Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL, USA.
Department of Biochemistry & Molecular Biology and Center for Lung Biology, University of South Alabama College of Medicine, Mobile, AL, USA.
Biochem Pharmacol. 2021 Apr;186:114477. doi: 10.1016/j.bcp.2021.114477. Epub 2021 Feb 18.
Despite major advances, there remains a need for novel anesthetic drugs or drug combinations with improved efficacy and safety profiles. Here, we show that inhibition of cAMP-phosphodiesterase 4 (PDE4), while not inducing anesthesia by itself, potently enhances the anesthetic effects of Isoflurane in mice. Treatment with several distinct PAN-PDE4 inhibitors, including Rolipram, Piclamilast, Roflumilast, and RS25344, significantly delayed the time-to-righting after Isoflurane anesthesia. Conversely, treatment with a PDE3 inhibitor, Cilostamide, or treatment with the potent, but non-brain-penetrant PDE4 inhibitor YM976, had no effect. These findings suggest that potentiation of Isoflurane hypnosis is a class effect of brain-penetrant PDE4 inhibitors, and that they act by synergizing with Isoflurane in inhibiting neuronal activity. The PDE4 family comprises four PDE4 subtypes, PDE4A to PDE4D. Genetic deletion of any of the four PDE4 subtypes in mice did not affect Isoflurane anesthesia per se. However, PDE4D knockout mice are largely protected from the effect of pharmacologic PDE4 inhibition, suggesting that PDE4D is the predominant, but not the sole PDE4 subtype involved in potentiating Isoflurane anesthesia. Pretreatment with Naloxone or Propranolol alleviated the potentiating effect of PDE4 inhibition, implicating opioid- and β-adrenoceptor signaling in mediating PDE4 inhibitor-induced augmentation of Isoflurane anesthesia. Conversely, stimulation or blockade of α-adrenergic, α-adrenergic or serotonergic signaling did not affect the potentiation of Isoflurane hypnosis by PDE4 inhibition. We further show that pretreatment with a PDE4 inhibitor boosts the delivery of bacteria into the lungs of mice after intranasal infection under Isoflurane, thus providing a first example that PDE4 inhibitor-induced potentiation of Isoflurane anesthesia can critically impact animal models and must be considered as a factor in experimental design. Our findings suggest that PDE4/PDE4D inhibition may serve as a tool to delineate the exact molecular mechanisms of Isoflurane anesthesia, which remain poorly understood, and may potentially be exploited to reduce the clinical doses of Isoflurane required to maintain hypnosis.
尽管取得了重大进展，但仍需要新型麻醉药物或药物组合，以提高疗效和安全性。在这里，我们表明抑制 cAMP-磷酸二酯酶 4（PDE4）本身并不会引起麻醉，但可显著增强异氟烷在小鼠中的麻醉效果。用几种不同的 PAN-PDE4 抑制剂（包括 Rolipram、Piclamilast、Roflumilast 和 RS25344）治疗可显著延迟异氟烷麻醉后翻正的时间。相反，用 PDE3 抑制剂 Cilostamide 治疗或用强效但不能穿透大脑的 PDE4 抑制剂 YM976 治疗则没有效果。这些发现表明，增强异氟烷催眠作用是穿透大脑的 PDE4 抑制剂的一种类效应，并且它们通过与异氟烷协同抑制神经元活动而起作用。PDE4 家族包括 PDE4A 至 PDE4D 四种 PDE4 亚型。在小鼠中敲除任何一种 PDE4 亚型本身并不影响异氟烷麻醉。然而，PDE4D 敲除小鼠在很大程度上免受药理学 PDE4 抑制的影响，这表明 PDE4D 是增强异氟烷麻醉的主要但不是唯一的 PDE4 亚型。用纳洛酮或普萘洛尔预处理可减轻 PDE4 抑制的增强作用，表明阿片和β肾上腺素能受体信号在介导 PDE4 抑制剂诱导的异氟烷麻醉增强中起作用。相反，刺激或阻断α肾上腺素能、α肾上腺素能或 5-羟色胺能信号传导不会影响 PDE4 抑制对异氟烷催眠作用的增强。我们进一步表明，用 PDE4 抑制剂预处理可在异氟烷下经鼻感染后增加细菌进入肺部的数量，这提供了第一个例子，即 PDE4 抑制剂诱导的异氟烷麻醉增强可严重影响动物模型，在实验设计中必须将其视为一个因素。我们的研究结果表明，PDE4/PDE4D 抑制可能成为阐明异氟烷麻醉的确切分子机制的工具，而这些机制仍知之甚少，并且可能被用来减少维持催眠所需的异氟烷的临床剂量。
