Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.
Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.
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DOI：
10.3389/fnsys.2015.00165
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发表时间：
2015
影响因子：
3
通讯作者：
Rayport S
中科院分区：
文献类型：
--
作者：
Mingote S;Masson J;Gellman C;Thomsen GM;Lin CS;Merker RJ;Gaisler-Salomon I;Wang Y;Ernst R;Hen R;Rayport S
遗传药物治疗是一种早期药物开发策略，用于在特定配体发育之前在小鼠模型中识别新的中枢神经系统靶点。在这里，我们首次实施了这一策略，以解决以谷氨酸为基础的精神分裂症药物治疗的潜在治疗价值，包括抑制谷氨酸再循环酶磷酸酯活化谷氨酰胺酶。编码谷氨酰胺酶的GLS1基因组成型杂合的小鼠表现出精神分裂症恢复表型，其关键方面是对促精神病性安非他明刺激的运动反应减弱。如果恢复力是由于谷氨酰胺酶在成年期缺乏，那么谷氨酰胺酶抑制剂应该有治疗潜力。然而，由于缺乏神经活性谷氨酰胺酶抑制剂，这很难进行测试。因此，我们采用遗传药物疗法来研究成人诱导GLS1杂合性是否会减弱安非他明的反应性。我们产生了条件型floxGLS1小鼠，并将其与全球的cagert2re / +小鼠杂交，产生GLS1 iHET小鼠，对他莫昔芬诱导GLS1杂合性敏感。在他莫昔芬治疗成年GLS1 iht小鼠一个月后，我们发现大脑中GLS1等位基因丰度和谷氨酰胺酶mRNA水平降低了50%。虽然GLS1 iHET小鼠在使用他莫昔芬之前出现了一些重组，但对mRNA水平没有影响。然后我们询问诱导GLS杂合性是否会减弱对精神病性安非他明刺激的运动反应。在使用他莫昔芬之前，对照组和GLS1 iHET小鼠对安非他明的反应没有差异。他莫昔芬治疗1个月后，苯丙胺诱导的GLS1 iht小鼠过度运动被阻断。5个月后，该街区基本得到了维护。因此，基因诱导的谷氨酰胺酶还原-模仿药物抑制-强烈减弱对精神病前挑战的反应，表明谷氨酰胺酶可能是精神分裂症药物治疗的新靶点。这些结果表明，在开发特异性神经活性抑制剂之前，如何实施遗传药物治疗来测试中枢神经系统靶点。我们进一步讨论了遗传药物治疗在神经精神药物开发中的优势、局限性和可行性。
Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAGERT2cre∕+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction—mimicking pharmacological inhibition—strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development.