮质信息与多巴胺信号值，以介导可用行为选项之间的动作选择。中棘神经元是直接或间接纹状体输出通路的组成部分。多巴胺D2受体拮抗剂选择性激活间接通路中棘神经元是其抗精神病疗效机制的关键因素。虽然PDE10A在所有中型多刺神经元中表达，但啮齿动物研究表明，PDE10A抑制在几个关键试验中具有行为效应，这些试验对多巴胺D2受体抑制进行了表型复制。这一发现提出了一种假设，即PDE10A抑制也优先激活间接通路中棘神经元，这一假设与PDE10A抑制剂的电生理学、神经化学和分子效应一致。这些数据支持了整个行业研究和开发PDE10A抑制剂作为新型抗精神病药物的努力。令人惊讶的是，来自3家公司的PDE10A抑制剂在精神分裂症患者中未能证明与标准治疗D2拮抗剂相同的抗精神病活性。考虑到PDE10A抑制剂和D2拮抗剂之间的显著相似性，了解为什么只有后一类是抗精神病药，为这种治疗疗效的基础提供了一个独特的窗口。考虑到这一点，我们回顾了PDE10A抑制的数据，作为反向翻译PDE10A抑制剂有限的抗精神病疗效的一步，希望为开发更好的治疗精神病和精神分裂症的新方法提供信息。
PDE10A, a phosphodiesterase that inactivates both cAMP and cGMP, is a unique signaling molecule in being highly and nearly exclusively expressed in striatal medium spiny neurons. These neurons dynamically integrate cortical information with dopamine-signaled value to mediate action selection among available behavioral options. Medium spiny neurons are components of either the direct or indirect striatal output pathways. Selective activation of indirect pathway medium spiny neurons by dopamine D2 receptor antagonists is putatively a key element in the mechanism of their antipsychotic efficacy. While PDE10A is expressed in all medium spiny neurons, studies in rodents indicated that PDE10A inhibition has behavioral effects in several key assays that phenocopy dopamine D2 receptor inhibition. This finding gave rise to the hypothesis that PDE10A inhibition also preferentially activates indirect pathway medium spiny neurons, a hypothesis that is consistent with electrophysiological, neurochemical, and molecular effects of PDE10A inhibitors. These data underwrote industry-wide efforts to investigate and develop PDE10A inhibitors as novel antipsychotics. Disappointingly, PDE10A inhibitors from 3 companies failed to evidence antipsychotic activity in patients with schizophrenia to the same extent as standard-of-care D2 antagonists. Given the notable similarities between PDE10A inhibitors and D2 antagonists, gaining an understanding of why only the latter class is antipsychotic affords a unique window into the basis for this therapeutic efficacy. With this in mind, we review the data on PDE10A inhibition as a step toward back-translating the limited antipsychotic efficacy of PDE10A inhibitors, hopefully to inform new efforts to develop better therapeutics to treat psychosis and schizophrenia.
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影响因子：
64.8
作者：
Cui, Guohong;Jun, Sang Beom;Jin, Xin;Pham, Michael D.;Vogel, Steven S.;Lovinger, David M.;Costa, Rui M.
通讯作者：
Costa, Rui M.
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
2.7
作者：
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通讯作者：
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