Department of Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Chuo-ku, Niigata, 951-8585, Japan.
Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Niigata, 951-8510, Japan.
Transl Psychiatry. 2019 Aug 1;9(1):181. doi: 10.1038/s41398-019-0519-1.
Clozapine is an antipsychotic agent prescribed to psychotic patients exhibiting tolerance and/or resistance to the conventional antipsychotic medications that mainly drive monoamine antagonism. As the pharmacological fundamentals of its unique antipsychotic profile have been unrevealed, here, we attempted to obtain hints at this question. Here, we found that clozapine directly acts on ErbB kinases to downregulate epidermal growth factor (EGF)/neuregulin signaling. In cultured cell lines and cortical neurons, EGF-triggered ErbB1 phosphorylation was diminished by 30 μM clozapine, but not haloperidol, risperidone, or olanzapine. The neuregulin-1-triggered ErbB4 phosphorylation was attenuated by 10 μM clozapine and 30 μM haloperidol. We assumed that clozapine may directly interact with the ErbB tyrosine kinases and affect their enzyme activity. To test this assumption, we performed in vitro kinase assays using recombinant truncated ErbB kinases. Clozapine (3-30 μM) significantly decreased the enzyme activity of the truncated ErbB1, B2, and B4 kinases. Acute in vivo administration of clozapine (20 mg/kg) to adult rats significantly suppressed the basal phosphorylation levels of ErbB4 in the brain, although we failed to detect effects on basal ErbB1 phosphorylation. Altogether with the previous findings that quinazoline inhibitors for ErbB kinases harbor antipsychotic potential in animal models for schizophrenia, our present observations suggest the possibility that the micromolar concentrations of clozapine can attenuate the activity of ErbB receptor kinases, which might illustrate a part of its unique antipsychotic psychopharmacology.
氯氮平是一种抗精神病药物，用于治疗对传统抗精神病药物表现出耐受性和/或抵抗性的精神病患者，这些药物主要通过单胺拮抗作用发挥作用。由于其独特的抗精神病作用机制尚未阐明，因此我们试图在此方面提供一些线索。在这里，我们发现氯氮平可直接作用于 ErbB 激酶，从而下调表皮生长因子 (EGF)/神经调节蛋白信号。在培养的细胞系和皮质神经元中，30μM 氯氮平可减弱 EGF 触发的 ErbB1 磷酸化，但不会影响氟哌啶醇、利培酮或奥氮平。10μM 氯氮平和 30μM 氟哌啶醇可减弱神经调节蛋白 1 触发的 ErbB4 磷酸化。我们假设氯氮平可能直接与 ErbB 酪氨酸激酶相互作用，并影响其酶活性。为了验证这一假设，我们使用重组截断 ErbB 激酶进行了体外激酶测定。氯氮平（3-30μM）显著降低了截断 ErbB1、B2 和 B4 激酶的酶活性。急性给予成年大鼠氯氮平（20mg/kg）可显著抑制大脑中 ErbB4 的基础磷酸化水平，尽管我们未能检测到对基础 ErbB1 磷酸化的影响。结合先前发现的 ErbB 激酶喹唑啉抑制剂在精神分裂症动物模型中具有抗精神病作用的研究结果，我们的研究结果提示氯氮平的毫摩尔浓度可能会减弱 ErbB 受体激酶的活性，这可能是其独特抗精神病作用机制的一部分。
