中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (10): 2041-2047.doi: 10.4103/1673-5374.308097

• 原著:神经损伤修复保护与再生 • 上一篇    下一篇

b2 和 a2肾上腺素受体介导N-去甲基喹硫平的促神经发生作用

  

  • 出版日期:2021-10-15 发布日期:2021-03-19
  • 基金资助:

    这项工作得到了Astra Zeneca制药公司和Generali Fondazione Generali的部分支持

β2 and α2 adrenergic receptors mediate the proneurogenic in vitro effects of norquetiapine

Valeria Bortolotto1, 2, Pier Luigi Canonico2, Mariagrazia Grilli1, 2, *   

  1. 1Laboratory of Neuroplasticity, University of Piemonte Orientale, Novara, Italy; 2Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy
  • Online:2021-10-15 Published:2021-03-19
  • Contact: Mariagrazia Grilli, MD, mariagrazia.grilli@uniupo.it.
  • Supported by:
    This work was partially supported by the pharmaceutical company Astra Zeneca and by Fondazione Generali.

摘要:

调节成体海马神经发生(ahNG)有助于提高临床相关抗抑郁药,包括非典型抗精神病药的治疗效果。临床前研究结果显示,抗抑郁药喹硫平(QTP)有促进成体海马神经发生的作用,该药物是一种高亲和力的去甲肾上腺素转运蛋白(NET)抑制剂,并且有人提出这种活性有助于其抗抑郁作用。目前,尚无关于喹硫平及其代谢产物N-去甲基喹硫平对成体神经发生作用的研究。实验研究了QTP和NORQ对成年鼠神经干/祖细胞及其后代的作用及介导其作用的受体活性,并应用β2/a2肾上腺素能受体(AR)选择性拮抗剂评估这些受体是否可以介导喹硫平及其代谢产物N-去甲基喹硫平(NORQ)的作用。实验证实这两种药物均能产生体外促神经生成作用,这可能取决于其抑制NET的能力并涉及b2 和 a2肾上腺素受体。

https://orcid.org/0000-0001-9165-5827 (Mariagrazia Grilli)

Abstract: Positive modulation of adult hippocampal neurogenesis may contribute to the therapeutic effects of clinically relevant antidepressant drugs, including atypical antipsychotics. Quetiapine, an antipsychotic which represents a therapeutic option in patients who are resistant to classical antidepressants, promotes adult hippocampal neurogenesis in preclinical studies. Norquetiapine, the key active metabolite of quetiapine in humans, has a distinctive receptor profile than the parent compound. The drug is indeed a high affinity norepinephrine transporter inhibitor and such activity has been proposed to contribute to its antidepressant effect. At present, no information is available on the effects of norquetiapine on adult neurogenesis. We extensively investigated the activity of quetiapine and norquetiapine on adult murine neural stem/progenitor cells and their progeny. Additionally, selective antagonists for β2/α2 adrenergic receptors allowed us to evaluate if these receptors could mediate quetiapine and norquetiapine effects. We demonstrated that both drugs elicit in vitro proneurogenic effects but also that norquetiapine had distinctive properties which may depend on its ability to inhibit norepinephrine transporter and involve β2/α2 adrenergic receptors. Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committees (IACUC) at University of Piemonte Orientale, Italy (approval No. 1033/2015PR) on September 29, 2015.  

Key words:

adrenergic receptors, adult neurogenesis, antidepressants, antipsychotics, depression, neural progenitor cells, norquetiapine, quetiapine

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